Alkermes plc (ALKS) Earnings Call Transcript & Summary

Good morning. Good morning, and welcome. I would like to -- first like to remind everyone to please mute your line when you're not speaking. For media and press, the FDA press contact is Lindsey O'Keefe. Her e-mail and phone number are currently displayed. We'll wait for it to be displayed. There it is. My name is Dr. Raj Narendran. I will be chairing today's meeting. I will now call the October 9, 2020, Joint Meeting of the Psychopharmacologic Drug Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting to order. Dr. LaToya Bonner is the designated Federal Officer for today's meeting, and we'll begin with the introductions. I will pass it on to Dr. Bonner.

Good morning. My name is LaToya Bonner. I am the designated Federal Officer for today's meeting. For the record, all voting members have confirmed via e-mail that they have viewed the pre-recorded presentation for today's meeting in their entirety. I will now proceed forth with the introduction. When I call your name, please introduce yourself by stating your name and affiliation. Please also state for the record that you have viewed the FDA and Alkermes, Inc., pre-recorded presentation in their entirety. We will start with Dr. Dunn. Please introduce yourself into the record.

This is Dr. Walter Dunn. I am an Assistant Clinical Professor at UCLA. I confirm that I have viewed the presentations.

Next is Dr. Fiedorowicz.

Yes. This is Jess Fiedorowicz. I'm Professor of Psychiatry at the University of Ottawa, with an adjunct appointment at the University of Iowa. I have reviewed the presentations.

Thank you, sir. Dr. Iyengar?

My name is Satish Iyengar. I'm from the Statistics Department at the University of Pittsburgh, and I also confirm that I've viewed everything.

Dr. Jain?

Good morning. This is Dr. Felipe Jain. I'm a psychiatrist at Massachusetts General Hospital and Assistant Professor at Harvard Medical School. I confirm I have reviewed the presentations.

Thank you, sir. Dr. Jeffrey?

Good morning. This is Dr. Jessica Jeffrey. I'm an Assistant Professor of Child and Adolescent Psychiatry at UCLA. I confirm that I viewed all presentations in their entirety.

Thank you. Dr. Krishna?

Hello, this is Dr. Sonia Krishna. I'm a Child, Adolescent and Adult Psychiatrist, Affiliate Faculty at Dell Medical School at the University of Texas, Austin. I confirm I have viewed the presentations in their entirety. Thank you.

Thanks. Dr. Narendran?

This is Dr. Raj Narendran. I'm a psychiatrist at UPMC. I'm also a professor in the Department of Radiology and Psychiatry at the University of Pittsburgh. I confirm for the record that I viewed the presentations provided by the agency as well as Alkermes.

Thank you, sir. Dr. Thomas?

Hello. This is Dr. Patrick Thomas. I'm a Psychiatrist at the Menninger Clinic and Assistant Professor at Baylor College of Medicine, and I confirm I have reviewed the presentations.

Thank you, sir. Ms. Kim Witczak?

Good morning. Kim Witczak from Woodymatters, and I'm the Consumer Representative on the committee. And I confirm that I have reviewed all the materials provided by the FDA and the sponsor.

Thank you, ma'am. Next, we'll have Dr. Boudreau.

Good morning. I'm Denise Boudreau, Scientific Investigator at Kaiser Permanente Washington and also Affiliate Professor at the University of Washington, and I confirm that I've reviewed the FDA and sponsor materials.

Thank you. Dr. Calis?

Good morning. This is Karim Calis. I'm Director of Clinical Research and Compliance with the National Institute of Child Health and Human Development at NIH, and I'm also Chair of the NIH Intramural IRB. And I affirm that I reviewed all of the material in the presentation.

Thank you. Dr. Meisel?

Good morning. Steve Meisel, I am the Director of Medication Safety for M Health Fairview, an integrated health system based in Minneapolis, and I confirm I reviewed the materials.

Thank you. Dr. Mehta? I can hear you.

Hi, this is Reema Mehta. I'm Head of Risk Management and Safety Surveillance Research at Pfizer, Non-Voting Industry Rep, and I confirm as well.

Thank you, ma'am. Next is Dr. Amirshahi.

Good morning. Maryann Amirshahi, I'm an Emergency Medicine Physician, Medical Toxicologist and Clinical Pharmacologist. I'm Associate Professor of Emergency Medicine at Georgetown University School of Medicine, and I practice at Washington Hospital Center and the National Capital Poison Center. And I confirm that I have reviewed the presentations in their entirety.

Thank you, ma'am. Dr. Bohnert?

Hi. I'm Amy Bohnert. I'm the investigator with the Department of Veterans Affairs, Health Services, Research and Development. I'm also an Associate Professor with the Department of Anesthesiology and Psychiatry at the University of Michigan, Epidemiologist by training. And I have read all of the materials -- or sorry, I have reviewed all of the videos in their entirety.

Thank you, ma'am. Dr. Krebs?

Good morning, Erin Krebs. I'm Chief of General Internal Medicine and a Health Services Researcher at the Minneapolis VA Health Care System and Professor of Medicine at the University of Minnesota. My research focuses on chronic pain and opioid management. And I confirm that I have viewed the presentations in their entirety.

Thank you. Mr. Racher?

Good morning. This is Matthew Racher, Certified Recovery Peer Specialist and Patient Representative. I confirm that I have viewed the presentations in their entirety.

Thank you, sir. Dr. Zacharoff?

My name is Kevin Zacharoff. My areas of expertise are anesthesiology, pain and substance use disorders. I am the Course Director of Pain and Addiction, Faculty and Clinical Instructor at the Renaissance School of Medicine at Stony Brook University, and I confirm that I have viewed all the materials provided.

Thank you, sir. We will now move to our FDA participants. Dr. Dunn?

Yes. Good morning. This is Dr. Billy Dunn. I direct the Office of Neuroscience at the FDA.

Thank you, sir. Dr. Bastings?

Good morning. This is Dr. Eric Bastings, Acting Deputy Director of the Office of Neuroscience FDA.

Thank you, sir. Dr. Farchione?

Hi. This is Tiffany Farchione. I'm the Acting Director of the Division of Psychiatry here at FDA.

Next is Dr. Fischer.

Hi, Bernie Fischer, Acting Deputy for Division of Psychiatry at FDA.

Thank you. Dr. Staffa?

Good morning. Judy Staffa, Associate Director for Public Health Initiatives in the Office of Surveillance and Epidemiology at FDA.

Thank you, ma'am. Next is Dr. Southammakosane.

Hi, Cathy Southammakosane. I'm a Medical Officer in the Division of Psychiatry.

Thank you. And last will be Dr. McAninch.

Hi, Jana McAninch. I'm the Senior Medical Epidemiologist for the Nonmedical Use Teams in the Division of Epidemiology in OSE, CDER, FDA.

Thank you. I will now turn the meeting back to our Chair, Dr. Narendran.

Thank you. For topics such as those being discussed today -- at today's meeting, there are often a variety of opinions, some of which are quite strongly held. Our goal is that today's meeting will be a fair and open forum for discussion of these issues and that individuals can express their views without interruption. Thus, as a gentle reminder, individuals will be allowed to speak into the record only if recognized by the chairperson. We look forward to a productive meeting. In the spirit of the Federal Advisory Committee Act and the Government in the Sunshine Act, we ask that the advisory committee members take care that their conversations about the topic at hand take place in the open forum of the meeting. We are aware that members of the media are anxious to speak with the FDA about these proceedings. However, FDA will refrain from discussing the details of the meeting with the media until its conclusion. Also, the committee is reminded to please refrain from discussing the meeting topic during breaks or lunch. Thank you. I will now transfer it to Dr. Bonner, who will read the conflict of interest statement for the meeting.

Thank you, sir. The Food and Drug Administration is convening today's joint meeting of the Psychopharmacologic Drug Advisory Committee and the Drug Safety and Risk Management Advisory Committee under the authority of the Federal Advisory Committee Act, FACA, of 1972. With the exception of the industry representative, all members and temporary voting members of the committee are special government employees or regular federal employees from other agencies and are subject to federal conflict of interest laws and regulations. The following information on the status of this committee's compliance with federal ethics and conflict of interest laws, covered by but not limited to those found at 18 U.S.C. Section 208, is being provided to participants in today's meeting and to the public. FDA has determined that members and temporary voting members of the committee are in compliance with federal ethics and conflict of interest laws. Under 18 U.S.C. Section 208, Congress has authorized FDA to grant waivers to special government employees and regular federal employees who have potential financial conflicts when it is determined that the agency's need for a special government employee's services outweighs his or her potential financial conflict of interest or when the interest of a regular federal employee is not so substantial as to be deemed likely to affect the integrity of the services, which the government may expect from the employee. Related to the discussion of today's meeting, members and temporary voting members of the committee have been screened for potential financial conflicts of interest and their own as well as those imputed to them, including those of their spouses, of minor children and for purpose of 18 U.S.C. Section 208, their employers. These interests may include investments; consulting; expert witness testimony; contracts, grants, CRADAs; teaching, speaking, writing; patents and royalties; and primary employment. Today's agenda involves discussion of the efficacy, safety and benefit risk profile of new drug application, 213,378, olanzapine/samidorphan oral tablet submitted by Alkermes, Inc., for the proposed indications of schizophrenia and bipolar I disorder. This is a particular matters meeting during which specific matters related to Alkermes' NDA will be discussed. Based on the agenda for today's meeting and all financial interests reported by the committee's members and temporary voting members, no conflict of interest waivers have been issued in connection with this meeting. To ensure transparency, we encourage all standing committee members and temporary voting members to disclose any public statements that they have made concerning the product at issue. With respect to FDA's invited industry representative, we would like to disclose that Dr. Reema Mehta is participating in today's meeting as a non-voting industry representative, acting on behalf of regulated industry. Dr. Mehta's role in this meeting is to represent industry in general and not any particular company. Dr. Mehta is employed by Pfizer. We would like to remind members and temporary voting members that if the discussions involve any other products or firms not already on the agenda for which an FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement, and their exclusion will be noted for the record. FDA encourages all other participants to advise the committees of any financial relationships that they may have with the firm at issue. Thank you. I will now turn the meeting back over to the Chair.

Thank you. We will now proceed with FDA's opening remarks from Dr. Bernie Fischer.

Good morning, and welcome to this Joint Meeting of the Psychopharmacologic Drug Advisory Committee and the Drug Safety and Risk Management Advisory Committee. The purpose of this meeting is to discuss a new drug application submitted by Alkermes, Inc., for ALKS 3831, a fixed-dose combination product of the antipsychotic olanzapine and samidorphan, an opioid receptor antagonist that is a new molecular entity. The samidorphan in this combination product is intended to mitigate olanzapine-associated weight gain. The application for ALKS 3831 was submitted under the 505(b)(2) pathway. Under this pathway, an applicant is able to rely on FDA's previous findings of safety and effectiveness for an approved product to support their own application. In this case, the applicant has conducted a relative bioavailability study comparing ALKS 3831 to an approved form of olanzapine. The relative bioavailability study allowed the applicant to propose ALKS 3831 for the same schizophrenia and bipolar indications as olanzapine. During development, FDA advised the applicant to provide evidence that the addition of samidorphan does not interfere with the efficacy of olanzapine and to demonstrate their product's weight mitigation effect in a dedicated study. We recommended that the weight mitigation study be at least 6 months long. We also recommended 2 co-primary endpoints, the percent change from baseline and body weight and proportion of subjects with at least 10% weight gain from baseline. We also indicated to the applicant that in addition to the effect on weight gain, FDA would consider changes in metabolic laboratory parameters in the review of their application. The applicant's development program included a Phase II proof-of-concept study, study 302; a 6-month weight mitigation study, study A303, which was conducted according to FDA recommendations; and a 4-week antipsychotic efficacy study, study A305. The program also included two 12-month open-label extension studies, 1 each for studies A303 and A305. The details of these studies are provided in the background document and were reviewed in the agency's presentation. As discussed in our background document and presentation, study A305 supports the conclusion that samidorphan does not meaningfully impair olanzapine's efficacy. Although this study only enrolled people with schizophrenia, we have no reason to believe the samidorphan component would uniquely interfere with olanzapine's efficacy for bipolar disorder. Therefore, in conjunction with the relative bioavailability data mentioned previously, we believe the applicant has demonstrated that ALKS 3831 would be effective in treating schizophrenia and bipolar disorder. Regarding Study A303, the pivotal weight mitigation study, both co-primary endpoints were statistically significant. The mean change from baseline and weight between the ALKS 3831 and the olanzapine groups at week 24 was negative 2.38%. The proportion of subjects with a weight gain of 10% or more from baseline at week 24 was approximately 18% in the ALKS 3831 group and 30% in the olanzapine group. Waist circumference conference, a prespecified secondary endpoint, was significantly different between the 2 groups and favored ALKS 3831. There was also a nominal difference in systolic blood pressure favoring ALKS 3831. However, there were no meaningful differences in metabolic laboratory values between ALKS 3831 and olanzapine. And there is a suggestion, as detailed in our background document, that blood glucose parameters may be less favorable with ALKS 3831. Finally, there were no differences in measures of quality of life between the 2 groups. FDA requested long-term follow-up studies to ensure that any weight mitigation observed during study A303 was not merely a delay of weight gain, that is -- that the initial weight mitigation effect continued beyond the acute trials. We did not ask the applicant to include an olanzapine arm in these studies, so comparisons can only be made via cross-study looks at historical data, which is inherently limited. Nevertheless, we did not see a late excess of weight gain in either of the long-term studies. In general, the adverse event profiles of ALKS 3831 and olanzapine were very similar. However, the samidorphan component does confer additional risk. Because samidorphan is an opioid antagonist, it can precipitate withdrawal in patients who are physically dependent on opioids. A patient taking samidorphan was hospitalized for precipitated withdrawal during ALKS 3831 development. Samidorphan may block opioid-related analgesia when medically necessary or prevent a high in people with an opioid use disorder. In these latter situations, there's a hypothetical risk of overdose if the patient tries to overcome this blockade. A patient taking ALKS 3831 was hospitalized for opioid overdose during product development, although it's unclear if this event was actually connected to the samidorphan. As detailed in our background document, epidemiologic data support the potential risk of samidorphan, some of what would be the indicated populations have a higher rate of opioid use compared to the general population. And despite contraindications in labeling, opioids and products containing the opioid antagonist, naltrexone, are frequently co-prescribed. FDA agrees with the applicant and many public comments that addressing medication-induced weight gain is important. However, FDA would like to remind today's audience that ALKS 3831 is not intended as a weight loss treatment. In other words, ALKS 3831 is not intended to treat people who have already gained weight on olanzapine, neither would ALKS 3831 prevent all of the weight gain associated with olanzapine. Most people taking ALKS 3831 also gains weight, albeit less than with olanzapine. What the applicant has demonstrated is that in people who are not currently taking olanzapine, starting ALKS 3831 instead of olanzapine may present some of the weight gain that a person might have otherwise experienced with olanzapine alone. In reviewing this application, FDA is considering several issues. One is whether the degree of the statistically significant weight mitigation was robust enough to be clinically meaningful. We are also considering why olanzapine-mediated weight gain is an important safety issue and whether mitigation of weight gain and the absence of a clear effect on metabolic parameters addresses the safety issue. We are also considering the apparent benefits of the product, taking into account the opioid antagonist risks of the samidorphan component. After viewing presentations by the applicant and the agency as well as considering comments from the public, the committees will address these questions and points of discussion: number one, has the applicant presented adequate evidence that samidorphan meaningfully mitigates olanzapine-associated weight gain?; number two, has the applicant adequately characterized the safety profile of ALKS 3831?; number three, is labeling sufficient to mitigate the risks related to the opioid antagonist action of samidorphan?; and number four, what, if any, additional data are needed to address outstanding issues? Finally, on a practical note, we have a large group of multidisciplinary scientists and FDA leadership involved in this meeting. There may be slight delays in our responses to the committees as we confer virtually to make sure that we identify the optimal respondent to any questions asked, so thank you in advance for your patience. With that, I will turn it back over to the Meeting Chair.

Thank you, Dr. Fischer. Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision-making. To ensure such transparency at the advisory committee meeting, FDA believes that it is important to understand the context of an individual's presentation. For this reason, FDA encourages all participants, including Alkermes' nonemployee presenters, to advise the committee of any financial relationships that they may have with the applicant, such as consulting fees, travel expenses, honoraria and interest in the applicant, including equity interest, and those based upon the outcome of the meeting. Likewise, FDA encourages you at the beginning of your presentation to advise the committee if you do not have any financial relationships. If you choose not to address this issue of financial relationships at the beginning of your presentation, it will not preclude you from speaking. We will now proceed with Alkermes' Summary Presentation. I'll hand it over to Alkermes.

Good morning to the Chair, members of the Advisory Committee, the Agency and other attendees. My name is Sarah Akerman, and I'm a Senior Medical Director at Alkermes and a psychiatrist with Board Certification in Psychiatry and Addiction. We're pleased to be speaking with you today about olanzapine/samidorphan, also referred to you by the abbreviation OLZ/SAM, for which we're seeking indications for schizophrenia and bipolar 1 disorder. I will be presenting today a summary of the video presentation and briefing documents. No new data will be presented in this summary. Basis for the development of OLZ/SAM is grounded in the fact that olanzapine is a highly effective antipsychotic. FDA-approved since 1996 under the brand name Zyprexa, the field has extensive clinical experience with olanzapine. And while it's highly effective, it has a very concerning side effect of weight gain, which is [Technical Difficulty] the majority of patients do gain weight on olanzapine, and this is for some individuals approximately 60%, clinically significant weight gain, which not only impacts their quality of life but lead over time to [Technical Difficulty] as well as increased morbidity and mortality. There are currently no FDA-approved pharmacological treatment [Technical Difficulty] antipsychotic-associated weight gain. And as you heard from Dr. René Kahn and Dr. Ginger Nicol in the reported presentation, prescribers are at times faced with a difficult decision of switching [Audio Gap] by good antipsychotic efficacy, which carries inherent risk for the patient. Samidorphan is an opioid receptor antagonist or blocker. The opioid system has been shown to play a role in food reward and metabolism, so our approach adds samidorphan to olanzapine. And as you've seen in our clinical data, samidorphan mitigates or prevents olanzapine-associated weight gain while maintaining its known antipsychotic efficacy. The proposed indications and therapeutic range for OLZ/SAM would be consistent with the Zyprexa prescribing information, with the addition of a fixed-dose of 10 milligrams of samidorphan to mitigate weight gain. We are not seeking an indication for weight mitigation. At the end of our Phase II program, we aligned with the agency on the Phase III registration package, including 2 studies, both in schizophrenia. The first was an antipsychotic efficacy study comparing OLZ/SAM to placebo with an olanzapine active control, and the second was a weight mitigation, also referred to you as a weight efficacy study, comparing OLZ/SAM and olanzapine with endpoints that were specifically chosen to demonstrate clinically meaningful changes in weight. The data that we'll be focusing on today is in patients with schizophrenia. We are also seeking an indication for bipolar I disorder, both as a monotherapy and as an adjunct to lithium and valproate, consistent with the current indication. The fourth is bipolar indication. We aligned with the FDA on a bridging strategy. The strategy [indiscernible] olanzapine in bipolar I disorder as well as 2 necessary components, which we accomplished: first, establishing that the olanzapine exposure within OLZ/SAM [Technical Difficulty] Zyprexa; and second, demonstrating similar antipsychotic efficacy to olanzapine in the schizophrenia program. We also established that there were no drug-drug interactions with lithium or valproate. In addition to the Phase III study, we've conducted an extensive safety and efficacy evaluation with 27 clinical studies, including 3 long-term open-label studies evaluating up to 3.5 years of OLZ/SAM treatment. I'll describe the Phase III studies in more detail, the first of which is the antipsychotic efficacy or 305 study, which met its primary and key secondary endpoints. The efficacy of olanzapine alone is well-known to the field. The antipsychotic efficacy of OLZ/SAM was established in a 4-week double-blind, randomized, placebo-controlled study in acutely ill patients with schizophrenia, comparing OLZ/SAM to placebo, with olanzapine added as an active control. The primary endpoint was the change from baseline in positive and negative syndrome scale total score at week 4 for OLZ/SAM compared to placebo. This figure represents the primary outcome measure of PANSS total score, with change from baseline on the Y-axis and visits and weeks on the X-axis. OLZ/SAM is in blue, olanzapine in orange and placebo in gray. A decrease in PANSS score indicates symptom improvement. And at the end of 4 weeks, we saw significantly greater improvement in PANSS total score for patients treated with OLZ/SAM compared to placebo. A similar improvement is seen in the olanzapine treatment arm as expected. The key secondary endpoint of change from baseline and CGI-S score demonstrated similar findings to the primary endpoint. Long-term improvements in PANSS and CGI-S scores were also observed in open-label studies with over 76 weeks of treatment with OLZ/SAM. So in this study, we demonstrated the antipsychotic efficacy of OLZ/SAM compared to placebo. This efficacy was similar to what is known for olanzapine and was also demonstrated across multiple Phase II and Phase III studies as well as in long-term safety studies. This leads to the conclusion that OLZ/SAM has retained the known antipsychotic efficacy of olanzapine, supporting the indications of both schizophrenia and bipolar I disorder. The second Phase III study is the weight efficacy study, which also met its coprimary and key secondary endpoints. The effects of OLZ/SAM on weight were examined in a 24-week double-blind, randomized controlled study in stable outpatients with schizophrenia. 561 patients with body mass index between 18 and 30 were randomized to treatment with OLZ/SAM or olanzapine. One coprimary endpoint examined the percent change from baseline in body weight at week 24. The other coprimary endpoint examined the proportion of patients gaining greater than or equal to 10% of their body weight. This 10% cutoff was chosen as this signifies a clinically meaningful amount of weight gain for a patient. For instance, in a person weighing 170 pounds, this represents 17 pounds in weight gain over just 24 weeks. The key secondary endpoint examined the 7% cutoff as this is widely used in psychiatry studies and antipsychotic labeling. The coprimary and key secondary endpoints were met in the study with p-values listed here in the right-hand columns. The difference in percent change in weight reflects the mean change in the whole population of the study, and this difference was 2.38%, which was significantly different from olanzapine. For patients gaining greater than or equal to 10% of their body weight, the risk difference between OLZ/SAM and olanzapine was 13.7%, and for the 7% cutoff, it was 15.9%. Both values, again, being significantly different from olanzapine. This figure represents the coprimary endpoint of percent change from baseline and body weight by week, with study weeks on the X-axis and the percent change from baseline in weight on the Y-axis. At the end of the 24 weeks, the percent change in body weight with OLZ/SAM is significantly lower than olanzapine. There was some initial weight gain with OLZ/SAM, which stabilized from 4 weeks on and was stable for the remainder of the study. The weight gain with olanzapine alone continued throughout the 24 weeks, and the difference between the treatment groups continued to grow, resulting in a very different trajectory for OLZ/SAM than what is known to occur with olanzapine. The long-term stability of weight with OLZ/SAM is seen in patients continuing treatment for 76 weeks in the extension study. Next are the categorical coprimary and key secondary endpoints. First to the table on the left. OLZ/SAM led to a 50% reduction in the risk of gaining clinically meaningful weight, defined as gaining either greater than or equal to 10% or 7% of body weight. The figure on the right is the cumulative responder flat, with a cumulative percentage of patients on the Y-axis and the percent change from baseline in body weight at week 24 for all patients. And you can see that the OLZ/SAM curve in blue is consistently shifted to the left of the olanzapine curve in orange, and this shows us that OLZ/SAM reduced the risk of weight gain compared to olanzapine no matter how clinically meaningful is defined along this curve. The widest separation point between these curves is at the important cutoff points of 10% and 7%, and this indicates that the risk reduction with OLZ/SAM treatment is more pronounced in those patients who are most susceptible to the greatest weight gain associated with olanzapine. This 50% reduction in risk is not only seen in the weight data, again, shown here on the left, but also seen in waist circumference and systolic blood pressure. The figure in the center is showing the exploratory endpoint of change from baseline in waist circumference comfort for OLZ/SAM in blue and olanzapine in orange over 24 weeks. Waist circumference is an accepted proxy for central adiposity and central fat is a major driver of downstream metabolic impairment. [ And third ] to the changes in weight at 24 weeks, there were lower increases in waist circumference for OLZ/SAM. The differences in waist circumference occurred earlier than the changes in weight, suggesting that changes in the distribution of weight may occur earlier than changes in actual weight. OLZ/SAM also reduced the risk of gaining 5 centimeters in waist circumference by 50% compared to olanzapine, and the changes in waist circumference were stable in patients on OLZ/SAM, continuing for 76 weeks. The figure on the right shows the [ postop ] finding of systolic blood pressure. Systolic blood pressure on olanzapine treatment increased by greater than 2 millimeters of mercury, where it was unchanged with OLZ/SAM, and systolic blood pressure is an independent risk factor and established biomarker, every 2 millimeters of mercury increase in systolic blood pressure is associated with an approximately 7% higher long-term risk of death due to cardiovascular disease. The benefits of blood pressure were further reflected by a 50% reduction in the risk of shifting from normal to hypertensive blood pressure levels. Stability of blood pressure was demonstrated in patients remaining on OLZ/SAM treatment for 76 weeks. Taken together, these data indicate a reduction in 3 important cardiometabolic risk factors. Unlike the changes in weight, waist circumference and blood pressure, we did not see differences in metabolic laboratory parameters between OLZ/SAM and olanzapine in 24 weeks. This plot shows the change from baseline in lipid and glycemic parameters at week 24 with olanzapine in orange and OLZ/SAM in blue. Changes were generally small and similar for both treatment groups. We included these parameters as exploratory endpoints, understanding that observing weight-related differences in these parameters may be compounded by several factors, including weight independent effects of olanzapine, inconsistencies in fasting status and, importantly, study duration. While we were confident that 6 months was sufficient to see differences in weight, it was not clear that this time frame was sufficient to observe weight-driven changes in metabolic parameters. And also since this is a weight prevention and not a weight loss study, patients were non-obese and generally metabolically healthy entering the study. As Dr. [indiscernible] noted in his presentation, 24 weeks was likely not sufficient time to see a difference between the treatment group in a population with this profile. What we do know is that over time, weight gain is a major driver of glucose and lipid abnormalities, with prevalence of diabetes and dyslipidemia increasing progressively with increasing BMI. With long-term OLZ/SAM treatment in the open-label studies, lipid and glycemic parameters remained stable through 76 weeks. When we look at a composite view, we see benefits for OLZ/SAM versus olanzapine across multiple cardiometabolic risk factors. In [indiscernible], each row denotes a clinically meaningful change for that risk category. The circles denote the absolute risk difference for OLZ/SAM versus olanzapine along with the confidence intervals. And you could see that in the 24-week study, treatment with OLZ/SAM was associated with a significant reduction in the risk of weight gain, obesity, central adiposity and hypertension. Lipid and glycemic parameters crossed 0 and therefore showed no difference between OLZ/SAM and olanzapine. And as we saw in the previous slide, changes were generally small for both treatment groups at 24 weeks. The stability of these parameters were seen in the long-term study through 76 weeks. So to summarize the weight effects, OLZ/SAM reduced the mean percent change in weight versus olanzapine and resulted in a 50% reduction in the risk of clinically meaningful weight gain. We also saw improvements in waist circumference and systolic blood pressure. The stability of waist circumference, blood pressure and metabolic parameters is also seen in long-term studies. The next section of data I'll show you is the safety data, which demonstrated an overall safety profile consistent with olanzapine with less weight gain. Our understanding of the safety profile of OLZ/SAM is informed by an extensive safety data accumulated for Zyprexa. Effects of samidorphan have been studied in over 600 patients and healthy volunteers. Supportive to this is well-established clinical experience with the class of opioid antagonists, which are used in the field of addiction as a treatment for opioid or alcohol use disorder, including in patients with comorbid conditions or bipolar disorder. As we monitored our clinical studies, we focused on the known safety profiles of both components, while being vigilant to new unexpected adverse events or amplification of known signals that might have emerged from the combined use of olanzapine and samidorphan. The overall safety profile of OLZ/SAM is informed by a total of 1,601 unique exposures to OLZ/SAM, with 1,262 of those in patients with schizophrenia, providing a total of 910 person years of exposure in this population. Close to 400 patients were on OLZ/SAM treatment for more than a year, and the study is going up to 3.5 years. Now I'll review the adverse events or AEs. The colored columns here represent the studies. Adverse events were generally mild to moderate in severity and similar between the OLZ/SAM and olanzapine treatment group. There were few treatment discontinuations due to AEs across treatments, most were related to the exacerbation of underlying schizophrenia. Various AEs were infrequent and, again, were largely related to the exacerbation of underlying psychiatric disease. Neither olanzapine nor samidorphan have demonstrated any evidence of abuse potential. Our overall experience to date suggests that the safety profile of OLZ/SAM is generally consistent with that of olanzapine, with the exception of less weight gain. I'll next discuss [Technical Difficulty] known historically about olanzapine and opioid antagonist. As a second-generation antipsychotic, olanzapine is known to cause effects such as weight gain and metabolic changes as well as effects such as extrapyramidal and anticholinergic effects. For opioid antagonist, important risks that were not commonly seen across our clinical program in an evaluation of 1,600 patients but are known class risks include precipitated opioid withdrawal in patients who are physically dependent on opioid agonist, attempts to overcome opioid blockade with opioids which could lead to fetal [Audio Gap] reduced or inadequate opioid analgesia when taking an opioid analgesic with an opioid antagonist. To adjust these risks, we have proposed a contraindication for patients dependent on or chronically using opioids as well as warnings and precautions describing these risks. We know that opioid use and opioid use disorder do occur more frequently in patients with schizophrenia or bipolar disorder than in the general population. The FDA has raised the point that these risks could be mitigated through labeling, and we agree. In addition, because patient safety comes first, we have leveraged our experience in patients with serious mental illness and proactively proposed a robust educational plan to ensure the potential prescribers and patients understand the contraindications and warnings and precautions. Our pharmacovigilance plan ensures safety data collection, signal detection and regulatory reporting in accordance with the current regulations. To summarize the Phase III program for OLZ/SAM, we demonstrated antipsychotic efficacy compared to placebo and mitigation of olanzapine-associated weight gain, while maintaining the known efficacy of olanzapine. The durability of the antipsychotic and weight mitigation efficacy was also seen in longer term data and replicated across the program in nonclinical species, healthy human volunteers and in patients with schizophrenia. The safety profile is consistent with what is known for olanzapine with the benefit of less weight gain. Class risks associated with opioid antagonists are well-characterized and can be managed through labeling pharmacovigilance activities and educating. So I'd like to turn now to 4 points for consideration raised by the FDA and would like to give our findings on these important points. First, the changes in weight seen with OLZ/SAM are both statistically and clinically meaningful. The endpoints that we aligned with the FDA on were carefully selected for clinical meaningfulness in this [Audio Gap] and we met both coprimary and key secondary endpoints. The mean difference in weight gain between OLZ/SAM and olanzapine is in line with what we anticipated for a 24-week study in a nonobese and generally metabolically healthy population. This mean difference also increases over time, altering the known trajectory of weight gain associated with olanzapine. And not only do we show significant difference in the population mean weight gain, OLZ/SAM also shifted the overall weight distribution curve towards less weight gain. This resulted in a 50% decrease in the risk of gaining greater than or equal to 10% or 7%. We also saw this 50% reduction in risk across several cardiometabolic risk factors, including weight gain, waist circumference, a measure of central adiposity and systolic blood pressure. Second, the safety of OLZ/SAM is well-characterized. Greater than 900 person years of exposure data demonstrated that safety profile for OLZ/SAM was consistent with olanzapine with the benefit of less weight gain. Third, the class risks associated with opioid antagonists can be managed through labeling. Labeling and education will provide an appropriate balance of communicating these well-characterized risks while avoiding barriers for patients who are often challenged with access to medication. And fourth, ongoing studies will provide additional supportive data. We are committed to future research on OLZ/SAM. In addition to our ongoing open-label extension study, we're evaluating the efficacy of OLZ/SAM in patients most vulnerable to weight gain and have an ongoing study in early illness enrolling schizophrenia [indiscernible] and bipolar I disorder patients. We've also developed a comprehensive pediatric study plan to evaluate OLZ/SAM in pediatric patients with schizophrenia or bipolar I disorder. Our current data package, however, is complete to support approval of OLZ/SAM. The totality of data demonstrate a favorable benefit risk profile for OLZ/SAM, a potential new treatment option that addresses an important unmet need for patients with schizophrenia or bipolar 1 disorder. We are fortunate to be joined today by 4 clinician scientists and experts in the fields of psychiatry, addiction and lipid disorders and metabolism. We also have a number of Alkermes attendees available to answer any questions you may have. Thank you for your time.

Thank you for the summary presentation. We will now take clarifying questions for Alkermes. Please use the raise hand icon to indicate that you have a question. And remember to put your hand down after you asked your question. Please remember to state your name for the record before you speak and direct your question to a specific presenter, if you can. If you wish for a specific slide to be displayed, please let us know the slide number if possible. Finally, it will be helpful to acknowledge the end of your question with a thank you and end your follow-up question with that is all my questions, so we can move on to the next panel member. First question is from Dr. Zacharoff.

Yes. This is Kevin Zacharoff from Renaissance School of Medicine at Stony Brook University. My questions are for Dr. Akerman. And first question with respect to Slide CS20. And I don't know if you're going to bring that up, but Dr. Akerman, my question on this slide really focus around, when we say educate the health care professionals, are we talking about educating the health care professionals who would likely prescribe this medication or are we talking about a more general broad health care education activity?

If I can have slide up, please. We've proposed a comprehensive educational plan. This is some of the components here that would be directed both to health care professionals and patients. We'd like to propose an initial communication to all potential prescribers and then ongoing education as appropriate, and this will include information about the contraindication, warnings and precautions. And we also have a number of patient-directed materials such as the doctor discussion guide and wallet card that could be helpful for patients as they discuss this potential medication with their providers.

Okay. So then it seems to me the education would be directed towards the prescribers, so we might consider that, that might be a psychiatrist, for example, or some other health care provider. My question to you is, is there any plan to provide educational materials to clinicians that might find themselves in a situation of needing to give opioid analgesics to patients who are on this medication, such as emergency department physicians or orthopedists or other -- even anesthesiologists like me, for example? Is there any plan at this time to provide some kind of educational programs or materials to those potential prescribers?

Yes, absolutely. I think that's a very important point. We would most certainly be interested in informing anyone who could come into contact with a patient taking this medication, and we're happy to work closely with the agency to ensure that our educational plan is robust and gets to all HCPs and patients who need this information.

Okay. And then 1 more question with respect to Slide CS23. And while we're bringing up that slide, Dr. Akerman, my question would be, in the event that OLZ/SAM does need to be discontinued because the person -- the patient does become a candidate to receive an opioid analgesic on an acute basis, let's say, how long after discontinuation of the medication would a prescriber of an opioid need to wait before they prescribe the opioid and wouldn't experience the opioid antagonism?

Yes. I would imagine that would be based on clinical judgment, depending on the opioid and how long the patient was receiving treatment. But I'd like to ask my colleague, Dr. [ Rege ], to comment on what is known. Dr. [ Rege ]?

Yes. I'm Dr. [ Rege ], clinical pharmacology from Alkermes. In our clinical trial that was looked at, effect of samidorphan in blocking the effect of remifentanil which is known very potent opioid agonist, there was a -- the data indicated about 48 hours of blockade, which would be the time period that we will be recommending and within 48 hours the new activity was recovered after stopping the samidorphan dose.

So in the event that somebody is on this medication and is in a motor vehicle accident, for example, just -- I heard you say remifentanil, I'm assuming that's the only opioid agent that the testing was done with?

The clinical trial that was done used remifentanil as an opioid to test against the samidorphan. There are other opioid agonists [Audio Gap] data that's available. So the half-life of samidorphan is around 7 to 11 hours, which, again, I think within 24 hours, one would remove at least 90%. The patient would clear about 95% of the drug within 24 hours. So that's an indicator of any other less active opioid agonists may be able to get prescribed after 24 hours rather than something very potent like remifentanil that could take about 48 hours.

Okay. So I'm going to keep it to clarifying questions, and we can save the discussion for this afternoon. So just 1 last question to you, then, sir. And that would be, is there any study of people needing acute opioid analgesia before the 24 to 48 hours has passed for medical purpose?

We do have issues of instances within our clinical trial program. I can ask Dr. Yagoda to speak to those. And then I'd like to turn to Dr. Kathleen Brady, who can let us know what is known in the field about analgesia in the context of opioid antagonist. Dr. Yagoda?

Sergey Yagoda, Medical Director. The use of opioid was restricted on our clinical program. However, we have an example when one of the patients had gotten into a car accident and was injured. They had pelvic fracture impact. And the patient was well informed of the pain management aspect. They were carrying the emergency card with them, and they were able to communicate with the ER physicians on the ongoing participation in the study where they receive opioid antagonist that the ER physician was able to contact the investigator, and they worked out the pain management plan when the patient received acute opioids in combination with paracetamol in the immediate acute stage and then they transitioned to oxycodone/paracetamol. The patient recovered. They did not report inadequate analgesia throughout the recovery period.

And Dr. Brady, can you comment on what is known about analgesia in the context of opioid antagonist?

Certainly. Hi. This is Kathleen Brady. Can everyone hear me, I just want to make sure I got my off-mute okay.

Yes, I can hear you.

Okay. Great. So the opioid analgesics have been around -- I mean the opioid antagonists have been around in the treatment of alcohol dependence for 20-some years now and so are increasingly commonly used. And there are pretty well-designed protocol for analgesia in the face of opioid antagonists that I think most people that were -- most physicians and ED docs and trauma surgeons are aware of, and these certainly include the use of regional blockade, the use of non-opioid analgesics and then careful application of opioids under -- to overcome the blockade under these very -- where patients are in hospital and can be scrutinized very carefully. So I think we've learned a lot about how to produce analgesia in the face of opioid antagonism, and I think the field is well-versed in this.

Okay. Thank you. That concludes my questions.

Thank you. This is Raj Narendran. Is there -- I'm going to ask my question because it's sort of related. Does Alkermes have any PET occupancy data at the neuroreceptor in humans for samidorphan at 10 milligrams to definitively say what percentage of neuroreceptors are occupied and for how long? Do you have any PET data?

We do not have PET data, but what we do have is animal data that I could ask Dr. [ Rege ] to speak to.

That's fine. If you don't have PET data, it might be worth considering down the line. And next question, I'll pass it to Dr. Dunn.

This is Walter Dunn from UCLA. My question is, I'd actually like to hear a comment from both the sponsor and the FDA, perhaps starting with the sponsor. So this is not the first time that the advisory committee has heard about samidorphan. So there was an application for ALKS 5461 back in 2018. This is the combination product of buprenorphine and samidorphan. And in that briefing document, they mentioned that samidorphan is metabolized to 2 full mu opioid receptor agonists, right? So you start with the antagonist, but it's metabolized to 2 agonists. There wasn't any mention of that in any of the material that I saw this time. Can you comment on if that's -- what's the role of those agonists, what potential problems that may kind of arise from that? Both a comment from the sponsor and the FDA, please. Thank you.

I'll ask Dr. [ Rege ] to comment on this question.

Dr. [ Rege ], clinical pharmacology in Alkermes. Slide up please. So yes, there are 2 major metabolites for samidorphan. You're right that in the RDC-9986 that has -- that is the main metabolite that has an opioid agonist effect. But what we see -- what you see on the slide here is the affinity values, which for mu, kappa and delta for 9986, they were at least 20-fold lower than the parent molecule. In fact, kappa is around 100-fold lower. And so when -- in a clinical situation, the -- when in presence of the samidorphan, that we expect that the samidorphan antagonism will outcompete any agonism. There won't be any likelihood of this metabolite engaging any of the receptors. In terms of the receptor occupancy data, we did look at the rat, and we see about 90% -- over 90% receptor occupancy at mu receptor at equivalent concentration of a 10-milligram dose. So again, there is no likelihood of any of these metabolites having ability to engage any mu receptors and confer any effect. So overall, in vivo situation, we don't expect any of those metabolites contributing to any pharmacologic effect to samidorphan, and all we see is the receptor antagonist effect for samidorphan [indiscernible].

And I'll just add this is confirmed by no evidence of abuse potential for either olanzapine or samidorphan across the clinical program.

So that's based of the assumption that the patient is taking consistent doses of the medication. So I think in this patient population, assumption is inconsistent adherence. So if you've got a patient who is taking it 1 day and not the other, and as you mentioned previously, in 24 hours, you're losing about 90% of the blockade. How does that factor into the safety equation then? And then could you also comment on the half-life of the metabolites?

I'll ask Dr. Rege to comment on the half-life, but we did see, I will note that we saw good adherence across our clinical program, which is consistent with adherence, which is known to be the case for [Audio Gap] Dr. Rege?

Yes. Bhaskar Rege, Clinical Pharmacology from Alkermes. Can I have the slide 83, please? So the half-life of 9986, which is the metabolite that we were discussing it [indiscernible] periodically, it's around 24 hours versus the half-life of samidorphan is around 7 to 11 hours. There is a third metabolite that has a similar half-life as samidorphan. Again, as we saw, none of the data that we indicated in the remifentanil study where we see a 48-hour blockade, but none of that data really indicated that any of the 9986 metabolite contributed to any effects because we actually see a receptor blockade rather than any of the agonist effect due to the metabolite, even if it has a longer half-life.

So just as a quick follow-up. So just to clarify, hypothetically, patients taking the combination product consistently for, let's say, a month and then starts to take it inconsistently once every 2 days or so, so in that window where their samidorphan concentrations are below or achieving less than 90% occupancy, you've got more new opioid agonist activity present, and that hypothetically could put the patient at increased risk for an overdose if they took another mu opioid agonist. Is that -- would that be a correct interpretation of a safety concern?

Well, I'd like to ask Dr. Kathleen Brady to comment on what is known about opioid risk associated with -- opioid overdose risk associated with antagonists. But just to note that opioid use would be contraindicated in conjunction with OLZ/SAM use. Dr. Brady, could you comment on opioid risk of overdose?

Yes. The opioid, the risk of opioid overdose that's associated with antagonist therapy is generally thought to be associated when an individual with opioid use disorder is placed on an opioid antagonist, which, again, that would be contraindicated with OLZ/SAM, and then they abruptly stop and resume their usual dose of opioids because one of the things that happens with opioids is people get tolerant tremendously -- very quickly, and so they'll lose that tolerance very quickly when they're taking an antagonist. And if they administer the same dose of opioids that they're used to administering, they're likely to have -- they're likely to overdose. It is not -- there is a little bit of animal data that suggests using opioid antagonist when they abruptly discontinued, there is super sensitivity of the mu receptors, but that has not been demonstrated in clinical populations at all. There's a human laboratory study by [indiscernible] and colleagues, where they gave individuals -- they tested morphine sensitivity, gave a couple of weeks of daily naltrexone, tested morphine sensitivity with abrupt discontinuation and saw no change in terms of CO2 or respiratory depression. Thank you.

Could the FDA comment on this on -- about these metabolites? Is it a concern of yours? I don't have off the top of my head, the binding affinities of a standard opiate versus these metabolites. So I'm wondering if it's -- if the binding affinities are not high enough for you to be concerned about that agonist activity of the metabolites? Could you comment on that?

Dr. Dunn, we're going to wait for agency because they have their own time. Okay? So we'll...

Great. Okay.

They'll have 30 minutes. Next question is going to be Dr. Krishna.

Hi, this is Sonia Krishna, affiliate faculty at Dell Medical School at Boston. I just wanted to clarify what the demographics were for A303, what the average age was in baseline weight with absolute numbers? I've appreciated the percentages, but really want to see what the absolute weight reduction or at least prevention of gain was. I saw 3 to 6 kilograms, just wanted to clarify that.

Yes, absolutely. I wanted -- I'll ask Dr. McDonnell to speak to this, but noting that you've asked about the demographics and the absolute weight change. Dr. McDonnell?

David McDonnell, Alkermes. Slide up, please. So this is a slide looking at the baseline characteristics in the A303 study, and we see the baseline characteristics were generally well balanced between the treatment. The body weight at baseline was 77 kilograms, and the BMI about -- between 25 and 26, both -- very similar between both.

Does that answer your question, Dr. Krishna?

Yes, that covered most of it, but if you could remind me what the absolute percentage change changed to in terms of kilograms, that would be helpful.

Yes. So the absolute change in body weight, so the -- with OLZ/SAM was 3.18 kilograms, with olanzapine was just 5.08 kilograms and the difference of 1.9 kilograms.

Your next question is from Ms. Witczak.

I have 2 questions. One, that just came out of the one prior speaker. But the first is, given that we know that antipsychotics and Zyprexa has a lot of off label use. Have you -- I'd love to hear your -- kind of what you're thinking is behind that because, obviously, this is a great concern with what's happening in the real world is off-label with the -- with Zyprexa and the weight gain. So I'd be interested about that. And then I noticed on the slide -- so that's question one. Question 2 was in that slide on the demographics. And I just wanted to make sure that I understood something correct that only like 64% of the people actually completed the study, is that what the completion rate was, completion percentage? And if it was, only 64% completed. What were the reasons for dropping out?

Your first question, the indications for pills for OLZ/SAM would be consistent with data for Zyprexa, which we'll be recommending. To your second question, the reasons for dropout, I'll ask Dr. McDonnell to that, noting that the dropout in missing data is what was anticipated in schizophrenia trial of this duration. Dr. McDonnell?

David McDonell, Alkermes. The treatment completion in the study, you're right, was over 64% in this study, and that was actually -- that's high for a study of this duration in this study population. Most antipsychotic studies that are 24 weeks duration or longer tend to have discontinuation rates that are higher than that. The reasons for discontinuation in the study -- slide up, please. The majority of the reasons that patients discontinue in our clinical studies is for withdrawal by subject, lost the follow-up, and they're -- they tend to be the highest reason for discontinuation and then the adverse events were similar between the treatment groups for OLZ/SAM and olanzapine.

Okay. This helps right there. I think -- because I see that the adverse events are a little bit higher with the combined products. But again going back to the question on off-label, I know that this is what we're testing or this is what was studied, but there are a lot of knowns out there given the fact that olanzapine has been on the market for a long time, and there's been all kinds of issues with off-label. So just being more proactively looking at this and what could be anticipated. So that would be a comment or I would love to hear your comment based on what I just said.

Yes, absolutely. Thank you. So Dr. René Kahn is joining us and has extensive experience with research on olanzapine. Dr. Kahn, could you comment on the question about off-label use?

Yes. Thank you, Dr. Akerman. This is Dr. René Kahn. And just with my conflict of interest, I do get honoraria and consulting fees from Alkermes. Yes, there's a lot of experience with olanzapine over since the approval in 1996, and I do think it is really mostly used in schizophrenia and bipolar illness, maybe sometimes in psychotic depression, but I'm not so sure that the off-label use is really extensive in olanzapine, certainly not because it's really only approved in the indications that I just mentioned. So not so sure whether it is in a clinical, normal practice going to be a major problem. Thank you.

Okay. We can talk -- we can discuss that later this afternoon on my concerns. Thank you.

Thank you. [Operator Instructions] Next question is Dr. Thomas.

Dr. Thomas, Baylor College of Medicine. I have 2 questions. One is in 2 parts. This is directed towards Dr. Brady and Dr. Rege, apologies if I'm mispronouncing that. The first question is, so my understanding of samidorphan is not only that it has a longer half-life, but also a higher binding affinity than naltrexone, which the presenters have compared it to -- for in terms of efficacy and safety or other safety data for it. So I guess, one, is that accurate? And two, if that is, especially for Dr. Brady, do you think that the protocols that exist for dealing with acute pain management for people on antagonist would be altered or import more morbidity if they had to overcome this with over a longer time and with a higher affinity binding antagonist?

I'll ask Mr. Rege to speak to the binding affinity first and then to Dr. Brady. Thank you.

Bhaskar Rege, Clinical Pharmacology at Alkermes. So from binding affinity perspective, can I have slide C-91? So binding affinity perspective, in regards to the mu receptor, naltrexone -- samidorphan only is twice as more -- have a more affinity than naltrexone. For kappa, they have a very similar affinity between naltrexone and samidorphan. And for delta, it is about thirtyfold more affinity on samidorphan.

And Dr. Brady, could you comment on pain management with an antagonist?

Yes. So I think, again -- this is Kathleen Brady. And I am a paid consultant for Alkermes, just for a conflict of interest. But the -- as you know, pain management is a very clinically-driven process and so individual pain thresholds as well as pain regimens differ tremendously from one individual to the other. And so I would say that these fairly minor differences in binding and half-life or something that would fairly easily be managed using the protocols that are already well-established with careful patient monitoring because no matter which antagonist an individual is on, there'll be a time when the antagonism is wearing off and agonist become more potent, I mean, in that. And it's hard to say precisely for any individual what that time point is. So clinicians know to monitor carefully. Thank you.

Hi. It's Dr. Thomas again. And I guess my second question, and this is related to the slide regarding labeling. So having the antagonist there, there's the question of, if you have someone who is in a using population of opioids, whether that would import increased risk of death in relapse. And there's actually some good data, Dr. Brady has already brought this up, around I think a 6-month study of VIVITROL versus SUBOXONE in which one of the outcomes was that there actually wasn't an increased risk of overdose, at least relative to one another, but you could potentially kind of extrapolate that for this. However, these are people that were in a recovery program and actively working on it. So is there any -- I guess my question is, is there any thinking about the labeling to designate that people are on this and they either would come opioid dependent or they come into treatment opioid dependent labeling around them being in recovery or the stage of recovery because certainly if they're early in recovery, there might be -- and they're not in treatment, there might be more risk around that as opposed to someone who's been in recovery -- working on recovery program.

Yes. Thank you. This is something we considered very carefully. And I'd like again to have Dr. Brady weigh in on her clinical impression, but there will be a contraindication for patients who are currently physiologically dependent on opioids and would really be clinical judgment if someone had a remote history of opioid use. Dr. Brady, could you comment as well?

Yes. I've said this is definitely an issue of clinical adjustment. But if we think about current opioid use disorder, it's actually anytime in the last 3 months. And so anybody -- and it's gold standards, this is going to be the clinical interview. And I think that anybody probably who have had opioid dependence or actually is even at high-risk is somebody you probably want to think very carefully about using this particular drug. And there's -- it's a very small percentage of population of individuals with schizophrenia. It's only somewhere between 5% to 10%. There's -- so there's still 90% of patients for which this would not even be an issue. So I think one would want to tread very cautiously in people with recent histories of opioid use disorder.

Sorry, just 1 follow-up question for that. So is the idea that the labeling that it would be contraindicated in people with opioid use disorder cover even if they were not initially and then became [indiscernible] 01:18:54 started to have that issue as opposed to designating anything around recovery or how that works when they're -- when -- if they were to become dependent?

So current contraindication we're proposing would be in people who are physiologically dependent on opioids and -- because opioid disorder is a broader diagnosis, it would be at the discretion of the clinician if someone had a remote history of opioid use.

Thank you. We have 12 minutes. I've got another 4 questions. [Operator Instructions] Next question is from Dr. Boudreau.

Yes. A quick question because a lot of mine were answered. With regards to the educational materials, I'm sorry if this was discussed, I've gone in and out a little bit with myself. Do the materials contain information about the risk that -- of opioid overdose, even post discontinuation of the medication? I mean I know that you addressed the fact that the data is pretty limited around, I think, it's only animal studies with regards to the up-regulation of new receptors with naltrexone, which is one of the hypothesized mechanisms by which they've observed elevated risk of overdose after treatment discontinuation. It doesn't sound like you've looked at that in your clinical program with regards to animal studies, but I'm just curious about educational materials. And with regards to that, given that adherence to the base medication sometimes isn't great and that these patients could present in emergency departments in places and not say that they're taking the medication because they have discontinued it, but still could be at risk for an undetermined time following discontinuation.

Yes. We agree it's important to include all of these potential risks associated with opioid antagonist, and that would include the risk of overdose if someone were to attempt to overcome the blockade. There is risk of precipitated opioid withdrawal and the risk of inadequate analgesia. And these risks will be included in the contraindications and warning and precautions as well as any educational materials for both HCPs and patients.

Thank you. Next question is from Iyengar.

This is Satish Iyengar from the University of Pittsburgh. I have what maybe a discussion question. The studies that I see here are on schizophrenia. How strong is the evidence that extrapolation to bipolar disorder is feasible?

Yes. I'd like to ask my colleague, Dr. DiPetrillo to comment. We align with the agency on a bridging strategy. Dr. DiPetrillo, could you outline this?

Yes, Lauren DiPetrillo, Regulatory Affairs. And as mentioned by Dr. Fischer this morning, we did align with the agency on a bipolar bridge. And if I could have slide up, this really is rest on 2 key points. One, in regards to demonstrating that the olanzapine exposure in OLZ/SAM is bioequivalent to Zyprexa, which is shown here and then also showing similar antipsychotic efficacy to olanzapine across our schizophrenia program. And then, if I could have a slide up, the bipolar bridge is also supported by several other lines of evidence, namely that we know that olanzapine associated weight gain is disease-independent and noted as a concern for both patients with bipolar and schizophrenia. We also know that the weight mitigation of OLZ/SAM is disease independent as we've seen this in healthy volunteers and in schizophrenia patients. We have no drug-drug interaction with lithium or valproate. And then importantly, in looking at the literature, opioid antagonist, when given concurrently with patient's antipsychotic agents does not affect bipolar symptom control, and in fact are included in treatment guidelines right now for patients with co-occurring substance use disorder. But in regards to your question on how this translates, I'd like to actually turn it over to Dr. Kahn to speak about his clinical expertise of using olanzapine in both bipolar and schizophrenia patients.

Yes. Thank you very much. Yes, if I can just show up the slide on the efficacy of olanzapine in Slide #16. In bipolar illness and you can see there -- slide comes up. You can see there that olanzapine is highly effective as a treatment of mania. And also the time to discontinuation is actually the shortest or the least pronounced in patients with mania. So I really think that olanzapine is very well shown and very well studied and considered also in the confidence in intervals. Bipolar illness is a highly effective antimanic agent and a highly effective drug to maintain mood stability in bipolar illness. So I think there's a very long history for both efficacy in the short-term and in the long-term in bipolar illness. So I think a drug that includes the high efficacy of olanzapine and bipolar illness with the mitigated weight gain is really something we need currently. Thank you.

Next question is from Dr. Jeffrey.

Jessica Jeffrey from UCLA. For study A303, I found it interesting that participants did not report changes in quality of life. Will you please review the tool used to assess quality of life and discuss your interpretation of these results?

Yes. So I'd like to ask Dr. McDonnell to speak to these data, followed by Dr. Ginger Nicol, to give her impression of the importance of weight gain to patients. Dr. McDonnell?

David McDonnell, Alkermes. We did look at the quality of life in our clinical studies. And as you may expect, the results may have been confounded by the fact that both patients will be treated with active treatment, both patients receiving olanzapine, and we know that patients who are treated with olanzapine tend to have high-quality of life. So -- a slide up, please. These are the quality of life measures that we used in our clinical program, and we use the [indiscernible] in 303 and the impact of weight on quality of life in 303. The impact of weight on quality of life is actually -- we were trying to look for a measure that could impact -- look at the effects of weight. And we chose this one because it is used in weight loss products, however, probably was not well suited to a product that prevents weight gain. And what we saw in the outcome of the scale as we saw patients entering with high levels of quality of life, so a high score indicates a high level of quality life, and those levels stayed high for the full duration of the study. And when you look at the individual items on the impact of quality of life, it may well be that the actual well-being on the treatment affected them. So this is something we've seen consistent in the clinical program that both -- patients are all on olanzapine, so they tend to do well in the quality of life. One of the things we did look at, if we did a patient exit interview for patients who are on OLZ/SAM in our open-label extension study and -- slide up. This is only a subpopulation of the patients, but it did get -- it was and is biased by their patients who remained on OLZ/SAM. So obviously, they chose to remain on it. But what we saw was in those patients, generally speaking, quite positive effects on their emotional and mental well-being, on their self esteem and social activity. The patients were doing well when treated with OLZ/SAM, obviously, within the limitations of how this interview was done. And then I'll ask Dr. Nicol to talk to the effects of weight on quality of life in general. Dr. Nicol?

Hello. This is Ginger Nicol. I'm a Child and Adult Psychiatrist, and Obesity Medical Specialist at Washington University in St. Louis, and representing the clinical risk-benefit perspective here. For disclosure, I'm a paid consultant for Alkermes. And one of the things that we know about quality of life measures in randomized clinical studies of patients with schizophrenia is that -- just as Dr. McDonnell said, most of the people that enter the study, there are limitations on how sick or well they can be. And so when they're already on a medication that's very effective, or are stabilized, these measures tend to be high. And I think it's meaningful that they didn't change over the course of the study. And then what we know from at least 1 study, slide up, please, asking about -- asking patients with schizophrenia, what influences their decision to take medication. But I know there are many psychiatrists here listening today. This is a population that we really do struggle with treatment compliance. And so this is an online study. So everybody was anonymous, that patients with schizophrenia, asking them what's the most important thing in terms of medication side effects that drives their decision to repeat medication. And you can see here that in that study, looking across the spectrum of potential weight gain, you see the number of respondents saying, "yes, that would mean I don't want to take the medication." This is really, I think, pretty obvious here with this slide. But in general, and working with patients, the first episode of schizophrenia, in particular, which is more typically mild population, these folks are very concerned about weight gains. They may not really understand or care about some of the other longer-term side effects associated with weight gain, but weight gain is very important. And having the discussion with patients and families, especially in that critical period where we need to get them treated so we can impact long-term functioning. Thank you.

Next question is from Dr. Bonhert.

I was curious, if I understood correctly in the dose-finding study or Study 302, there was a lack of dose response effect on weight of the samidorphan. I'm curious -- or I hope you could comment on why you went forward in the next studies with the highest dose.

Yes. I'll ask Dr. McDonnell to speak to the dose finding study, Dr. McDonnell?

David McDonnell, Alkermes. In the Phase II 302 study, which is our dose finding study, it's important to point out that the primary outcome of that study was actually an efficacy outcome. And as you would expect, the different doses of samidorphan that was studied in that study did not have an effect on the efficacy outcome because olanzapine was treated as required by the clinician. With regard to the weight effects, this was an important secondary endpoint in the study. We did study 3 different doses of samidorphan in the study. We studied a 5-milligram dose, a 10-milligram dose and a 20-milligram dose, and I acknowledge that the FDA said that they didn't see a dose difference in the state of -- side up, please. But we -- when we got the results of this Phase II study based, upon this data, which, here, we're looking at the percent change from baseline and body weight by week, in orange is the olanzapine-treated patients, in blue is the patients who had samidorphan. The solid blue line is the 10 milligrams of samidorphan, and the dotted lines are the 20 milligrams and 5 milligrams of samidorphan. And what we saw is we saw the best mitigation of weight with the 10-milligram samidorphan dose. And obviously, when we're looking at a medication that doesn't cause weight loss, we want to try and maximize the amount of weight that they prevent. And we looked at those data, and there are some other data. And the clinical side of it, samidorphan was tolerated at all 3 doses. There was no real difference in the tolerability of samidorphan, but we felt that this was the dose to maximize that mitigation of weight in our Phase II study, and we chose that dose as a fixed-dose to move. Slide down.

Thank you. It's about 11:30. I still see a couple of hands up, but I wasn't sure Dr. Dunn, Dr. Iyenger have questions, but I was thinking we can move to the agency's question session. And if there is extra time, you guys can -- we can give you a chance to complete it. So let's move to the agency's question, clarifying questions to the FDA. [Operator Instructions] Our first question is Dr. Dunn because he had that follow-up question.

Great. Walter Dunn, UCLA. So yes, this is a follow-up question to the agency. So regarding the presence of the new opioid agonists as far as the metabolite, how problematic is that? Is that a concern? And then as a related question, what's your stance on fluctuating levels of new blockade? So again, the observation is that within this patient population, medication adherence is highly inconsistent, and that's -- again, that's the presumption rather than the exception. And then as a related question, what's your position on the use of this on a PRN basis?

Sorry, the last 1 threw me a bit. This is Tiffany Farchione, by the way. What do you mean by on a PRN basis?

Oh. Yes. So basically, so the 2 clinical situations I can envision are a patient is taking a standing dose of OLZ/SAM and then occasionally, you prescribed, let's say, a 5-milligram dose of olanzapine or any potential exacerbations of symptoms or kind of -- and treating kind of early kind of psychotic episodes before they get bad, allowing the patient to kind of take it on an as-needed basis based off of [indiscernible] 01:34:40

Yes. I mean I think that that's kind of outside the scope of what we're talking about here. I mean we're really talking about the indication that they're seeking, which is a chronic treatment indication for schizophrenia or bipolar I disorder. But as far as the previous question about -- and again, this is not something that we brought up in our recent documents or anything like that because it really wasn't an issue that we were particularly concerned about. I know that you're -- you referenced the previous briefing materials from the last advisory committee. And really, under that application, the main reason that we were concerned was because, with that other application, the samidorphan was combined with buprenorphine, which is an opioid agonist. And so we had concerns about the -- and they were hypothetical concerns, but we had hypothetical concerns about potential additive, new agonism effects between diprenorphine and samidorphan metabolite. So that's where the concern came from in the past, but we don't have anything really to add on this application. The other thing to think about is that with -- again, with the previous application, there was a human abuse potential study, and samidorphan didn't produce positive effects in the human abuse potential study either, so...

Dr. Farchione, just as a follow-up. Your first comment about this use as -- in a chronic population. So I guess maybe the better question is, is there a concern for safety, if there is fluctuating levels of new blockade?

So we -- I mean, again, we haven't evaluated it in that context. And I don't anticipate that it would be used in that manner. As your -- if that's related to the PRN question, I'm not sure why someone would use this as a PRN basis.

So I guess, maybe -- I guess, again, under the presumption that patients, even if we prescribe it to them chronically or just kind of standing, they're not going to use it every single day, right? They're going to be on and off, maybe 60%, 70% of the time they're taking their medications. So yes, I guess, maybe that would be the closest.

Yes. Perhaps I can throw this over to Judy Staffa because I think that this might be -- I think your question might be coming from some of what was in the OLZ presentation. So let me pass that over to her. Judy?

Judy Staffa here. Yes, I think that is one of the concerns that was raised in Dr. Celeste Mallama's presentation is the fluctuating levels of the antagonist sitting on the receptor. And I think that related to some of the concerns about overdose. And I think that those fluctuating levels come not from a prescribed PRN regimen, but more from a, what we know, as you mentioned, about the difficulties with adherence to medications in this patient population. So I think that's where those concerns are reflected. Yes, we've posed them and are anxious to here what folks think about that, who treat these patients and know even more about this condition and this concern.

Our next question is from Dr. Zacharoff.

Yes, this is Zacharoff from Renaissance School of Medicine at Stony Brook University. And this is in reference to the presentation that we previewed by Dr. Mallama, with respect to considerations of risk associated with real-world settings of opioid use. Dr. Mallama, in one of your slides, at the conclusion of that prerecorded presentation, there was mention about use of alternatives in the event that somebody requires acute analgesic treatment if they're on this medication, and I'm just wondering what alternatives were being referred to. Because as we heard in the example given earlier to my question from the sponsor that there was a situation where somebody was in a motor vehicle accident, suffered a fractured pelvis, and I presumably presented to the emergency department requiring analgesic treatment. I know there was some mention of acetaminophen, but I don't think most clinicians would consider acetaminophen to be adequate analgesic treatment for someone who's post MVA with a fractured pelvis. So just one clarification about what alternatives were being referred to.

Hi, this is Celeste Mallama with FDA. In regards to pain management, alternative dose would be non-opioid alternative. I think I can also pass this question to my colleague, Dr. Alicia Lopez, if you want to add something?

This is Dr. Lopez with the FDA. And the case that's in reference that you're referring to, that was based on a literature review. And within the literature, it was stated that the surgical team used a multimodal approach to pain management. They did use opioids. In this case for postsurgical pain, they used a hydromorphone pump, pain pump. And non-opioids that they used -- they -- at the end of surgery, they infused a nerve block, and then they also used the acetaminophen. They reported they didn't believe the nerve block alone would be sufficient to manage the postsurgical pain, but that was the combination that they opted for within that case that was reported. Thank you.

Next question is from Dr. Fiedorowicz.

Yes. This is Jess Fiedorowicz in Ottawa. My question is for the FDA. I heard the rationale for the bridging strategy to a bipolar I indication rest on bioequivalents for olanzapine and a trial in schizophrenia. And then there were some studies cited by the applicants in bipolar disorder, and those included 2 small trials with comorbid alcohol use disorders. A practice guideline recommending naltrexone for use with alcohol use disorder and then a very small trial that was just research letter. And all of those studies were with naltrexone. So in my mind, I'm struggling with seeing how there's like a single bridge here. It seems more like a series of bridges, perhaps something more familiar to what my colleagues in Pittsburgh might be familiar with. We have links from schizophrenia to bipolar disorder and then from naltrexone to SAM. And if that's the case, I think the rationale for each of those may be somewhat tenuous, right? We have -- the first is, if naltrexone holds and why not just use that, which is much cheaper? And then the second, there's a lot of burgeoning literature on opioid neurotransmission and it's relevant to the mood disorders. And so I'm just wondering what your thoughts are on this sort of complicated and tenuous bridging strategy? And also, is there any precedence for that -- for this sort of complex bridging strategy?

Yes. Hi, this is Bernie Fisher. So usually when an applicant comes in and is going through a 505(b)(2) pathway, then we make sure that they have comparative bioavailability. And that lets us generalize that their drug has the same blood levels and would lead to the same efficacy and safety as a listed drug or a drug that's already approved. In this case, we -- this applicant did do that and what we really wanted to see was does the samidorphan interfere with the blood levels, interfere with the action at the receptor, interfere downstream somehow. And so we didn't think that they needed to do a bipolar study and the schizophrenia study because most of the drugs that are approved for both indications, we assume at least partially, through a D2 receptor blockade. So we were satisfied that if there was no interference in the efficacy with the schizophrenia study, we didn't feel that there was going to be a unique interference with the bipolar group as far as efficacy.

Does that answer your question, Jess?

It answers my question. I'm not sure that I find it compelling, but I appreciate the answer.

Our next question is from Dr. Krebs.

This is Erin Krebs. My question is related to the weight gain issue, specifically with switching from olanzapine to the OLZ/SAM formulation. And I'm referring specifically to figures that were in the FDA documents, so the -- really looking at the extension studies, where there's an open-label extension after an initial randomized trial and then included in the presentations, the FDA presentation we watched earlier. I'm -- at least my impression here is that the weight gain is happening early when the drug has started, whether that's olanzapine alone or the olanzapine/SAM. And the benefit that seems to be there in terms of prevention of additional weight gain or of excess weight gain seems like it's with the patients who are olanzapine-naive starting initially. And at least from the figures that I'm looking at, it didn't seem that, that was occurring with patients who were switching from olanzapine to olanzapine/SAM. So I guess the reason I'm just wondering if you could comment on that or conversation about that is I imagine if this product becomes available as something that prevent weight gain that patients who've had been on olanzapine had weight gain may want to switch to this new product with hope that, that would halt the weight gain. Is that something that can be commented on at this point or do we just not have data that are adequate?

Hi. This is Julie Golden. I'm a clinical reviewer with the Division of Diabetes, Lipid Disorders, and Obesity at FDA, and I collaborated with the Division of Psychiatry on this application. So I am also looking at the figures that you cite in the FDA briefing document. These were basically patients who had -- when they switched over in the open-label phase to ALKS 3831, we're following those patients from the beginning of the controlled period. And so they are not randomized from the beginning, that's the first point. The second point to make is that while these longer-term switch data seem -- potentially suggest of a stabilization of weight, I think it's premature to make that statement at this point because we don't have randomized data at that time. So we don't have any data suggesting that patients who have been on olanzapine for, say, 3 months or 6 months and then switch over to ALKS 3831 will mitigate the weight gain. That would require additional randomized period post-olanzapine. The only data that we have that's potentially suggestive was in the FDA presentation of 302, where -- which included a 1-week olanzapine lead-in period, and then patients who gained weight were stratified in that period. And so there is some suggestion, although that's a very exploratory early study. We can't make any comments about whether that pattern would be seen in future studies, but there was some suggestion of an enhanced treatment effect in patients who gained weight with olanzapine in that 1 week period. Beyond that, I think it's just speculation.

Does that answer your question, Dr. Krebs?

Yes, I think so.

So I do not see any more questions for the agency. Does anybody else have any more questions for the agency? We have 10 more minutes. I see a couple of hands. Dr. Dunn, you have a follow-up question?

Yes, a follow-up question, maybe for 1 of the bio panelists at the agency. So can you comment on the binding affinity of those metabolite compared to a standard kind of opioid that someone would be taking? I appreciate that metabolite have, I think, it was a tenfold lower binding affinity compared to samidorphan, but how does it compare to a standard new agonist people will take for analgesia?

So I think -- this is Tiffany Farchione again. I think that we -- the person we would need in order to actually answer that question is not in the presenter room, so we would have to actually get that person, call them in and everything. So we can work on -- and we'd also apparently have to look up the answer as well, but we can try to get that to -- there's no direct comparison studies, but we can try to get that response to you before the end of our part of the session here.

Yes, that would be great. I mean, I'm just trying to -- yes, if you could get -- if you just kind of give me some idea of how problematic it's going to be, how does it compare to like morphine or oxycodone or something like that.

Yes. I mean -- and I also wonder if perhaps if the applicant has a ready answer to this. Again, like I said, we have to look this up, but perhaps they're prepared with a backup side or something of that nature?

Yes. Just to clarify the question. Are you asking about the binding affinity of samidorphan?

No, these -- the metabolites. The metabolite that has the new agonist activity.

Yes. And maybe before I turn it over to Dr. Rege to speak to that. I want to also mention that we've conducted a thorough human abuse potential study. In our clinical data, we see no evidence of abuse potential. Dr. Rege?

Yes. Bhaskar Rege, Clinical Pharmacology in Alkermes. So I'd like to show -- I mean I think your concern is whether the metabolite would import any pharmacologic effect. I think there are repetitive evidence, clinically speaking, I mentioned remifentanil study earlier, but I can also show you the human abuse potential study data that also confirmed that there was no indication of any [Audio Gap] metabolite, which is in vitro has shown to be a new agonist. Slide up, please. What you'll -- so as the slide is coming up, what you'll see on the slide is, I'm going to show you the primary endpoint analysis data, and that relates to the -- so the slide is going to take a little bit of time to come up, but let me explain in terms of what [Audio Gap] actually, the human abuse in vitro study with samidorphan, that was done up to 30-milligram of dose. This is 3x the target dose of samidorphan. And the study was conducted in accordance, and that's there. So on the scheme here, you will see that the data for the primary endpoint, which is the difference of the Emax drug liking, visual/analog scale relative to placebo if stopped, and what you see is a point estimate as well as a 90% interval. And there were 5 treatments [Technical Difficulty] in the study. There were 2 doses of samidorphan used, the 10-milligram which is a target dose and a 30-milligram, which is a supratherapeutic dose, but 3x higher. The study also included the negative control is naltrexone at 100-milligram and also 2 positive controls is oxycodone and then pentazocine. The -- with the positive control that are oxycodone and pentazocinem, which you see as a dotted line in a B at 15 was considered to test whether the study had adequate assay sensitivity and the criteria there was a lower interval to be at least above [indiscernible] and that's in accordance with the FDA guidelines. You see that data that both oxycodone and pentazocine suggests -- data suggested that the study had adequate assay sensitivity. The next point of comparison was whether samidorphan was different than placebo and then the criteria that was used in accordance with discussion with the agency is that the upper 90% interval to be below 11, and that 11 threshold was set based on a [indiscernible] analysis or multiple historical HAP study data looking at the placebo responses and a prespecified criteria that was set as 11. Both samidorphan doses, 10 and 30, were well below that 11 threshold and similar to naltrexone. [Audio Gap] and I think these data also suggested that what -- the data we have in terms of an in vitro for a metabolite really didn't confer any effect, clinically speaking, whether it's abuse potential, signal or any of the PK/PD data that has been looked at, the ability of samidorphan to block remifentanil effects.

Yes. A quick follow-up question, if I can. so the way these studies were conducted, how long after the last administration of samidorphan were the subjects interrogated about their liking for the compound?

So it was up to 72 hours after their dose of samidorphan.

Okay. So the assumption is, at that point, there should have been no more new blockade from the samidorphan. And then that, if there was any effect from the metabolite, it would be unopposed activity at the mu receptor. Would that be accurate?

That's correct. So there was -- at 72 hours, there shouldn't be any new blocked and still [Audio Gap]

2 more questions for the agency.

Sorry, Raj, this is Tiffany. Before we move on, I do just want to emphasize that the agency agrees with what the applicant just presented as far as their human abuse potential study is concerned. So I'm hoping that, that covers Walter's question adequately.

Yes.

Thank you, Tiffany, for the clarification. Last 2 questions, Dr. McAninch.

Actually, this is Jana McAninch from FDA. I wanted to just follow-up on a question that was asked earlier. But if there's a new question, we should probably go to that first and then I can comment afterwards.

Dr. Meisel?

Steven Meisel from Fairview. Question for the agency here. There is a drug called Contrave that the agency approved a year or 2 ago for weight loss. That is in many respects comparable because it's got the naltrexone and it's designed for weight loss, but has the same risks, at least in principle, if somebody needs emergency opioids because they come into the ED after a trauma or something like that or require surgery or dental procedures or something. Could the agency please comment on the relative risk of opioid overdose or lack of effectiveness or those kinds of elements with Contrave versus the product the applicant is asking for today?

This is Judy Staffa from FDA. I think we did look into this, as you remember from our background materials as well as Dr. Mallama's presentation. There are some similarities because we saw this as a product that was approved for a population that contains an opioid antagonist but is not approved for use in a population that actually has opioid use disorder. So it was kind of a different group than the other populations out there who are administered naltrexone, as was talked about before. So we looked into our post-marketing experience, and I can turn it -- I'll turn it over to some of our speakers that are more familiar with those detailed data. But again, we also noted that the population -- this population is not exactly the same as the population taking a product that contains an opioid antagonist for weight loss. This is a different population. And so we included it for -- because it's the only product we know of that has that particular characteristic. And so I'm glad you brought it up because I think we do think it might be relevant. But we've done a review, and I think there's some limited information available. And I'll turn it over to, I think, Dr. Lopez, for that part of the review. Is that correct, guys?

And if I could just clarify my question because in both of these cases, the prescriber of the target drug, whether it's this 1 or Contrave, would be different than the people who would be prescribing an opioid for unrelated condition. And so it's that educational Phase IV type of stuff.

That's correct, yes. That's what we thought because we also noted that in the Contrave label, opioids are contraindicated yet when -- in one of our reviews, we noted that, I think it was around 11% of those patients did have evidence of an opioid when we looked at prescription data. And we did also note that when we look at the olanzapine population, the current patients treated with olanzapine, when we look at national prescription data, we also see that, in those patients, if we take a snapshot and look over the most recent year, we see that about 20%, 21% of those patients have a prescription for an opioid. So that was kind of we were trying to get an understanding of the differences between those populations. But again, Dr. Lopez can provide a little bit of information about what we saw in the Contrave review, but just remembering that samidorphan is not approved as part of any other product. So we really can't look directly at another product with samidorphan. And I think we've already talked about some of the differences between samidorphan and naltrexone. So Dr. Lopez, can you just provide a high-level view of what you saw in the review?

Yes. This is [ Alicia Lopez ]. And the review looked at data that came from the FDA adverse event reporting system. Within that review, we were looking specifically at interactions for patients who had an adverse event who are using both an opioid at the same time as they were using Contrave. And what we ended up seeing was there were 13 specific cases where we could identify somebody using those 2 medications concomitantly, and where they did experience symptoms that were associated with an opioid withdrawal syndrome. We also identified 1 case which was previously discussed about inadequate analgesic effect for somebody who was not taking an opioid regularly and had an acute incident where they needed to have an opioid for surgery. Now with that, it is important to note the limitations of the [ fares ] data as well as the strength of it. So as far as the structure of that data includes all marketed products approved and off-label uses as well as all patient population. So it is looking at a large portion of the patient population. The limitations to it though are that we cannot assess a causal relationship between the event and the product. Therefore, [ it's not like ] -- contain enough information for us to fully extract the relationship to the event. And then also we don't receive every report that -- of event that can occur. So there is usually an underreporting of the events within that data. Something else that I would like to point out that we've [ just encountered ] that there were some cases where a patient who was prescribed an opioid or prescribed Contrave and were using those concomitantly, the prescriber wasn't always aware of that concomitant use. So prescriber may have prescribed Contrave to somebody who has previously established on an opioid without being made aware by the patients that they were using opioid or vice versa. There were also evidence of nonmedical users. Somebody may have used a product that was not prescribed to them -- or misused, I should say. They were not using a product prescribed to them but it may have been prescribed to somebody else. And so then they have these 2 medications on board. And they wouldn't have had the opportunity to be counseled by a prescriber about that -- the potential for an adverse event.

And this is Judy Staffa again. I just want to add some more clarification. Thank you, Dr. Lopez. When I spoke about the prescription data that we saw that about 11% of patients who had a prescription for Contrave also had a prescription for an opioid. That raises concern because clearly, they were prescribed an opioid but we don't -- what we don't have a window into is to whether that was prescribed with instructions to stop taking the other product while taking the opioid or to hang on to the opioid. We don't know what specific instructions may have come with that. We just know that the patient had a prescription in their name for both.

Thank you. That's helpful.

We don't have any more questions from the members. But Dr. McAninch, if you want to just -- you could take over.

Sure. Thank you. Yes. This is Jana McAninch from the Division of Epidemiology. There was a question earlier on about off-label use of olanzapine. I just wanted to point out some information that is in your FDA briefing document on diagnosis associated with use of olanzapine-based on office-based physician survey. This is on Page 107 of the PDF or Page 49 of the appended Division of Epidemiology review. And basically, it looks like 31.5% of mentions were associated with the diagnosis of schizophrenia; 21.3%, schizoaffective disorders; 20.3%, bipolar disorder. So cumulatively, it's about 73% of those top 3 with the remainders consisting of different depressive disorders, anxiety adjustment and psychosis codes, in case that's helpful.

Thank you, Dr. McAninch. I think with that, we could -- we will now break for lunch. We could reconvene in 1 hour sharp at 1:00 as scheduled, 55-minute lunch. Panel members, please remember there should be no chatting or discussion of the meeting topics with other panel members during the lunch break. Additionally, you should plan to rejoin a little bit earlier, 12:45, to ensure you're connected before we reconvene at 1:00. Thank you. [Break]

It's the open public hearing. I hope everyone's back. We will now begin the open public hearing session. Both the FDA and the public believe in a transparent process for information gathering and decision-making. To ensure the transparency of the open public hearing session of the advisory committee meeting, FDA believes that it is important to understand the context of the individual's presentation. For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with the sponsor, its product and if known, its direct competitors. For example, this financial information may include the sponsor's payment of expenses in connection with your participation in the meeting. Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships. If you choose not to address this issue of financial relationships at the beginning of your statement, we will not preclude you from speaking. The FDA and this committee place great importance to the open public hearing process. The insights and comments provided can help the agency and this committee in their consideration of the issues before them. That said, in many instances and many topics, there will be a variety of opinions. One of our goals today is for this open public hearing to be conducted in a fair and open way, where every participant is listened to carefully and treated with dignity, courtesy and respect. Therefore, please speak only when recognized by the chairperson. Thank you for your cooperation. Speaker #1, your audio is connected now.

The depression -- dear committee members, thank you for the opportunity to address you today. My name is Phyllis Foxworth, and I am with the Depression and Bipolar Support Alliance. DBSA was created for and led by individuals who themselves having those experience. It is this first-person experience that informs our comments. We have not received funding to respond or to speak at the meeting today. However, we have received funding from a sponsor for activities at DBSA. Living with bipolar can be life-threatening. The risk of death by suicide is 10 to 30x higher than the general population. It is estimated that 20% to 60% will [Audio Gap] suicide at least once in their lives. Yet the history of therapeutic interventions to treat bipolar have been delayed due to suicidal stigma and negligence. Until the mid-'90s. The only medication available was lithium salt. Bipolar is far from a problem solved, many people discontinue a therapeutic intervention because of the side effects. A DBSA study revealed weight gain as a side effect that most lead patients to discontinue medication. This side effect, cannot only have a severe impact on individual's physical health, but could take a tremendous toll on their mental health. For example, the report for the 2018 DBSA patient-focused drug development meeting identify the inability to live up to one's professional potential as a major impact of the disorder. While there are a myriad of reasons behind this challenge, the role of weight gain brought on by therapeutic interventions must be considered. Not only do studies reveal that discrimination around body weight is rampant in our society, but employers often make hiring and promotion decisions based on a person's weight. This includes access to highly visible projects that can lead to promotion or outright dismissal. Whole health is just as important. 40% of respondents to a DBSA survey stated their overall health was worse since first experiencing symptoms. Contributing to this revelation is that many people are forced to weigh the risk/benefits of side effects, and make difficult decisions on whether to prioritize treatment of their physical health or their mental health. This is a very personal decision. Yet many within the medical and scientific community label people who choose to make a difficult decision to prioritize their physical health over the mental health as noncompliant. DBSA [ hopes ], if not patients that are noncompliant but the medical and scientific community that is noncompliant by not providing adequate therapeutic interventions. DBSA urges the committee to put the patient at the center of decision-making around approval of this application. When treating bipolar, success should be defined by considering the patient's whole health requirements and their own unique definition of a life well lived, If I have communicated anything, I hope it is this: patients count. Bipolar is not a problem solved. Patients want and need solutions that support a pathway to whole health and thriving. Individuals will evaluate the risk and benefits of solutions based on their own life circumstances. I respect there are many variables taken into account when considering this application. However, I urge the advisory committee to prioritize patient-desired treatment outcomes as part of your evaluation. Thank you for your time today.

Thank you. Speaker number two, your audio is connected now. Please unmute your phone.

Good afternoon. My name is Andrew Sperling. I'm with the National Alliance on Mental Illness. I've received no compensation from the sponsor to appear here today. NAMI does receive financial support for support programs and other activities from the sponsor. So I've been at the National Alliance on Mental Illness now for more than 20 years. And I can tell you when I was receiving the [ nominations ] largest advent organization advocating on behalf of people living with mental illness and their families. I've yet -- maybe in all my years at NAMI, I have yet to meet someone living with schizophrenia or any other mental illness or their family members, that's completely content with the treatments that are available. They all have complicated side effects. They take a long time. They often -- 6 to 8 weeks before -- after you initiate therapy before you see any clinical benefit. But we do know that some are better than others. And this was validated in the NIMH CATIE trial more than 15 years ago. And olanzapine had the lowest switch rate. In other words, as the proxy for efficacy. But we also know from the CATIE trial that there was significant weight gain and metabolic syndrome associated with olanzapine that you've heard about this morning. So this -- we believe at NAMI that patients should not have to choose between significant weight gain or efficacy -- effectiveness and dealing with their side effects. And that's why we want to see new or better treatments. This is not an incremental lens. This is a game changer for people that are at risk of obesity and all the complications of just diabetes that come with it. I'm going to close on a personal note. My brother [ James ] has been living with schizophrenia since 1996. He has tried just about every medication that's out there. I could go through the long list but I don't have time. But his longest period of clinical stability was around [Audio Gap] from about 2008 to about 2015 when he was on Zyprexa, when he was on olanzapine. But I can tell you his weight -- his -- he put on significant weight. My estimation, probably during that period, probably close to 70 pounds. And he now faces that dilemma of do I go with the most efficacious drug knowing that I'll have significant weight gain associated with it. Patients should not have to make this choice. We need to do better, and we need better treatments. And I appreciate your time, and thank you for your attention.

Thank you. Speaker #3, your audio is connected now.

Thank you. Good afternoon. My name is Luke Kramer. I'm the Executive Director for the STARR coalition. We're a nonprofit organization bridging the gap between mental health research and advocacy. In disclosure, the STARR has received 1 grant from Alkermes since our inception 6 years ago, and -- but we have not received any honorarium or other reimbursements for our participation today. I once worked with a man who I would watch cling to a telephone pole screaming. He later described being at the top of a tall building, being battered by storms and about to fall to his death, and he lived his life in terror. I also worked with another gentleman who spent every waking moment convinced he was dying, and all he could do was smell his own flesh rotting. There are countless stories like this, and I know many of us know countless people who, right at this moment, have had their lives torn apart by schizophrenia and bipolar. I'm honored to have my office in a day treatment facility where over 100 brave individuals with treatment-resistant, treatment-resistant mental illness come each day. They all know that we're meeting. Several of the submitted letters to you guys, but we talked extensively about this particular compound, especially the opioid component and their concerns. Even with those with the history of dependency, every comment came back around to, look, we trust our treatment team, and we're willing to try anything that can relieve our symptoms. Someone even asked will we even be talking about an opioid component if it was a proven drug for prostate cancer or heart disease. I've been watching this transcript kind of come up through the bottom. And imagine if we substituted the word schizophrenia and bipolar with the term terminal cancer. If we had a medication that we showed reduced tumors that had adverse side effects, and then the company decided to invest years of research and untold resources to transform that compound into something that would still stop the growth of tumors, but then would drastically reduce harmful side effects. If it was any other indication, would we be sitting here today debating whether people should have access to this life-saving therapy. We're not here with really any concern about the efficacy of this compound. We believe that the data speaks for itself. But we are concerned with people like me, and my peers and others who are living with a diagnosis, and a lack of urgency for getting new therapies to the public. We are concerned when we see respected biopharmaceutical companies peel away from this space because they've given up on this process or they see inequity with mental health therapies. We all know that recovery is much, much more than just swallowing a pill. But we also know without medications that are proven to be effective, we -- many of us cannot even begin to get a foothold to begin that journey. Please consider those who are looking to all of us to be a voice for them. Thank you for your time.

Thank you. Speaker #4, your audio is connected now.

Good afternoon, and thank you for allowing me the opportunity to speak with you today. I have not received financial consideration from the sponsor to speak. However, DBSA does receive funding for our sponsorship programs. My name is Kathy Bernstein. And while I work with the Depression and Bipolar Support Alliance, today, I speak on behalf of myself, a daughter and a caregiver to my mother. Today, I speak from our family's experience in caring for our mother, a woman who raised 6 kids, a husband and managed a chaotic household, who now at the age of 84, lives with dementia in an assisted living community and is in need of complete care. Today, I will share how medications designed to stabilize moods have had a life-changing impact on my mother, her ability to care for herself and subsequently, our family. Mom has lived with anxiety and depression for which she has taken medication, most of her adult life. The untimely death of 2 children only exacerbated her symptoms. As she aged, she began showing signs of dementia. Her cognitive and executive functioning deteriorated slowly, accelerating in times of increased anxiety. At the same time, mom began losing feeling in our hands and feet limiting her mobility. As I mentioned, mom's a super woman. She's an amazing cook. Social. Smart. She loves to read books. She could do the New York Times' Sunday crossword puzzle. And she was an avid bridge player. Two years ago, my mom fell and crashed, hurting her femur which changed her life. She was hospitalized, and surgery was performed. Because of her dementia and anxiety, and perhaps heightened by the quickness in which things around her happened as well as pain medication she was given, she became unhinged, disoriented, verbally abusive and combative. Her doctor added olanzapine to her medication regimen. And while it helped settle her down and made it easier to care for her, it had negative consequences, too. Weight gain, one of the known side effects, was dramatic. Mom quickly shut up and weighed from 140 to 160 pounds. For women with limited mobility to begin with, this was a game-changer. Rehabilitation was impossible. She was too weak to carry the excess weight that occurred in what seemed like overnight. Today, she's 100% wheelchair-bound. She cannot get up on her own out of a chair. She can't leave her room. She can't toilet herself or shower herself. She needs complete care. Because she is dead weight, I am no longer to take her out of the facility she lives in. She's stuck. And while she's less combative and calmer, her executive functioning has decreased significantly and she gets very disoriented at times. She can no longer play bridge, read books or do those crossword puzzles. My mom, the patriarch of our family, is gone, her quality of life is gone. She tells me every day that she prays for God to take her. There has to be more options that may help people like my mom who need medications to be well in one aspect of life that don't take away from other areas. Thank you.

Speaker #5, your audio is connected now.

Hi, I'm Linda Stalters, the CEO of Schizophrenia and Related Disorders Alliance of America, or SARDAA. We have received no financial support from the sponsor to participate in this hearing, and we have received sponsorship funding for our activity from the sponsor. I was formerly an [ APRM ] with background in education, inpatient, home health care and a solo practitioner, specializing in schizophrenia [indiscernible] bipolar and borderline personality illnesses. I now serve as an executive and advocate for the most severely neuropsychiatrically ill and pursuing improved treatment and services while educating and supporting diagnosed individuals, their families, professionals and the public. It is critically important for you to acknowledge these illnesses can be terminal illnesses without treatment. Over 50% of individuals living with psychosis do not receive medication or care. Thus without treatment, approximately 170,000 are homeless and almost 380,000 are incarcerated. I have cared for and heard reports from many patients that olanzapine was very effective in managing their symptoms. But they either discontinued without notifying their clinician or changed to a less-effective medication due to the unacceptable weight gain and slid into psychosis that's leading them to homelessness or incarceration. People with a brain illness such as schizophrenia or bipolar deserve treatment and care, not brutality of homelessness or incarceration. I actually had a patient once who said they would rather die of diabetes than give up taking olanzapine because of their symptom relief. We know the people with these illnesses die on average 10 to 28 years earlier than the general population. Some of these early deaths can be attributed to the side effects such as metabolic disorder, sometimes related to medication. There is more hope for people with schizophrenia spectrum and bipolar if they receive well-tolerated efficacious treatment. Don't people with these illnesses deserve a meaningful and fulfilling life? Of course, they do. Antipsychotic medications including olanzapine are the primary medications for people living with schizophrenia and bipolar disorder. However, symptomatic individuals and their caregivers continue to suffer and beg for symptom relief without side effects such as weight gain. There is little research and development for new and improved medications for schizophrenia and bipolar illnesses. Development of new efficacious medications is vitally important to improve and actually save millions of lives affected by these illnesses. The introduction of domain 3831 and olanzapine with samidorphan showing similar symptom management of -- as olanzapine without weight gain is an important medication advancement for people who struggle to live a meaningful life in the face of psychosis. Therefore, I support the approval of Alkermes 3831.

Thank you. Speaker #6, your audio is connected now.

Hello. Hi. I'm Michelle Hammer. I created a mental health clothing brand, Schizophrenic.NYC, to start conversations about mental health. And I received no funding from the sponsors. I think what's different about me speaking right now is that I have schizophrenia and I take olanzapine. And I have to say that olanzapine really did kind of change my life. It made my head calm. It made my brain quiet. And I was warned before I took olanzapine that it could really make me gain weight. And the first week I took olanzapine, I believe I gained about 10 pounds. But what I did is I told my doctor, "I gained 10 pounds in a week," and he said, "oh, here's another pill. Just take this pill, you'll lose that weight." And that was really convenient. All I had to do is take another pill which is good, but it would be convenient if I didn't have to take another pill. I think the more frustrating side effects of olanzapine is the complete sedation. If I take olanzapine before I go to bed at night, which I do, and just like last night, my partner started vomiting up blood, and I had no idea this even happened. Certainly, I said things in the middle of the night, like, "oh, I'm sleeping, leave me alone," which is extremely rude, but I have no memory that I said that. And if I had not taken olanzapine, I would have been able to help my partner who was vomiting up blood. But I couldn't because olanzapine knocks you out so hard. Also I've slept until 4:00 p.m. in the afternoon because of olanzapine. There's a lot of things that need to be changed. And I think it's not just the weight gain. I think there's a lot more options that can be changed about olanzapine, and psychiatric drugs, and everything for the -- for schizophrenia drugs. There's more than just weight gain options, I would say. And that's really what I wanted to mostly get across because weight gain is a big deal. I have friends that have gained a lot of weight on psych meds. And it just makes them extremely depressed, and that's going to affect your mental health as well. When you're extremely depressed because you're overweight, how does that help your depression? It really doesn't make any sense, does it? So really, there's my story, I take olanzapine. I like it. I wish there was something where I didn't have to take something from the side effects. But there's tons of side effects on it. So I think we do need to come up with something better, and I support what Alkermes is doing. Thank you.

Thank you. Speaker #7, your audio is connected now.

Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Meg Seymour, a senior fellow at the center. Our center analyzes scientific and medical data to provide objective health information to patients, professionals and policymakers. We do not [ accept by ] making drug or medical device companies so I have no conflicts of interest. We agree that weight gain and metabolic risks is a major problem with atypical antipsychotics because of the health risks and because weight gain can result in patients discontinuing their medication. Although ALKS 3831's study suggest that fewer patients taking the drug gain more than 10% of their baseline body weight than those taking olanzapine alone, we have concerns regarding the safety compared to an absolute difference between the groups below 14% and perhaps as little as 12%. The risk-to-benefit equation is particularly questionable because most of the patients on the weight gain study were male, black, overweight at baseline and were adults 55 years old or younger. None of us can predict how generalizable these findings would be for most patients who take antipsychotics. Many of them whom are white, some of whom are women, and many of whom are teenagers or over 55. As FDA the scientists noted in their review, there's a considerable risk that as an opioid antagonist, some [ of the drugs ] may lead to opioid withdrawal symptoms or to accidental overdose. Regardless of whether patients are prescribed an opioid or are abusing them, these risks are present. These risks are especially concerning for patients with bipolar disorder who are more likely to be using opioids than the general population. Labeling alone is not enough to mitigate these risks. Patients and providers [ through their ] actual data on the safety of the drug for those with opioid dependence. It is not enough to assume that patients and prescribers will heed or understand the warnings of the label. Although fewer than 14% of patients may benefit from this drug by experiencing lower weight gain, the risks are too high to justify approval. Thank you.

Thank you. Speaker #8, your audio is connected now.

Good afternoon. My name is Ralph Aquila. I am a psychiatrist. I've had the good fortune of having different roles in my 30-year career. I was actually involved in the [ HGAJ ] trials, which were the trials that helped launch olanzapine, commercially known as Zyprexa back in the day. What I do nowadays, I work on the west side of Manhattan in "Hell's Kitchen". Nowadays actually referred to more as Hell's Kitchen than [Audio Gap] because the neighborhood's changed quite a bit since when I started there. But what I continue to do is treat hundreds of patients mostly that have been on olanzapine. And I will say that olanzapine has been a major benefit for the vast majority of the patients that I've treated. One of the things that I think is important to underscore and something that I have been -- along with my team, I've been looking at since the early '90s is medical comorbidities. And I think some of the previous speakers underscored excess mortality, in particular in schizophrenia, of anywhere from 15 to 25 years sooner than the general population. Anything that can help us to mitigate these horrible adverse events. And in particular, I think, the new Alkermes product with the addition of samidorphan, is something that can be extremely helpful in the trenches when we're looking at how do we get patients with schizophrenia to move forward with their lives. Again, I've been involved in numerous research trials. I do believe that second-generation agents are superior than first-generation agents. And again, what I've seen is that olanzapine has been an extremely helpful medication. The weight gain that then can lead to other metabolic factors is certainly something that is a major concern. But I would say that as I have looked at the data of the new product, the Alkermes product, I think, that it's certainly worth trying in patients. I have spoken with my patients about it, and I know that they also would very much like to try an olanzapine that might mitigate the weight gain. So I am really interested in doing that. And I do apologize that left out at the beginning. I am not receiving any compensation for this presentation at the moment. But I am on the advisory Board for outcomes for Alkermes for this specific molecule. And have received compensation in the past for that but not receiving anything for today. I want to thank you for your attention, and good afternoon.

Thank you. Speaker #9, your audio is connected now. Speaker #9, you may want to unmute yourself.

All right. Can you hear me?

Yes, we can hear you now. Thank you.

Thank you for the support. This opportunity to address the joint meeting. My name is Alan Podawiltz, and I'm not being remunerated for this presentation today. However, I am a primary investigator at study sites for the Alkermes A 307 and 308 study, which supports the activities here in my department. I have no other sponsorships to -- [ consorts ] report. I'm a psychiatrist working in Fort Worth, Texas. I participated in the Texas Medical Algorithm Project in the late '90s that included at that time, a newly released olanzapine medication. I've been familiar with the olanzapine for treatment of schizophrenia for 23 years. I found olanzapine to be one of the most effective medications in the treatment of psychosis caused by schizophrenia and bipolar. I've seen patients recover quicker from their acute psychosis, remain in remission from their psychosis longer and attain significantly higher quality of life. However, by 2005, it became evident that the patients prescribed olanzapine could gain weight and contribute to what we now call metabolic syndrome. The weight gain metabolic concerns often limited my long-term use of olanzapine. I was pleased to be invited to this study of this new medicine. I have 3 cases I'd like to report: one from 1998, and the 2 most recently from the medication being discussed today. Case 1, 38 year old male, 20 years of debilitating symptoms of schizophrenia. He's been hospitalized greater than 20 times in local and state psychiatric facilities. I initiated treatment with olanzapine. As he improved, not only did the psychosis stabilize but he gained insight into his chronic illness. As the standard, I ask about the dose of medication side effects and if he thought the medication could be increased or decreased. After about 2 months, he, without my prompting this time, stated that he the thought the dose should be increased. I increased the dose of olanzapine. He had worked as a bellman at a local hotel off and on for years. In the spring of our work together, he decided to start a lung care company. By the end of the first summer, he had 5 employees. He diversified for the winter to include holiday [ lives ]. He never returned to the hospital in that 3 years I worked with him. He did gain 30 pounds. I'd like to note that I am not aware of which arm of olanzapine-samidorphan study, the next 2 cases were randomized. Case 2. 21 year old female, first break schizophrenia caused due to dropout of college of her junior year. She was really psychotic with derogatory [ interim ] stimuli and intrusive [ coronary ] thoughts that others could hear her voices in her head. Over the course of about 4 weeks, she admitted to less and less intrusive thoughts and the belief that others could hear her thoughts. She stabilized over the next 9 months and subsequently returned to school. No weight gain. Case #3. 20 year old male, first break schizophrenia going to school on an athletic scholarship. Experienced a significant psychic break requiring psychiatric hospitalization. Over the course of a year, he's no longer isolating at home. Does not feel that others are out to hurt him. He's currently in the process of interviewing for a public service job. No weight gain. The medications discussed today would be my choice for acute and long-term treatment of schizophrenia and bipolar disorders. Thank you.

Thank you. Speaker #10, your audio is connected now.

Okay. Thanks. My name is Chris Bullard, thanks for having me. I live with bipolar, one diagnosis. I work in the field of mental health with Sound Mind Live. we're an organization focused on ending the stigma around mental health through the power of music. I've also, for the past 2 years, led a music support program for those diagnosed with mental illness at not only here in New York City. I have not received payment from the sponsor to be here today. Sound Mind Live, as an organization, has received fiscal support for some of our events. And I'm here to tell the committee about this huge impact and side effects that olanzapine has had on myself and those I have worked with who live with bipolar disorder. And after each time I've been hospitalized, I've been put on olanzapine. And each time, while, it's really helped me to stabilize have also been extremely reticent to take it because of the side effects that's been known to have. And since my initial diagnosis, I've also sat in countless bipolar support groups. And while these groups are more than anything, usually a source of hope for those attending. They can also sometimes bring a sense of fear and discouragement around certain medications because of the side effects. And olanzapine is definitely one of those, in some cases. In these groups I have attended, we've consulted people who now live with severe weight gain issues, diabetes and when you were pointed to olanzapine being a big contributor to this and also seen a number of people go off their med and refuse to take olanzapine after their first hospitalization because they fear they'll see the same kind of side effects and weight gain in the long term. And I myself have really struggled also with that sedation impact of it, missing work, leading me personally to take less of the drug than prescribed in the past, which I regret. And hopefully the mental health community can really work towards this weight gain issue and the sedation effects that also were mentioned earlier. I think all medications tend to have side effects, but these side effects shouldn't make the very prospect of living a healthy life unachievable. And olanzapine has this immense potential to really help stabilize individuals and speaking from lived experience can really help with psychotic features. However, it's still currently among those drugs that with people I've worked with and spoken to kind of has led to people having like medication fatigue of continually searching for a medication that's not going to lead to these side effects that are causing things like severe weight gain or heavy sedation, and we can make any strides towards lessening those side effects. I think it's a huge step in the right direction, which is why I definitely supports trying to reduce these side effects in terms of weight gain associated with the drug. So again, really appreciate you taking the time to listen to me today, and thanks.

Thank you. Speaker #11, your audio is connected now.

My name is Jason Wright, and I have received no compensation from the sponsor but have in the past, been involved in an advisory Board. I'm happy to be able to tell you my story. Not too sure where I'm going, but [ what ] The story of where going is being written still. Real quick though, I'm the editor and founder of Oddball Magazine, and the President of the Oddball Foundation, a 501(c)(3) pending nonprofit foundation, newly established to promote mental health and social justice advocacy through art. I'm also a podcaster from The Oddball Show. Have written 2 books and a third on the way. And I am a proud husband of [indiscernible] Wright. And I have a dog [ OB ] . It's a [ dog ]. But it wasn't easy to get where I am today. My medication began at 15 when I was diagnosed ADHD. I did not realize that this medication that I would take would soon become a catalyst to more medication over 25 years later. I think that I might be on the right regimen, but I still think there is room for adjustment. In that 25 years, I've struggled to find the right medication, the right living situations, the right doctor, the right job, the right life. I went from a happy, care-free kid to a problem-riddled, confused and sad adult. I was a smoker and a jerker, and I used that along with my medications to get through, and I did. I also and practiced guitar as well. In that 25 years, I went from a thin kid to a fat kid to a thin adult to a fat adult to where I am now, which I would say was the former and sadly now the latter due to an unprecedented time full of uncertainty and walking out the street and jeopardizing my safety of myself or others. The extreme nature of this pandemic and the sedative nature, it has caused and made me gain about 27 pounds from where I was at before. But before that -- before this pandemic, the weight was from the meds. That 25 pounds that I gained back, I had lost from the 30 pounds I gained from the weight [ that came with the ] antipsychotic, olanzapine. I tried my hardest to get off olanzapine. Though I noticed the effects were good, but I had to make a choice of slightly effective medication with horrible weight gain causing me a bad self image and possibly so much more problems, or make a change, a leap of faith to basically -- the last med that there was that I could take and it's not great, but it's what I have right now. I live a good life. But I stayed -- if I stayed on the olanzapine, I don't know where I would be. I've heard people gain much more than 30 pounds on that drug but I still know people who take it. I couldn't let myself be a meds statistic due to medication. I wanted to speak up to say that the reason that this medication doesn't always work for people is because the side effects are often worse than the original feelings of sadness, auditory hallucination or whatever it may be. And sadly, once one is on medication, it seems almost impossible to get off of it. That is a difficult pill to swallow. But where I am at now, drug-free, healthy, successful, smoke-free for almost 4 years now. I couldn't get there without the help of the right medication. I am still working on the right balance because we are trying to balance something. But one thing that I think I might have finally got right is my meds, and that took about 25 years to do. And there are still days when I feel that I'm not where I want to be, but that's the ups and downs of life, I guess. Please consider my story only as a recovery story because that's sad, confused adult is no longer confused nor sad. I'm doing really well. Excited for what the Oddball Foundation is going to do for the mental health community and how this world will change once we can change it. Thanks for listening. I am Jason Wright, Editor of Oddball Magazine, podcast host of the Oddball Show and the President of The Oddball Foundation. If you want to find out more about us or The Oddball Foundation mission, please visit oddballmagazine.com, The Oddball Foundation. Thank you.

Thank you. Speaker #12, your audio is connected now.

Nice to be with you all this afternoon, and good afternoon. I'm Roger McIntyre, Psychiatrist and Professor of Psychiatry and Pharmacology, the University of Toronto. I also head the Mood Disorders Psychopharmacology program at the University Health Network in Toronto and very pleased to say I'm also the Chair of the Scientific Advisory Board for the Depression and Bipolar Support alliance. Affiliations, professional aside for a moment, what I am is I'm an advocate, and I've been a passionate advocate of people who have been affected by mood disorders where I've been privileged to be employed for the better part now of over -- almost 2.5 decades now. And throughout that journey, wearing the hat as an advocate, as a clinician, as a researcher, as a person involved in policy and best practices, it is abundantly clear that the state of the union for treatments in bipolar must improve. It is a national health priority that treatments must improve, and access to alternatives is a priority. We didn't need COVID-19, but COVID-19 has only amplified the urgency. In my experience and certainly in my research, what has certainly been the case is that individuals who are so privileged to have access in a timely way to high-quality coordinated health care, the great majority either do not sufficiently respond and/or have problems with intolerability. In weight gain, with psychotropic agents broadly, especially with the second-generation class, with certain members of the class, including but not limited to olanzapine, being in fact one of the most common offending agents, the implications of weight gain, you've been hearing about it. It's obvious. I think it's very clear. It's not something that people desire to have weight that's inappropriate to their height and their overall health. And we know that it not only leads to people stopping medication but also leads people not even starting medications in the first place. And that unnecessarily prolongs the suffering and that unnecessarily leads to what could be progression of the illness. There's also a story unfolding and a very concerning story that, as people gain more weight, it could have very significant adverse effects on their cognitive abilities and certainly, don't want to make more harm to people who are affected for bipolar disorder. So it's very clear that having an option would be generally welcome. Having a specific option addressing the unmet needs in serious mental illness with a -- who are candidates for antipsychotics and a treatment with lower weight gain liability would certainly be a tremendous alternative and option for our field. I'll finish by saying I have not been provided any compensation for being here today. Thank you, everyone, for giving me your attention.

Thank you. Speaker #13 has withdrawn. So we'll proceed to Speaker #14. Speaker #14, your audio is connected now.

Thank you. My name is Debbie Plotnick, and I am the Vice President for state and federal advocacy at Mental Health America. I have received no compensation for being here today, although Mental Health America does receive some financial support for its programs from the sponsor. But I come here today to talk about my personal experience as a family member of a daughter with bipolar disorder and through my personal training as a social worker. And my daughter was experiencing the effects of her bipolar disorder, including extreme suicidality in early adolescence. And one of the medications that she was given straight away was olanzapine. And as I look back at her pictures at that time, she had been a skinny kid. She [ has a ] built like her dad, she's long and lean. But her pictures from late in middle school and high school show a very chubby individual, and that is because of olanzapine. And that was something that she then refused to take going forward. At the same time that my daughter was experiencing this, I was in graduate school as a social worker. And one of the programs that I worked for was club health, where I met people at all different ages, many of whom were taking olanzapine. And the reason I know they were taking olanzapine was as soon as they started taking it or when I met them, they didn't necessarily tell me their medication, many of them did, they were very heavy. And the young people will tell me how uncomfortable this made them, how it was -- how do you find a boyfriend or a girlfriend, and they would go off their medication. The people who are my age, and here I was, a slightly older student going back to graduate school, they were my age and they had diabetes. And they weighed a lot, a lot more than they should have. And many of the people that I worked with started dying. And they would have heart attacks, and they would die from many things related to metabolic disorder, and it was heartbreaking. But in my work now, one of the things that I work on is making sure people have access to medication. Well, many people don't want to take the medications that they have access, such as olanzapine. And they are blamed for that as being noncompliant. But what we have to do is we have to offer people alternative that will help them in getting better, in feeling better, engaging in life and not having to choose whether or not they die in their 40s or they are able to have ongoing relationships. Thank you.

Thank you. Speaker #15, your audio is connected now.

Good morning. My name is Dr. Jacob Ballon. I'm a clinical associate professor at Stanford University. I am the Medical Director of our lock inpatient acute unit at Stanford as well as the Co-Director of the INSPIRE Clinic, which is our psychosis clinic focusing primarily on people in early psychosis. I have previously been on an advisory board with the sponsor and an investigator in one of the trials, and I want to focus a bit on my experience with this drug and with the patients in the trials as well as thinking about where this drug fits in clinically beyond that. I have been part of the ENLIGHTEN-Early study, looking at the use of this medication and people in the early stages of bipolar illness or schizophrenia. It's been remarkable to me that when I look at not just the part which has been randomized, where I'm not sure which medication a person might be on, but when I look beyond to the extended phase of the study, where I know it's open-label and people are on this medication, how tenacious people have been in wanting to maintain this medication, including probably a great personal expense in order to be able to stay in the study, but they might otherwise have to discontinue because they would be too far away to logistically return otherwise. Many of the patients that I have in this continuation phase of the study are working full-time or have resumed going to school full-time, a testament largely to the efficacy of olanzapine that we have heard many people talk about but also their general willingness to stay on this medication because of the fact that they've been able to tolerate it very well. There's no secret that olanzapine is an excellent medication but as the weight gain can cause all kinds of problems such that I would typically want to use -- I would otherwise want to use olanzapine for people in the early stages of the illness, but I often cannot because of that risk. Beyond the issues with adherence to medication, I don't want to subject people to potentially life-shortening side effects and life-altering morbidity. I'm looking forward to hearing more of the results of early psychosis because I think this medication fits very well in that stage of illness for people, where we can hopefully get people to take a medication that they find both very effective for their psychiatric illness and tolerable to take but on, of course, sustained engagement as they get to treatment and feel uncomfortable with their medication for a long term. You've heard people talk already today about how challenging that can be. Weight gain is an important side effect, and it's not the only side effect, but it is one that sets the course for a number of other metabolic problems that can come down to a lot. And so I'm very strongly in support of this medication. I have seen the benefits for people already, and I thank you all for your attention.

Thank you. Speaker #16 has withdrawn, so we will proceed to Speaker #17. Your audio is connected now.

Good afternoon. Can you hear me okay?

Yes, they can hear you.

Yes. Oh, very good. And thank you for teeing up my slides there for me. So I am Michael Abrams, a health researcher at Public Citizen, and I have no financial conflicts of interest to disclose. Next slide, please. Regarding efficacy, the primary endpoint for this medication is, of course, weight gain. As we've heard evidence presented, it shows that the addition of samidorphan does not eliminate weight gain associated with olanzapine administration. It only reduces that weight gain by an absolute amount of approximately 2%, well below the 5% goal for weight loss drugs cited in the FDA briefing document, on Page 8 specifically. Additionally, this small effect was not coupled with same direction, significant differences across a number of metabolic and cardiovascular health indicators, including mixed results regarding weight -- waist circumference and blood pressure changes and unfavorable glycemia trends summarized by these 2 slides from the sponsor on the left and the FDA on the right. Next slide, please. Moreover, unfavorable or no results regarding lipid parameters, evident in the left panel, a slide from the sponsor, and unfavorable glycemic trends are highlighted in the center graph of the right panel as well. And as I said, both slides here are taken from the sponsor. Next slide, please. Regarding safety, there's, of course, been expressed a clear concern noted by both the sponsor and the FDA that use of an opioid receptor antagonist, samidorphan, comes with substantial risk for opioid overdose and death as persons with psychosis have a specially high-risk for substance use disorders, slide on the left from Dr. Yagoda. And I must add, individuals taking olanzapine, as we know, have substantial risk from medication discontinuity, which adds to that concern. Additionally, use of samidorphan carries with it risk of inadequate pain control from opioids when such pain control is needed. The right-hand slide from the FDA reminds us that over 1 in 5 adults on olanzapine can currently use opioid analgesia. Next slide, please. Moreover, data on quality of life, which should be noted as a key patient-reported outcome does not support this medication's overall benefit to risk profile over olanzapine alone. And the last slide, please. Accordingly, Public Citizen concludes that this particular application for olanzapine-samidorphan as a treatment for schizophrenia, bipolar offers only marginal benefits in weight gain reductions at best, with no or few physiologic or patient-oriented improvements demonstrated by clinical trials. Moreover, it intensifies what can be regarded as real risks for opioid overdose and death. We thus recommend that the Advisory Committee vote no on the 3 basic questions listed here on this slide, which we'll be talking about later today, and moreover that the FDA not approve this combination medication. Thank you very much.

Thank you. Speaker #18. Your audio is connected now.

Thank you. My name is Dr. Andrew Nierenberg. I am the Director of the Dauten Family Center for Bipolar Treatment Innovation at Massachusetts General Hospital and Professor of Psychiatry at Harvard Medical School. I have been doing clinical practice now for close to 40 years and have also been deeply engaged in research, mostly in mood disorders and depression and for the past 20 years focusing on bipolar disorder. Within bipolar disorder, my expertise, both in terms of clinical practice and research is in bipolar depression. And as many of you may know, the options for bipolar depression are limited. And currently, there are only 4 FDA-approved treatments for bipolar depression, including the olanzapine-fluoxetine combination, quetiapine, lurasidone and cariprazine. Out of those, the olanzapine-fluoxetine combination has the largest risk of weight gain and metabolic syndrome. And because of that, it is actually rarely used. In many of the talks that I give and I ask people what they're actually using out of those 4, it's usually less than 1%. And the paradox is that for some patients, for reasons unclear, they will only respond to olanzapine-fluoxetine. So the fact that they can not only not be prescribed it by their prescribers and they can frequently reject that as an option because of weight gain emphasizes the importance of having the samidorphan-olanzapine combination together. Now I failed to mention that I'm not being paid to be on this call, but I have been on the Scientific Advisory Board for Alkermes. But it is really in my role as a clinician and a researcher that I advocate that this be approved. Thank you for your time.

Thank you. Speaker #19, your audio is connected now.

Thank you. My name is Joseph P. McEvoy, MD. I am a Professor of Psychiatry at the Medical College of Georgia. I do clinical trials and have done so for multiple decades. I have done clinical trials supported by Alkermes. And my clinical research has focused on the biology and treatment of severe mental illness, schizophrenia and bipolar disorder. In particular, I served as the co-principal investigator of the CATIE Schizophrenia Trials. The goal of somatic treatment and psychosocial management for severe mental illness is sustained remission of positive affect of psychopathology. Sustained remission implies that psychopathology, like hallucinatory perceptions, delusional beliefs, disorganization of thought, are brought to levels of mild or less. In other words, they do not interfere with or drive behavior, they're not intrusive or distressing. Uninterrupted long-term treatment with an effective antipsychotic medication is necessary for sustained remission. The primary outcome measure of the CATIE Schizophrenia trials was time to all-cause treatment discontinuation. Treatment continuation implied that both treating clinicians and treated patients agreed that an assigned medication was adequately effective and tolerable enough to keep going. Olanzapine won the CATIE Schizophrenia trials, that is among the non-clozapine antipsychotic medications. Patients and clinicians kept it going longer. As many of the clinicians who've already spoken attest, olanzapine helps patients with severe mental illness to sleep. It rarely produces subjectively distressing extrapyramidal side effects such as akathisia. But I believe the evidence is compelling that it reduces the intensity of positive psychopathology more effectively than the other non-clozapine antipsychotic medications. I believe that for these reasons, patients with severe mental illness assigned value to olanzapine in their economies. They take it more consistently, and they're more likely to achieve sustained remission. However, as has been noted, weight gain and undesirable changes in metabolism greatly reduce the use of olanzapine, denying its benefits to many patients. The olanzapine-samidorphan combination is only a small incremental step towards making olanzapine more tolerable and, therefore, more available to patients with severe mental illness. I believe that the addition of samidorphan only partially reduces the associated weight gain and does little, if anything, to mitigate the olanzapine's unwanted metabolic effects. However, this is very much the same pattern and the same constellation we see in the broader population struggles with obesity, insulin resistance and dyslipidemia. There are no single agents that produce miraculous improvement across everything. We combine treatments. I believe that the olanzapine-samidorphan combination takes us an important step closer to approved management of psychopathology with olanzapine accompanied by very acceptable levels of tolerability. And I hope to be able to welcome it into our armamentarium. Thank you.

Thank you. Speaker #20, your audio is connected now.

Hi. My name is Cecilia McGough. I am the Executive Director of the nonprofit Students with Psychosis, formerly known as Students with Schizophrenia. Our mission is to empower student leaders and advocates worldwide through community building and collaboration. Students with Psychosis and me, personally, were not financially compensated for our time or contribution to this testimony today. Students with Psychosis has not received grant funding through the sponsor. The community of people living with schizophrenia deserve more treatment options. Weight gain side effects from medications can lead to or contribute to unhealthy eating patterns, self-image struggles and staying compliant to medication. As a person who lives with schizophrenia and an active voice and participant within the schizophrenia community, I speak to students living with psychosis every single day, I can say with confidence that we are not satisfied with the limited options in treatment and advocate for more variety in care, for dose and medication choices to help empower schizophrenia community members. We want more options. I started my medication journey back in 2014 during my sophomore year at Penn State. Admittedly, no one comes fully prepared when faced with the diagnosis of schizophrenia. But what I was most certainly not prepared to navigate through was an additional eating disorder due to the side effects of medication, which impact my quality of life to this day. I gained 60 pounds in my first treatment, which further shattered my self-image issues and put strains of the romantic relationship that I was in, but more importantly, put strains on my relationship with myself. Having this eating disorder consumes my life and was an additional burden that should not have been carried. This changed how I ate, this changed how I spent my time, this changed my self-image and ultimately contributed to going off medication multiple times, [ 6 ] psych ward stays and additional behavior of self-harm, suicidal thoughts and depression. I felt like both my mind and my body were against me and at war. If I chose just to take my medication, I sided with my brain health. If I stopped taking medication, I sided with maintaining a healthy weight. Schizophrenia treatment should not feel like a war within yourself. This war can lead to serious consequences, such as unhealthy eating patterns, self-image struggles and staying compliant to medication. Empower schizophrenia community members by giving them more treatment options and help mitigate weight gain side effects. Thank you for your time.

Thank you. Speaker #21, your audio is connected now.

Thank you very much. This is Dr. Thomas Kosten. I'd like to thank you for this opportunity. And note that I've got no compensation from the sponsor for today's presentation. But in the past, I have had some grant support from the sponsor related to studies in opioid dependence, not related to this particular medication. I'm a professor of psychiatry, pharmacology and neuroscience at the Baylor College of Medicine, and I'm the Director of the Substance Abuse Division there. What I'd like to talk about is opioid antagonists and safety, and that there was a lack of interactions with older drugs accept opioids -- with other drugs that accept opioids, which are blocked. And if an opioid-dependent person were to take it, it would precipitate withdrawal. Samidorphan, though, is safe at the doses that it has been given, and there are actually several studies supporting that. Samidorphan is an opioid antagonist. I've worked clinically with antagonists like naltrexone and samidorphan for over 40 years and established the naltrexone treatment program at Yale in 1980, the first treatment program in the country for this. And this was for our opioid relapse prevention. I've published review papers on the safety of naltrexone and other opioid antagonists such as nalmefene. And as an example, naltrexone daily dose is 50 milligrams a day and has been safely given at up to 500 milligrams per day. That's 10x the usual dose. However, at 600 milligrams, which is again about 10x the dose, some obese patients have had elevations of liver function tests, but these were transient and reversible after stopping the naltrexone. Thus, this very low dose of samidorphan will be safe even with potential overdoses of the combined medication. If opioids are used while taking the samidorphan combination, nothing will happen. There'll be no adverse reactions, there'll be simply no effect of the opioids on pain or respiration, cannot overdose, it's completely safe. However, in response to one of the previous speakers who wanted to ask about pain management, pain management opioids is, in fact, possible. Sentinel can be used at larger dosages, and it will, in fact, provide analgesia. Samidorphan itself also has no increase in overdoses. In fact, it's reducing overdoses, it's a blocker. And the potential of, after discontinuing samidorphan or this medication, or any opioid antagonist that you'd be more sensitive to having an overdose is a myth. There is no data to support that whatsoever. So this is a completely safe drug, and I think I laud the company for putting it together, and I think it is a service to the patients with bipolar and schizophrenia. Thank you very much.

Thank you. Speaker #22, your audio is connected now.

Great. Thanks very much. My name is Christoph Correll. I'm Professor of Psychiatry and Molecular Medicine at Zucker School of Medicine in New York as an adult psychiatrist. And I'm also a child psychiatrist and I'm the Chair and Professor of child psychiatry at the Charité University in Berlin. I've been a consultant, adviser, data safety monitoring board member for most of the companies that make antipsychotics and other psychotropic medications. I've been an adviser and also author on data for Alkermes ALKS 3831. I am not receiving any compensation for my giving my opinion during this public hearing. Since I've been involved in part of the data collection and interpretation, I will not speak at all on the data. Obviously, the committee has a difficult task of evaluating the benefits and potential risks, and that's never easy. And obviously, there are lots of data on the table to do that with. But I want to speak as a clinician and clinical researcher with over 20 years of experience and also having spent really half of my life researching side effects. Because I'm a child psychiatrist, I see side effects quite a bit in a vulnerable antipsychotic-naive population. And to put the olanzapine risk into context in our satiety study that we published in 2009 in JAMA. These were children and adolescents who are antipsychotic-naive, no more than 1 week of exposure. And many people now get olanzapine as one of the first choices in the emergency room or also on units. The mean, the average weight gain in 12 weeks was 19 pounds, 19 pounds with olanzapine. This is not the chronic patients you're seeing in these studies. Actually, the number needed to harm -- weight gain, more than 7% of the same, was 1 for olanzapine. 14% in these [ answers ] was 2 for olanzapine. And 21% of weight gain in 12 weeks, the number needed to harm was 4. So we have a medication that can be quite helpful, and you've heard other testimonies, but it has a lot of weight gain. And making the weight gain smaller, even though this will not be a perfect drug, even though we have other antipsychotics that have less weight gain or almost no weight gain at the moment, there are patients that require olanzapine and who only respond to olanzapine. And if you or I had to take a medication that works for us and has special efficacy and it has a lot of side effects, and we could take the exact same medication in terms of efficacy but had less weight gain, would we not want that? Well, weight gain has multiple implications. Adherence goes down. And Melissa DelBello, who also put a written statement in, and I were co-PIs on -- at PCORI, Patient-Centered Outcomes Research Institute-funded study where we randomized children and adolescents who are on antipsychotics, including also olanzapine to receive metformin or not. 1,460 patients have already been randomized. And we did a survey with NAMI and the Depression and Bipolar Support Alliance asking family members and patients, what should be our primary outcome for this Patient-Centered Outcomes Research Institute-funded study. And we were -- that said, it must be quality of life. What did the parents, what did the patients choose? Weight. We have a biological marker that's easy to measure. That is our primary outcome because patients and families recognize that many of the problems that come with second-generation antipsychotics, including poor quality of life, being bullied, having also problems with adherence center around weight. Now you've seen that at least in the data, there seems to be little of a metabolic signal, but we know that weight gain over time and waist circumference increase is related to metabolic outcomes. And when real-world patients are treated, as I told you in these antipsychotic-naive patients, there will be a lot of weight gain. And mitigating this can be helpful. When asking family members, and that's a study that Roger McIntyre published, who spoke earlier on...

Sorry. We're -- I think we have to conclude. I apologize.

Okay, then. So the -- okay then the last point is there must be also a consideration of risk, obviously. And I want to say that less than 10% of people with schizophrenia have opioid dependence. And I believe that with the REMS program, that should not deter the 90% of people with schizophrenia who can potentially also be treated with olanzapine to not receive it.

Thank you. Appreciate your point. Thank you. The open public hearing portion of this meeting has now concluded, and we will no longer take comments from the audience. The committee will now turn its attention to address the task at hand, the careful consideration of the data before the committee as well as the public comments. We will proceed with the questions to the committee and the committee discussion. I would like to remind public observers that while this meeting is open for public observation, public attendees may not participate, except at the specific request of the panel. After I read each question, we will pause for any questions or comments concerning its wording, then we will proceed with the voting. Our first 3 questions are voting questions, Dr. Bonner will provide the instructions for the voting. Dr. Bonner?

Thank you, sir. LaToya Bonner, DFO. Questions 1, 2 and 3 are voting questions. Voting members will use the Dolby Connect platform to submit their votes for this meeting. After the chairperson has read the voting question into the record and all questions and discussions regarding the wording of the vote questions are complete, the chairperson will announce that voting will begin. If you are a voting member, you will be moved to a voting breakout room. A new display will appear where you can submit your vote. There will be no discussions during the voting. You shall let -- you should select the vote -- the radio button, excuse me, that is a round circular button and the window that corresponds to your vote, yes, no or abstain. You should not leave the no vote check -- choice selected. Please note that you do not need to submit or send in your vote. Again, you need only to select the radio button that corresponds to your vote. You will have the opportunity to change your vote until the vote is announced as closed. Once all voting members have selected to vote, the DFO would announce that the vote is closed. Next, the vote results will be displayed on the screen. I will read the vote results from the screen into the record. Then the chairperson will go down the roster, and each voting member will state their name and their vote into the record. You can also state the reason why you voted as you did if you choose. We will continue in the same manner until all questions have been answered or discussed. Are there any questions about the voting process before we begin? Okay. I will turn the meeting back over to the Chair.

Thank you. Question #1, has the applicant presented adequate evidence that samidorphan meaningfully mitigates olanzapine-associated weight gain? Are there any questions about the wording of the question from the panel members? Please raise your hand if there are. I don't see any questions. No hands. So I think we could proceed. We will now begin voting on question #1. Dr. Bonner, you could take over.

LaToya Bonner, DFO. We will now move voting members to the voting breakout room to vote only. There will be no discussion in the voting breakout room. [Voting]

LaToya Bonner, DFO. Voting has closed and is now complete. The vote results are on display. I will read the total vote into the record for question 1: 16 yeses, 1 no, 0 abstain. I will turn the meeting over to the Chair.

Thank you. We will now go down the list and have everyone who voted state their name and vote into the record. You may also provide justification for your vote, if you wish to. We'll just start with the first person on the list, and then you guys can kind of go down and proceed. Dr. Iyengar? Dr. Iyengar, if you can unmute yourself.

Hello?

Go ahead, Dr. Iyengar.

Okay, sorry. This is Satish Iyengar from Pittsburgh, and I voted yes. I was largely convinced by Study 303. Thank you.

Dr. Racher? Dr. Matthew Racher, can you please unmute yourself?

Yes. This is Matthew Racher, certified recovery peer specialist and patient representative from Miami. I voted yes. I do believe that there's a meaningful mitigation of weight gain associated with this medication.

Dr. Jain?

Hello, this is Dr. Felipe Jain. I voted yes. Thank you.

Dr. Krebs?

This is Erin Krebs. I voted yes for the population studied. I do think it's an important question about whether there would be mitigation of weight gain in people who are already on olanzapine because I think many people will wonder if switching to this new product would help them with weight gain or not.

Dr. Boudreau?

Denise Boudreau, and I voted yes for some of the reasons that have already been stated and would echo what Erin Krebs just said also that it will be interesting to see in a real-world population how this -- what the difference, and if there is a significant difference in weight gain.

Thank you. Dr. Fiedorowicz?

Yes. Jess Fiedorowicz in Ottawa, I also voted yes. I did want to add some sort of clarification here as well about why I did. My expertise is in psychiatry and obesity medicine, and usually we have a 5% threshold for clinically meaningful weight loss. And this 2.3% -- [ 2.8% ] doesn't cross that. But I thought like we really need to consider the tremendous individual variability in risk for weight gain with olanzapine and some other antipsychotics. And for me, that made the co-primary categorical outcome of more than 10% weight gain compelling and for which a 50% reduction was showing. And I don't often advocate for dichotomizing continuous data, but I think given the individual variability here, a good argument can be made. I also think there's compelling reason to prevent and focus on prevention of weight gain, given that once a new weight set point is set that the brain continues to defend at that mass. So I felt that this is indeed clinically meaningful even though it doesn't cross the traditional 5% threshold for weight loss studies.

Thank you. Dr. Meisel?

Steve Meisel from Fairview in Minneapolis, I voted yes. I do believe it is -- the data are compelling that the mitigation of weight gain is statistical and clinically meaningful. That said, I do worry that in the real world, the impact will be less than in controlled trials as it is with most drugs and most conditions. I echo what Dr. Krebs has talked about, there will be a desire to switch people stabilize on olanzapine to this with the hopes that they would be weight loss, and that's going to be a nuance. That's going to be very, very important, should this drug be approved as that what this is all about. This is with de novo. And there's going to be a fair number of patients who are still going to gain weight just maybe not as much. And so whether that is something that is noticed in the community of patients who need to use this is, I think, an open question. If you're only gaining 10 pounds, you otherwise would've gained 20 pounds or that sort of thing, still gaining weight. And how noticeable is that going to be in terms of the yes, but it could have been worse sort of messaging. But on balance, I think the data is pretty compelling that it's meaningful mitigation.

Thank you. Dr. Krishna?

This is Dr. Sonia Krishna from Austin, I voted yes. Thank you.

Dr. Dunn?

This is Walter Dunn from UCLA. I voted yes. Based on the clinical trial data, I do believe that evidence suggests samidorphan does mitigate olanzapine associate weight gain. However, this is a very narrow yes as I still have reservations about the generalized ability of the data. First, the mean weight of the subjects in these studies was barely overweight with the BMI slightly over 25. In my clinical experience, this is not representative of chronically ill patients, a large percentage of which were overweight or clinically obese. So if you start with a subject population that's at lower risk for weight gain because of this as indicated by their BMI status, either through a combination of genetics, diet and behavior, you're not really seeing how effective this drug might be in a high-risk population. The second issue is that I don't know if this effect would be replicated in a real-world clinical population where adherence will certainly be much more variable. Now will the weight advantages of this compound be seen as patients are only 50% adherence to medication? And this is a theoretical concern, but based primarily on the half life of olanzapine and samidorphan. So half of olanzapine is 33 hours, for samidorphan, 7 to 11 hours. When you're taking both -- when you're taking the compound regularly, both drugs made at steady state, you have good coverage. But what happens when you lose 90% of the new blockade after 24 hours, which is akin to skipping 1 dose and this is studied by the sponsor. So what is the effect of olanzapine on appetite and weight gain when you're losing that new blockade? Now I don't imagine you lose total weight prevention benefit, but perhaps the weight advantages are attenuated. Now that's to say that this is not necessarily a limitation of the study because this is something that wasn't addressed. But we could use it actually clinically motivate our patients remain consistent. We can tell them, we're going to give you this medication. It's going to be very helpful for your psychosis or remove symptoms, and you're not going to gain as much weight as you otherwise could. But you need to stay on everything today. And so potentially, if we have that information, we can use that to help motivate our patients to be more adherent for the meds. But this is an information we don't have, but that's needed to guide patient care and education. Thank you.

Thank you. Ms. Witczak?

Kim Witczak, consumer rep, I voted no. And I voted no for the word "meaningful" mitigate weight gain. The percentage is one thing, but we actually look at the actual weight gain as is minimal. And then compare to what you use as kind of the weight loss standard. I also think the quality of life information that was patient recorded falls into this as well. And again, to some of -- even just what Walter -- just previous speaker had said, just the real world, what's going to really happen? This clinical trial was in -- is very much set up in one -- we heard some of the things like this, who was in the clinical trial, the type of BMI weights. But also, I'm concerned -- people are still gaining weight. And just -- and I would be more interested to what are -- why is it some -- one person gains and the other one doesn't, and some of those. But again, the word meaningful is where I got stuck with. So thank you.

Thank you. Dr. Calis?

This is Karim Calis from the NIH, and I voted yes. And I don't think anyone here would be debating the efficacy of olanzapine or the combination of -- with samidorphan. It's certainly not for schizophrenia. But in terms of the point of hand, which is the reduction in weight and weight mitigation, I think we don't have any specific guidance on how to best assess the mitigation of antipsychotic-induced weight gain in non-obese individuals. And we do know that weight gain is a treatment-limiting adverse effect of olanzapine, which by all accounts is a very effective drug for these indications. And so what concerns me still is that we have a very modest effect at best on weight gain mitigation and certainly less-than-compelling effects on metabolic parameters. And that's been demonstrated here. But again, mitigating weight gain and inducing weight loss are quite different entities. And I think the standards for that are -- how we look at them is going to be different. I still would have reservations and concerns about sort of long-term safety data with samidorphan, and also with regards to the positive information on long-term adherence and long-term effects on metabolic parameters. But I still think that in terms of meeting the study end points as discussed with FDA, I think, that the applicant has met that bar. Thank you.

Dr. Jeffrey?

Jessica Jeffrey, UCLA. I voted yes for the reasons previously stated. But additionally, I want to make a mention that I believe it's important to note the participants taking ALK 3831 in study A303 experienced less increase in waist circumference and had favorable to solid blood pressure. Notably, both central adiposity and higher blood pressure are associated with poor medical outcomes. Thank you.

Thank you. This is Raj Narendran. I voted yes. I would like to just reecho the comments of Dr. Fiedorowicz and Dr. Jeffrey, the categorical delineation of number of people who gained 7% -- over 7%, 10% as well as the central adiposity based on the weight size is what guided my vote. I will pass it to Dr. Thomas.

Patrick Thomas from Baylor College of Medicine. I voted yes.

Maryann Amirshahi from Georgetown University. I voted yes for the same reasons.

Dr. Bohnert?

Amy Bohnert. I voted yes. The motivation for doing so is very similar to those outlined by Dr. Meisel, so I won't repeat those comments. Thank you.

Thank you. Dr. Zacharoff?

Kevin Zacharoff, Stony Brook Medicine. I voted yes, but I would echo that it was a narrow yes, and that was with respect to with Ms. Witczak's comments. I think the word "meaningfully" could be determined to be different things to different people. I would certainly agree that for patients, any kind of weight loss or weight -- diminished weight gain would be a positive thing. But with respect to quality of life, metabolic outcomes, et cetera, et cetera, I wasn't 100% convinced. So it was a narrow yes for me. Thank you.

Thank you. We will now move to voting question 2. Voting question number two, has the applicant adequately characterized -- one second. I've been told to pause. Okay. We'll proceed again. Question number 2, has the applicant adequately characterized the safety profile of ALKS 3831, olanzapine samidorphan? Are there any questions about the wording of the question on the panel members? I do not see any raised hands. So I guess we could proceed to voting, Dr. Bonner?

LaToya Bonner, DFO. We will now voting -- to the voting breakout room to vote only. There will be no discussion in the voting breakout room. [Voting]

LaToya Bonner, DFO. Voting has closed and is now complete. The vote results are displayed. I will read the vote result into the record for question 2: 13 yeses, 3 nos, 1 abstain. I will turn the meeting back over to the Chair.

Thank you, Dr. Bonner. We will now go down the list again, and everyone who voted, state their name and vote into the record. You may also provide a justification for your vote, if you wish to. We'll start with Dr. Meisel.

Thank you. Steve Meisel with Fairview in Minneapolis. I voted yes. I do believe that we understand what the safety profile of this product is. I saw no serious signals about anything that would be unexpected or untoward. Clearly, the issue of what happens when a patient needs to have an opioid because of whatever surgery, fracture, dental procedure, whatever it may be, I think that's all the question, but I think we understand the question. And I think it's characterized that, that's going to be an issue to manage going forward. So I believe we understand what the safety profile is, and so I think it's been as well-characterized as we can get. Thank you.

Thank you. Mr. Matthew Racher?

This is Matthew Racher, a patient representative. I decided to abstain from voting on this question. Thank you.

Thank you. Dr. Jain?

This is Dr. Felipe Jain of Massachusetts General Hospital. I voted yes. However, it's qualified. The risks associated with use of an opioid antagonist, in general, are well-known and were well characterized with regard to schizophrenia in the studies we were presented. Regarding the schizophrenia-bipolar bridge, the 20-plus years of clinical research evidence we have with regard to use of an opioid antagonist in bipolar disorder is reassuring but not conclusive. And that's because samidorphan is a new molecular entity. I'm concerned that bipolar disorder has symptomatology and neurobiological underpinnings that overlap with but are not identical to those of schizophrenia, and that further safety research in bipolar disorder should be conducted. Thank you.

Dr. Krebs?

This is Erin Krebs, and I voted yes.

Thank you. This is Raj Narendran. I voted yes. I will pass it on to Dr. Fiedorowicz.

Yes. This is Dr. Fiedorowicz at Ottawa. I voted yes. I agree with Dr. Jain about the need for future research in bipolar disorder. Thank you.

Thank you. Next is Dr. Iyengar.

This is Satish Iyengar from Pittsburgh. I also voted yes. And I also agree with the comments that Dr. Jain made about the need for the study for bipolar.

Thank you. Dr. Krishna?

This is Sonia Krishna at Dell Medical School at University of Texas at Austin, I voted yes. Thank you.

Dr. Dunn?

This is Dr. Walter Dunn from UCLA, I voted no. I still have questions regarding the implications of these metabolites samidorphan in terms of their new agonist activity. No, not so much in the context of the new potential as I think those have been adequately addressed. The question I have is, is there going to be an interaction of these metabolites with the opioids? So theoretically, in the 1 or 2 days post discontinuation of olanzapine samidorphan, you're going to lose the new blocking property for the samidorphan and only have the new agonist activity of the metabolites. But during the period, would patients get a higher risk for complications with prescribed opioid use, greater than that would be expected from naltrexone. So I'm not aware of any new agonist metabolites of naltrexone. So what's not clear is if the binding affinity of these metabolites is of any clinical relevancy. So for example, after you discontinued samidorphan with a standard, safe starting dose of oxycodone or hydromorphone, result in a greater incidence of adverse events due to the [ agonist ] effect with these metabolites, what should the label say? Should this label say, in the one that you gave after you discontinued this, you need to lower your dose of your opiates or avoid opiates in this window of high risk. Again, I appreciate that this is somewhat of a high safety standard. You have to consider multiple what-if clinical situations in regard to safety. But I think this is a burden shared with any intervention designed to prevent a harm rather than addressing existing illness or disorder. And this is a role of samidorphan, sort of not to treat an illness or disorder, but rather to prevent weight gain which is a potential pathway for increased morbidity and mortality. Thank you.

Thank you. Dr. Thomas?

Patrick Thomas, Baylor College of Medicine. I voted yes for some of the reasons stated. But I do share some concerns about potential interaction of opioid agonists not knowing the binding affinity as well as if someone were to abuse -- taking advantage of having that [ person falls ] some overdose. Thank you.

Thank you. Dr. Calis?

This is Karim Calis from the NIH, and I voted yes. And it's a qualified yes. I agree with Dr. Jain. I won't repeat what he said. But I would like to say that certainly with the new molecular entity like samidorphan, we'd certainly like to have more long-term safety data. But I believe that with the long-term safety extensions with a combination, I feel like the sponsor has attempted to gather additional information. But I think we need to continue to look at long-term safety with this combination product. And I'm particularly interested in metabolic parameters as well and glucose in particular. Thank you.

Thank you. Dr. Jeffrey?

Jessica Jeffrey from UCLA. I voted yes for the reasons previously stated. However, I want to support the comments of Dr. Jain.

Thank you. Dr. Zacharoff?

Kevin Zacharoff, Stony Brook Medicine, I voted no. And my no was really based on some of the reasons mentioned by Dr. Dunn. In addition to, while I do feel that there was a very good characterization of the safety profile of olanzapine, I have very strong concerns with respect to whether or not the safety profile of samidorphan was adequately characterized. Don't necessarily consider testing with remifentanil to be representative of what would happen in real life. I think there are other opioids that could have been utilized, such as morphine, for example. I have no clear understanding as to what the appropriate course of action would be in the event that somebody does have an unintentional overdose. Do we reach for a different antagonist? Do we give more of this medication? It's really not clear to me. So I have a number of questions with respect to the safety profile of the samidorphan component of this medication. Thank you.

Thank you. Ms. Witczak.

Kim Witczak, consumer rep, I voted no. I voted no for some of the reasons that Dr. Zacharoff just mentioned. But it's a new entity, combined product. We don't know if there's the long-term safety areas [ like you could ] see in the real world as well as all the off-label like kids, the elderly. I'm concerned that who's prescribing these? And are they going to really understand it? I think even just knowing that -- even within the population that was studied, with having a higher than the general public with abuse disorders. So I think there's just a lot of concerns of the unknown that we don't know at this time. Thank you.

Dr. Amirshahi?

Maryann Amirshahi, Georgetown University. I voted yes. And I think that overall, they did a good job of characterizing the safety profile as best they could. I think that there are some limitations, particularly with regard to the metabolites of the samidorphan. And then also, one area that I think needs further study is going to be how we do manage an opioid overdose when this medication is on board. Thank you.

Dr. Bohnert?

Yes. This is Amy Bohnert. I voted yes. Dr. Amirshahi just characterized all of my reasons very well. And I think there's a need for -- or sorry, all of my limitations to that, yes. And I think there's a need for well-designed post-marketing surveillance for this.

Thank you. Dr. Boudreau?

Denise Boudreau. I voted yes, and nothing to add.

Thank you. So we'll be now moving to question number 3. Question number 3, is labeling sufficient to mitigate the risks related to the opioid antagonist action of samidorphan? Are there any questions about the wording of the question from the panel members? I see Dr. Iyengar.

Yes. This is Satish Iyengar from Pittsburgh again. This question is pretty narrowly stated, and I was just looking at the applicant's proposed risk mitigation strategy section. And there was a good bit there, not only about labeling, but also education. And I was wondering, are we voting on just the narrow statement?

This is Tiffany Farchione. I would say that we're voting on the narrow statement. I think that -- in terms of any kind of the educational materials and things like that, if they happen to be promotional that would all -- or even just voluntary-type stuff, we're not necessarily looking at a REMS per se. What we would really like to hear from the committee, as you do register your vote, is your rationale on why you voted the way you did. So again, remember, all of these things that are part of labeling can be part of your considerations. And if you say, yes, you should tell us that in what way you think labeling can help. So I realize that may have been a little [indiscernible]. Hopefully, that got with your question.

Thank you, yes.

We have another question from Dr. Dunn.

This is Walter Dunn from UCLA. So in terms of the question, is it regarding labeling in general? Or is it a labeling base off of what information we currently have with the current studies? So I guess, maybe the -- kind of what I'm really asking is, it's sufficient, provided you get more information. Or is it just a general question that, if we get far more information, labeling would be sufficient.

So we're obviously talking about the application -- this is Tiffany Farchione again. We're obviously talking about the application that we have in front of us with the information that we have for review. We do have the discussion question coming up where you can talk about what additional data, if any, you would like to see.

Thank you.

We don't see any further questions. So I think we can proceed with the voting. I'll pass it to Dr. Bonner.

LaToya Bonner, DFO. We will now move voting members to the voting breakout room to vote only. There will be no discussion in the voting breakout. [Voting]

LaToya Bonner, DFO. Voting has closed and is now complete. The voting results are displayed. I will read the voting -- the vote results to the record for question #3: 11 yeses, 6 nos, 0 abstain. Now I will transfer the meeting back over to the Chair.

Thank you. So we'll do the same thing. We'll go down the list and have everyone who vote state their name and vote into the record. Please also provide a justification as requested by the agency. I think it would be very helpful. We'll start with Dr. Meisel.

Thank you. Steve Meisel with Fairview in Minneapolis. I voted no. In fact, I think labeling will do absolutely nothing to mitigate the risks related to the opioid antagonist, the qualities of this drug. I'm mindful of the fact that the prescribers of this drug will generally be a psychiatrist. The psychiatrist will seldom be prescribing opioids. The people who'd be prescribing opioids are emergency room doctors, orthopedic surgeons, oral surgeons, anesthesiologists. And their knowledge of [indiscernible] -- the prescribers of this, all they're going to see if they happen to look at a patient's medication list, would be the fact that they're on some form of olanzapine antipsychotic. And the idea or the notion that there is going to be an interaction -- a negative interact or a problem with the prescribing of the opioids is going to fly right by them. It's just not going compute. There's not going to be any alert. There's not going to be any knowledge of that. They're not going to go back and read the label of this drug when they're prescribing an opioid in an emergency room or in a dentist office or a [indiscernible] floor or places like that. And so I think the conundrum here is that the labeling is designed for the prescriber. But the risks are not with when the prescriber uses it because they're not prescribing opioids in general. It's going to be with the people who are caring for the patient in nonpsychiatric situations. And so I don't think labeling is a strategy that's going to be very effective at all. Thank you.

Thank you. Dr. Thomas?

I'm Patrick Thomas, Baylor College of Medicine. I voted yes, answering the question narrowly about labeling sufficient to mitigate the opioid antagonist action. [ The other thing ] I can say is about the other action that we just -- aren't as characterized. I think that -- I share some of the concerns that was previously stated how we're just in the real world, even though [indiscernible] a little more well known. Sometimes people don't say it. And there's ways to manage that in ER. So I think that, that would be manageable.

Thank you. Dr. Bohnert?

Yes, this is Amy Bohnert. I voted yes. I share the concerns of the other 2 but I felt like on balance, the labeling would be sufficient for patients to make an informed choice about those potential adverse consequences of insufficient analgesia, overdose risk if they were already on long term [indiscernible] that's not [indiscernible] for medication and that's all.

Thank you. Dr. Jain?

This is Felipe Jain, Massachusetts General Hospital. I agree with Dr. Meisel 100% that those prescribing the opiates are often going to be not those who are starting the olanzapine-samidorphan combination and that it will be far too easy for non psychiatrists to not realize what medication the patient is taking and what its properties are and that it has opiate antagonistic properties. Additionally, and I struggled with this piece, although -- but I think that this is important. Although labeling has been sufficient for opiate antagonists when used for other purposes, the combination medication is different and poses unique risks. Particularly, this could be started when a person is manic or psychotic, or suffers from cognitive disorganization, which often accompanies those states. And that improves markedly once they're on the medication. They may not realize what they have been placed on and the implications of it being an opiate antagonist. And the time when they're most likely to have been explained that it's also an opiate antagonist is when they're initially started on the medication. That's when the drug label will be provided to them. So it's also well-validated that people who are manic and sometimes feel those who are psychotic do not remember everything that occurred prior to becoming stable on the medication. I think we're at a risk of this for the patients to not realize the implications of this medication having been started on them due to their unique vulnerability in the time period when it is likely that they will be started on the medication. Thank you.

Thank you. Dr. Krebs?

Erin Krebs. I voted yes. Given, I guess, that labeling is never really sufficient, but in the context of everything else, I think this narrow question, I thought, yes, was appropriate. I just wanted to say that I think there are kind of the 3 main risks of opioid antagonism. The first 2 that are really related to patient selection are the risk of precipitated withdrawal that could occur in anyone who has ongoing regular use of opioids and physiologic dependence, and then the risk of overdose that might occur with someone who has a behavioral opioid misuse pattern. And those things, the prescribed number is really the one who's going to be reading the indication -- or reading the label and needing to know that information in terms of patient selection because certain patients will be at much higher risk or only at risk of those, not everyone would be. So I think labeling is most helpful there. The third area and I think the others have brought up is this risk of ineffective analgesia and just other prescribers not being familiar with the drugs, not looking and recognizing that this opioid antagonist effect could affect the benefits that patients might receive from prescribed opioids. Here, I mean, this is a real issue in clinical practice right now as we see increasing use of opioid antagonists for a variety of conditions. Certainly in my facility, we have ongoing quality improvement activities, trying to develop systems and processes to catch these things. Where it is most important is in the patients who have acute pain with a severe trauma or a planned surgical procedure. And those -- it's really a relatively narrow group of clinicians who are involved in those clinical scenarios. That's not all doctors, that's ER doctors, surgeons, anesthesiologists. And I think increasingly, there's a lot of increasing awareness of the issues here because these are common issues with lots of other antagonist or combination drugs right now. The broader group of patients and probably that 20% prescribed olanzapine and opioid concurrently, the broader group of patients is not having that very severe acute pain but is having maybe acute or chronic musculoskeletal, dental, less severe pain conditions for which, frankly, opioids usually aren't the best choice and are not more effective than other analgesics. So here, the -- if a doctor doesn't catch it, the patient, the level of harm is likely to be low and there are plenty of alternative. And frankly, often an opioid isn't effective and you try something else anyway. So I think there is some likelihood that, that word won't get out in terms of that. But I think the magnitude of harm there is much smaller. So that's my long story. Thank you.

Thank you, Dr. Krebs. Dr. Boudreau?

Denise Boudreau, and I voted no. My colleague, Steve Meisel, articulated very well my thoughts. The thing I would add to that is I think patients that are on opioid antagonist, they're at risk even after -- for a time period in which they did continue. And you have a population that's high-risk for using opioids in general, higher risk for substance use disorders. I really would want to see some broader education and also some post-marketing data. Thank you.

Thank you, Dr. Iyengar?

This is Satish Iyengar. I voted yes, largely in response to the narrow question. But I -- this is not an area that I know enough about. And I defer to the earlier speakers, especially people like Steven Meisel, who have articulated their reasons for saying no. Thank you.

Thank you. Dr. Krishna?

This is Sonia Krishna from the University of Texas, Austin. I voted no for the reasons that Dr. Meisel and Dr. Jain brought up. I would add that most patients are reluctant to even reveal their opioid use. And if they did have some rare emergency and they did have to go to an emergency room, they probably would just say that they're on the medical for schizophrenia, maybe they would say olanzapine. But in general, I don't think that they would remember the combination of it. And I think that other providers who are non-psychiatric would be very hesitant to stop such a medication. Most of those doctors who have called me have just said, oh, we're going to leave the psychiatric meds alone. We don't want them to all of a sudden have a flare or relapse. So I think that there would be a hesitation to stop the medicine if people would only treat it as a psychiatric medicine. That said, I also would say that it is going to be marketed and sold. Even the psychiatrist as a medication that [indiscernible] and heading towards somewhat of a weight loss. And so I don't think that there'll be much focus on this being an opiate antagonist. I think it will just be remembered as an antipsychotic with less weight gain. Thank you.

Thank you. Dr. Dunn?

Walter Dunn, UCLA. I voted yes based off a very narrow interpretation of the question. So based on the first part, is labeling sufficient? I interpreted that as asking can labeling be sufficient? And I said, yes. But based off of what's been discussed, what's been available in the presented data, I don't think the current information we have can provide sufficient labeling. I think more questions need to be answered. And then this is, of course, related to the second part of the question, my concern remains about metabolites. Now the question asks specifically about the opioid antagonist action of samidorphan. I think if we're only addressing that aspect of it, I think labeling is sufficient. If the question had said related to the action of samidorphan, I probably would have voted no. Thank you.

Thank you. Ms. Witczak?

Kim Witczak, Consumer Rep. I voted no. I voted no because I think there are -- well, first of all, there is the assumption that psychiatrists are the ones that will know this. But the reality is, if you even looked at the FDA side, it's nurse practitioners and GPs are handing this out. And I do think that the patient will be thinking about it from a weight loss or less weight gain. So the fact that it has -- and then I think the people who would be prescribing the opioids are things in others that the ER doctors, the orthopedics, the dentists, people necessarily that may or may not know or be familiar. And I think one of the previous speakers said with the psychiatric medications, everybody -- people who are not in that space tend to realize like, don't you never stop? You got to be really careful with psych meds. So I think there'll just be some hesitations. And then I think it's really important, and I think the sponsor did say the training. But I think it is going to be extremely important to all the nonpsychiatrists, physicians, dentists, everybody. And I think it's also something else that the FDA should be looking at is how it's marketed and really look at the advertising and the marketing materials that are going to go physicians as well as the patients. Because I think the general public is going to see the idea that it's weight -- less weight gain. And I think that's going to be an advantage. I mean it is a sales advantage over the current products on the market. However, to be able to save the other part of it, and that is really -- and not just in the little box that probably gets vastly read and over some pretty pictures because that's not what people are going to hear. They're going to hear the weight loss and the weight -- less weight gain. So I think it's going to be really an important part -- if should this drug get approved. Thank you.

Thank you. Dr. Calis?

This is Karim Calis from the NIH, and I voted yes. And I think, again, it's a qualified yes based on the narrow wording of the question. I certainly agree with a lot of the comments that have been made so far of Dr. Meisel, Dr. Jain, Ms. Witczak. I think those are very reasonable and certainly things that I've taken into consideration. Labeling of itself with any drug, as another individual said earlier, is limited. But nonetheless, it's something that is important. And I think one of the things that I'd really like to see, and this is part of kind of more of an educational campaign, is to avoid any kind of misinformation about expectations. This is not a weight-loss drug. The modest effect that we see on mitigation of weight gain does not obviate the need for healthy lifestyle, diet, exercise, et cetera. So I think these are all important considerations. Certainly, we can address some of the safety issues that have already been brought up in the warning section. Also in limitations of use about this not being a weight loss drug and so forth. But lastly, I would leave with this comment, and that is, I think it's also incumbent on the applicant if this drug were approved that in their promotional material and their educational campaigns to not exaggerate the weight mitigation efficacy of this particular drug because it is certainly very modest, there's still certainly very limited information that we do know about the metabolic effects -- the metabolic parameters. And so there are limitations, and I think it's really important to keep those in context. So I will stop there. Thank you.

Thank you. Dr. Jeffrey?

Jessica Jeffrey from UCLA. I voted yes for the reasons previously stated, most closely aligned with Dr. Dunn. But I did want to add that I do believe potential risk could be mitigated through careful labeling and broad education to patients and medical providers, including physicians, dentists and MPs. I think one of the challenges here is broad education about potential risk to providers in multiple specialties, including psychiatry, emergency medicine, anesthesiology and primary care, of course, among others. So really, the devil is in the details of the labeling and the educational plan. Additionally, I think there should be thorough post-marketing surveillance. Thank you.

This is Raj Narendran. I voted yes. I have utmost confidence that the agency can fix it with labeling, always. But no, I really think -- I want to -- I think we know a lot. There's a lot more awareness about opioid antagonists. We have so many products like buprenorphine, naltrexone, there's long-acting Revia. People are a lot more in tune in ER and surgical places to be aware. And I think what they -- when they're not, they can always be caught by a good pharmaceutical, the pharmacy-based program to kind of flag that. So I think labeling can -- there's no reason to hold this drug to a completely different standard than where we hold naltrexone just because it's more widely known. I think we need to definitely do an education of all the other providers, like surgeons and ER docs, that it is going to be very hard to overdose and override at such a high antagonist effect if the occupancy of this drug is pretty high. So I think labeling and education can probably sufficiently address this concern. I will pass it to Mr. Matthew Racher?

Yes. This is Matthew Racher, patient representative. I just want to echo some sentiments that were previously described. I -- yes, I believe labeling is sufficient. I do also believe that as people were saying before, broader education from psychiatric providers in a health care treatment network is needed, and it's almost a -- definitely not a replaceable service to have that broader education to help patients understand the importance of the -- any adverse effects from the medication as they adhere to their treatment. So yes, I voted yes.

Thank you. Dr. Amirshahi?

Maryann Amirshahi, Georgetown University. I voted yes. And once again, this is a limited yes in the context of a drug label. And I think we need to keep in mind that really, a drug label is a guidance, but really in the day-to-day operation of prescribing medication, it actually plays a small part. When you consider the relative risks of this medication from a toxicologic standpoint, and what we know about other opioid antagonists, the risk of poorly treated pain or precipitated withdrawal, while is an adverse effect, is very rarely life-threatening. Whereas obesity and the consequences of obesity, which are often poorly controlled in the patient population that this medication would be approved for, is actually much more real. And I think that we do need to have targeted intervention and educational initiatives with this medication, particularly focused on providers that will be prescribing opioid medications, for sure. And then I think we also have to consider that these are not the only hard stops, particularly because there are clinical pharmacists, clinical decision support, particularly within EMRs now. And so I don't think we necessarily need to withhold this medication just based on the labeling alone. Thank you.

Dr. Fiedorowicz?

Yes, I'm Jess Fiedorowicz, [indiscernible]. I voted yes, although I'm re-considering the word sufficient and I don't know I answered the question accurately. A robust education campaign targeting more than prescribers is certainly needed. And if you read the question carefully, I guess it implies that maybe you only need labeling, and I would strongly disagree with that. I share the concerns about Dr. Meisel and even though we have a lot more experience now with opioid antagonists, I think some of these concerns could be magnified because this is not -- this is a new entity, and it's not well-known. A well-known antagonist on naltrexone might be easily recognized by emergency room physicians or any physiologists, but they may not recognize that samidorphan is an opioid antagonist, especially when it's buried in with olanzapine in the same name.

Thank you. Dr. Zacharoff?

This is Kevin Zacharoff, Stony Brook Medicine. I voted no for a variety of reasons, including what we heard from Drs. Meisel, Dr. Jain, Dr. Krishna. But there are a couple of other issues that guided me towards the no, including what we just heard from Dr. Fiedorowicz, with respect to the lack of familiarity with samidorphan. First point is that all opioid antagonists are not the same. I have no clue as to what this medication really would behave like in terms of opioid antagonist that I am familiar with. We heard the sponsor mention this morning something like what VIVITROL has, which is a card that a patient would carry along with them. I have the VIVITROL card in front of me. And what it says is VIVITROL is an opioid inhibitor. Suggestions for pain management include regional analgesia and non-opioid analgesics. In the event that opioid therapy is required, it should only be administered by health care providers specifically trained in the use of anesthetic drugs and management of respiratory effects of potent opioids, specifically the establishment and maintenance of patient airway and assessed ventilation. The patient should be monitored closely in a setting equipped for cardiopulmonary resuscitation in the event that an opioid is given. And to that point, Roger Chou published a case report on the website in January 2018 for the Agency for Healthcare Research and Quality titled, A Painful Medication Reconciliation Mishap. And basically it was a patient who was on naltrexone who broke their neck and obviously required opioid analgesic therapy. And he states that the dosage necessary in naltrexone blocking effects could be as much as 6 to 20x higher than the normal therapeutic doses required in the absence of an opioid antagonist. I have no clue as to what that would mean with patients who were still within the window of effectiveness of samidorphan. Speaking about VIVITROL, which has a REMS. I think it was Tiffany who mentioned a REMS earlier. It's not clear to me as to why this medication wouldn't have a REMS, but I would not consider this medication, with its opioid antagonist effects, for both people who are candidates for opioid therapy or who are unintentionally overdosing as a result of abuse. I cannot understand why this would be treated as a traditional education initiative as compared to a REMS. And in line with that, I'd just like to reiterate the idea that when we did look at the briefing materials, we saw the demographics of who's prescribing olanzapine. And there were many other health care providers, other than psychiatrists, that were doing the prescribing. Any other disciplines. Lot of primary care. I have no clue as to what the disciplines were of the osteopathic physicians or the nurse practitioners or the PAs because it wasn't broken up for those groups by discipline. But in no way, shape or form would I consider this to be a traditional label covers black box warning, covers the risks. In the event that there is going to be that card that the sponsor discussed this morning, that sounds to be much more like a REMS initiative. And I'm not understanding whether this is some kind of blend of a traditional risk mitigation strategy versus a modified REMS approach. But that's why I voted no. Thank you.

Thank you. I think we -- this concludes our voting questions. We move to question #4, which is a discussion question. Question #4, a discussion question. What, if any, additional data are needed to address outstanding issues with Alkermes 3831 or ALKS 3831, olanzapine/samidorphan? Are there any questions about the discussion question, wording of the discussion question? Don't see any raised hands. So I think we -- I would suggest if there's no hands, people could feel free to raise your hand to start the discussion. I'll start. This is Raj Narendran. I mean my only -- I don't think it's like an outstanding issue or I think, but I would have liked -- I would like to see a receptor occupancy study in humans to kind of characterize what the new receptor occupancy is after, sort of, acute dosing, chronic dosing. And also, like after you stop it, how long does the occupancy persist? Because I think that -- some of that, if we know that, I think that could be helpful to tell providers like is 50% new occupancy after 24 hours of stopping, or 48 hours of stopping? And then the pain management could be sort of cut by half of what it traditionally should be or should be more than half of what it should be. So I think it would be important to kind of get that PET occupancy data, which is typically done around Phase 0, Phase I. So I think I would -- that would be one of my thoughts. It would also be good to see a long-term study with the comparator, like olanzapine, past what was done for a year and see if the weight gain, sort of like the weight mitigation persist. Those are my thoughts. Next question. There's -- Dr. Krebs, I'll pass it on to you.

Two things. First, on the benefit side. I mentioned this before, but we don't have evidence that this is a -- that switching to this drug from plain olanzapine would have any benefits in terms of preventing further weight gain, much less weight loss. And one concern would be that a lot of people would be switched for no benefit, but greater cost with this new product. And so I do think the additional research on people who are currently on olanzapine and have experienced weight gain would be necessary. And just needing to be very careful that this isn't marketed in such a way that -- that a lot of switching occurs that is not beneficial to patients or that there's no evidence for that yet. And then on the harm side, I am concerned. I voted yes on the labeling thing, but I am concerned that the wording of the label and the educational materials and the advertisements does, I think, need to be carefully looked at in terms of making sure that their -- that the language is clearly understood. Especially because words like opioid dependence really do not have a shared meaning among physicians, health care providers or the general population these days. And so making sure that it's very clear what the contraindications are and what the risks are and who's at risk, I think likely, really careful work on that will be needed. Thank you.

Thank you. Dr. Dunn?

This is Walter Dunn from UCLA. So before I begin talking about my concerns about additional data, I know I just want to say that I agree with many of the public comments about how olanzapine is a really important tool in our inventory. And then anything that we can do to make it safer could only benefit the patient. So -- and I think taking that into consideration, as you kind of hear my comments. So the first thing is, I mentioned this before about having more information about how narrowly does this weight benefit exist? Meaning that if we drop below a 90% adherence rate, is most of the benefit lost? Because, again, I think we have to think about real-world implications. And even though we prescribe medications and expect our patients to take it every day, I mean, that's not the reality. And so I think it's important for the clinician to know, does this -- does adherence have to be at such a high rate that this is not -- that these benefits are not going to be achieved in the clinical practice? So I think that's important for us to know when we start the patient on this because there's no guarantee even if they take it 100%, that we're going to prevent the weight gain, right? And that benefit is further mitigated by the necessity to be 100% adherent, then I think for some clinicians, it might not be worth the risk to place them on [indiscernible] with olanzapine. And second, the issue about will this be effective for patients who are already or well into the overweight range or obese range. So does the study population, as I mentioned before, these are patients who are barely overweight, and I suspect for a lot of these patients in clinical practice, they're not going to be below a BMI of 25, and will the same benefits be seen there. Unfortunately, I don't think some of these questions can be answered post-marketing surveillance, right? Those are designed to look at adverse events. So I think perhaps a long-term or a Phase IV study would have to be conducted through this. The second issue, of course, I think I've mentioned this, is the metabolite properties in regards to interaction with opioid analgesics. Again, it's still unclear to me. I don't know if the actual study has to be done to see if there is some type of added effect. Perhaps the labeling could say there is a theoretical risk that there may be increased risk of adverse events if you take in opioid analgesic within 24 to 48 hours of discontinuing samidorphan. But I think that experiment -- or that study can be easily done. You place the patient on samidorphan, get the steady state, do you discontinue within that acute window afterwards. You give them a standard dose of oxycodone or something like that and see if there is an increased risk or increased rate of side effects. And then finally, I think it's important to be clear in the label to really specify what this medication can and cannot do. And I think one of the most important outcomes is really that of metabolic syndrome as a potential outcome. So that was not addressed in this study. It was only 6 months. We saw that it did mitigate weight gain. We didn't see -- we didn't really see that much difference in terms of the other measures. But I think metabolic syndrome is really kind of what we're hoping to prevent long term. And you heard from many of the public commentators that they're excited about using this in first episode patients, or they're already using in first episode patients or early psychosis patients. And it's clear from poor guidelines that olanzapine and clozapine are ones you should not start with in early episode patients. But the reality is you've got really sick patients of inpatient ward. This is one of the most effective medications, and you have to go to it because there's really not other options. But my concern is if there's not good data about -- if this has an effect on metabolic syndrome, clinicians are going to assume, well, if I prevent, if I mitigate weight gain, I'm lowering the risk of metabolic syndrome. And so maybe my threshold to use it in an early episode patient is lower, right? And so that would be my concern. So I think data really showing either that it does or does not have an advantage for metabolic syndrome would be important in guiding prescribing practices. Thank you.

Thank you. Dr. Fiedorowicz?

Yes. Jess Fiedorowicz in Ottawa. I'd like to see studies that focus on the many concerns we've brought up about generalizability. In addition to the mention of switching from olanzapine to olanzapine/samidorphan not being studied, I agree with Dr. Krebs that we need to be very careful that we don't present this as a weight loss medication, but one that prevents weight gain, and this [ doesn't ] seem to be very clear in the indication. And as I read it, that's not super clear. As mentioned by Dr. Dunn and others, it's also not clear if there's generalizability in those with obesity, which may represent over half of those with bipolar disorder or schizophrenia, and those that would be most interested in preventing further weight gain. And somewhat concerns of a running theme that came up in the public comments that may represent some sort of early premarketing with statements suggesting that this medication may prevent weight gain altogether. That's simply not true. This committee seems to be in agreement that any weight mitigation is fairly modest. And this combination product is still absolutely obesogenic. I also have to respectfully disagree with the agency and the applicant related to the rationale for this bridging to a bipolar I indication. I think there's a series of somewhat tenuous bridges here between naltrexone and samidorphan. And then those naltrexone studies, as I mentioned before, were already pretty limited and then as well as schizophrenia bipolar disorder. While it's likely that these may be similarly effective, I don't think this bridging strategy establishes that indication. And with the FDA clarification, there seems to be this assumption that effects are entirely D2-mediated. And that ignores a burgeoning literature on the relevance of opioid neurotransmission and circuitry and mood disorders. And I think this concern is relevant for both efficacy and safety. So those are some of the concerns I wanted to bring up for future study to address generalizability. Thank you.

Thank you. Next is Dr. Krishna.

I agree with the previous questions and comments in discussion. I also wanted to add that I would like to see this research done in [ up number ] of patients. So I know a pediatric study would be planned for the future. But even the current demographics were done in age 40, with the average being there. And if we're looking at first episodes trying to prevent the weight gain increase to the same extent as it would be on just olanzapine alone, I would like to see it done in maybe 18- to 25-year-old patients, i.e., from data and experience that the weight gain risk is much higher in younger patients. And so if there is a medication that sees that it mitigates some weight gain, it's going to be used even off-label in pediatric patients prior to getting the FDA indication. And I would just like more data showing that, hopefully, there's a greater mitigation because the risk would be much higher for them.

Thank you. Next is Dr. Meisel.

Steve Meisel with Fairview in Minneapolis. So one of the elements here that I don't think I heard discussion about, and it wasn't intended to, but it will be important for clinical -- the real world. And that is a person who was already stable on olanzapine, what are the implications of switching them over to this product? But better and different. I haven't seen any data to that effect or any discussion to that effect. First -- plus, it's not intended to do that. But you know full well that in the real world, there'll be a temptation to switch somebody over it in the hopes that it would cause the weight loss. Well, what are the implications of doing that, both in terms of any value whatsoever? And what additional adverse events might crop up should that happen in the real world? And so that would be the -- an area of additional data that I think would be really valuable to characterize this particular product. Thank you.

Is there anybody else who wants to add? Just going to scan for any other raised hands. Ms. Witczak?

Kim Witczak. Yes. Somebody had just said this, but I really want to see more on the common off-label use of the drug. Like with bipolar depression, it's being used sleep disturbances. This is the real world. I know that some psychiatrists cannot believe it, but it is happening in the GPs, children, PTSD. So I'd love to see more what's in study in those populations, in those -- what's happening. And then as well, I'm going to reiterate communication. I think we have to be all over this, watching the way it is presented to not only the public, through direct-to-consumer advertising, but also how it is promoted to the doctors. The meetings that are happening, the communication. Because I could see the big [indiscernible] -- because that is one of the concerns with cyproxin and some of those antipsychotics, is the weight gain. And so it sounds like a really great product. And it's definitely, from a sales perspective, it is going to be the point of differentiation, and it's going to be an easy thing to go into a physician's office. But -- so I think we have to be really careful about how it gets promoted because we could have -- it's a lot of potential issues down the road.

Thank you. If people could take the opportunity to lower their hands, so I don't call on you again. See a couple raised. Okay. I believe -- Dr. Fiedorowicz, do you have comments?

Sorry, I didn't put my hand down.

Sorry. Okay. If there's no additional comments -- I don't see anybody else. I could try to summarize this. So -- and what I heard in terms of -- from the panel members for additional data would be maybe a PET occupancy study to look at the immunoreceptor occupancy studies, to look at switching from olanzapine to olanzapine/samidorphan to see if it's beneficial, studies to see if patients were not really adherent as prescribed at 100% and what does that mean in terms of the benefits and risks of weight loss -- not weight loss, weight mitigation, as well as opioid overdoses and opioid mixing -- opioid agonist risks. Will it be useful -- it would be useful to see more patients with high BMI being enrolled to take this and see if it helps them as well. There's definitely some questions are raised about studies are required to look at the metabolic properties of samidorphan, especially if it has agonist efficacy and how that interacts with potential other opioid agonist when prescribed. Is it going to lead to increased harm? Studies to address that could be helpful. There's also people who are interested to see whether there'd be longer-term studies, not just to mitigate the weight gain and the waist circumference, but also, can it prevent the occurrence of metabolic syndrome or mitigate the occurrence of metabolic syndrome. Data in bipolar disorder was necessary. It was raised. Also, people want to see data in younger patients, not just pediatric, but also 18- to 25-year-old patients who tend to be first episode with psychosis and mood disorders. And there was also an interest in looking at additional data in PTSD and other off-label uses for which this medication could be prescribed. There's also some thought that better to characterize long-term adverse events could be helpful as well in post-marketing data. So are there any other thoughts or closing comments from the agency? I hope this is useful and helpful.

This is Bernie Fisher. Yes, very helpful. Thank you very much. No additional comments from me. Thank you.

So with that, I would like to thank members of the public, the FDA staff, especially the technical staff. Specifically, I'd like to call out Dr. Bohnert for having conducted a great meeting through the virtual format and also the sponsor for having done a great job. We will now adjourn the meeting. Thank you.