Axsome Therapeutics, Inc. (AXSM) Earnings Call Transcript & Summary

Good morning, and welcome to Axsome Therapeutics conference call. [Operator Instructions] With that, I would now like to turn the conference over to your host, Mark Jacobson, Chief Operating Officer at Axsome Therapeutics. Mark, please go ahead.

Thank you, operator. Good morning, and thank you all for joining us on today's conference call. This morning, we issued a press release announcing the approval of AUVELITY for the treatment of major depressive disorder. The release crossed the wire a short time ago and is available on our website at axsome.com. During today's call, we will be making certain forward-looking statements. These statements may include statements regarding, among other things, the efficacy, safety and intended utilization of our investigational agents, our clinical and nonclinical plans, our plans to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development plans, commercial plans and possible intended use of cash and investments. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, which are only made as of today's date, and the company disclaims any obligation to update such statements. Joining me on the call today from the Axsome team are Dr. Herriot Tabuteau, Chief Executive Officer; Nick Pizzie, Chief Financial Officer; and Lori Englebert, Executive Vice President of Commercial and Business Development. Also joining us on the call today is one of the leading experts on major depressive disorder. Dr. Dan Iosifescu, Professor Psychiatry at New York University School of Medicine. Herriot will first make some opening remarks. Dr. Iosifescu will provide an overview of major depressive disorder, and he will then discuss the clinical trial results and clinical profile of AUVELITY. Following Dr. Iosifescu, Lori will provide an overview of our commercial plans. We will then open the line for questions. The questions will be taken in the order they are received. And with that, I am pleased to turn the call over to Herriot.

Thank you, Mark. Good morning, everyone. This morning, we announced that the FDA has approved AUVELITY for the treatment of major depressive disorder, or MDD, in adults. The Axsome team is extremely pleased to deliver this breakthrough therapy designated new treatment to the millions of patients living with depression. This approval comes at a time when it is most needed, given the recent sharp increase in the pressure prevalence. AUVELITY is the first and only oral and NMDA receptor antagonist and the first and only oral antidepressant approved by the FDA as rapid-acting for MDD. We are proud to be the company to make available to patients and their physicians a first new oral mechanism of action approved for MDD in over 60 years. This achievement is the combination of the tremendous and focused research and development activities conducted by the Axsome team and our collaborators. AUVELITY is protected by a robust patent estate extending out to at least 2037 to 2040. Our commercial team is ready and the launch of AUVELITY is planned for early fourth quarter. The approval of AUVELITY reflects Axsome's commitment to developing life-changing medicines for people living with serious central nervous system disorders. This commitment is further reflected by our broad neuroscience portfolio, which now includes 5 commercial or late-stage product candidates and clinical programs in 8 different indications. Our commercial portfolio now consists of AUVELITY for MDD and Sunosi for EDS in narcolepsy and obstructive sleep apnea. And our AXS-07 candidate for migraine is in NDA-stage. These agents are followed by our 2 Phase III stage product candidates, AXS-12 for narcolepsy and AXS-14 for fibromyalgia, both of which have potential NDA filings in 2023. Lastly, we have important follow-on indications, including Alzheimer's disease agitation and ADHD, which are in or ready to enter Phase III trials. Overall, our industry-leading portfolio targets disorders experienced by more than 100 million patients in the U.S. alone. AUVELITY was developed using Axsome's innovative and efficient approach to clinical development. This approach allowed us to initiate a Phase II trial in MDD, obtained FDA Breakthrough Therapy designation, complete our efficacy and safety studies and file the NDA with a priority review in less than 3 years. We are pleased with the label for AUVELITY, some of the key features of which are highlighted here. These include its novel, oral, NMDA receptor antagonist and sigma-1 receptor agonist mechanism of action, a broad indication to treat MDD in adults and its rapid and durable efficacy with demonstrated improvement starting at week 1 that is maintained and increased through the end of treatment. AUVELITY was also found to be safe and well tolerated with no psychotomimetic effects and no weight gain. The AUVELITY label contains the boxed warning of increased risk of suicidal thoughts and behaviors in pediatric and young adult patients required for all approved antidepressants. AUVELITY is not approved for use in pediatric patients. With that, it is my honor to introduce Dr. Dan Iosifescu, Professor of Psychiatry at New York University School of Medicine. Dr. Iosifescu is a leader in the field and a recognized expert in depression treatment. Dr. Iosifescu, will present an overview of MDD and the Phase III results in clinical profile of AUVELITY.

Thank you, Herriot. It is a real pleasure to provide this overview of major depressive disorder and to discuss the results from one of the registration trials of this new and exciting novel treatment. My name is Dan Iosifescu, and I'm a Professor of Psychiatry at the New York University School of Medicine. I'm also the Director of the Clinical Research division, the Nathan Kline Institute for Psychiatric Research. Next slide. I will start by providing a brief overview of major depressive disorder, or MDD. It is important to highlight that MDD is a serious chronic, disabling and even life-threatening condition with very high rates of morbidity and mortality. The morbidity seen in patients with MDD includes profound distress in ability to work in impaired social functioning. MDD is ranked by the World Health Organization as the single largest contributor to global disability. In fact, 7.5% of all years [ lot ] Lived with disability in 2015 were related to MDD. This is because the condition starts when people are very young and affect a very large proportion of the population. The most severe feature of MDD suicides, which can be attempted or successful, it is important to point out that the increased mortality is seen even in patients with MDD who do not commit suicide. In the average patient with MDD, the condition results in a median of 10 years of life lot because of the condition. As it concerns the mechanism underlying the disease, a growing body of evidence from various areas of research have implicated the glutamatergic system in the pathology of depression. Of note, the glutamatergic system is the most significant excitatory neurotransmitter in the brain. Next slide. MDD at baseline levels has been considered a very prevalent condition. However, this already high prevalence seems to have increased dramatically since the start of the COVID-19 pandemic. We used to refer to the fact that the average yearly prevalence of MDD was roughly about 10% per year. As shown on this slide, this prevalence rate has jumped to about 28% in 2020 and climbed even higher to about 33% in 2021. This translates to roughly a threefold increase in the prevalence of MDD since the start of the pandemic. The increases start to be related not only to the stress and social isolation provoked by the pandemic, but also to the neuroinflammatory factors associated with the actual infection. Suffice it to say that depression is a major public health concern that has recently increased in magnitude, resulting in a massive amount of pathology that requires our care. Next slide. Unfortunately, the treatments that we currently have, have significant limitations. Chief among them are inadequate response and delayed onset of action. Inadequate response to currently available antidepressant is common and is seen in a large proportion of patients treated with this agent. The problem with inadequate response is compounded by the fact that current antidepressants are associated with a prolonged time to clinically meaningful response, it can take between 6 to 8 weeks or even longer to truly discern if a patient will improve or not with a current antidepressant treatment. The result of the delayed onset of action with current treatments is greater patient's offering, increased risk and greater expense. This is a burden that affects not only patients but also their immediate social networks and ultimately, the society at large. Very importantly, all currently approved oral agents for major depressive disorder were primarily through monoaminergic mechanisms. This is a very important point to consider as it may explain the high rates of inadequate response with current treatment for major depressive disorder. Next slide. Shown here is the time line of the approval of antidepressants in their respective mechanism of action. The first antidepressants were the monoamine oxidase inhibitors and the tricyclics, which were initially discovered in the 1950s and '60s. Over the next 6 decades, there were important antidepressant that were discovered and approved. However, all those agents work by modulating the monoaminergic neurotransmitter and receptors. For example, serotonin, norepinephrine, dopamine or a combination thereof. We knew that other brain pathways, such as the glutamatergic system are very relevant to the pathology of depression. But until recently, clinicians did not have agents to adequately address these other potential pathways in use for treatment. That changed in 2019 with the approval of intranasal esketamine, Spravato, for the treatment of depression. This was a significant milestone for the treatment of depression because the NMDA ionotropic glutamate receptor is the target of this treatment, a complete paradigm shift from the monoaminergic targeting of all the prior antidepressants. However, Spravato has its limitations. It requires an in-office administration since it would be unsafe for a patient to self-administer the agent at home. It is also a controlled substance, and it is associated with significant associative effects. This really leaves a very significant unmet need to have a glutamatergic modulating drug that would be available as an oral pill and could be taken safely by patients at home. With the approval of AUVELITY, patients and clinicians now have that oral glutamatergic modulating treatment. AUVELITY is a proprietary oral NMDA receptor antagonist, consisting of dextromethorphan and bupropion. The dextromethorphan is an antagonist of the NMDA ionotropic glutamate receptor and also a sigma-1 receptor agonist. The 2 mechanisms modulate glutamate transmission. The bupropion component is an amino ketone and a cytochrome P450 2D6 inhibitor, which serves to increase the plasma level of dextromethorphan. AUVELITY, therefore, uses the first new oral mechanism of action approved for depression in over 60 years. Next slide. I will now review the results of a large Phase III registration trial of AUVELITY and discuss its clinical profile. Next slide. Shown on this slide are the key efficacy results from the Phase III trial of AUVELITY in MDD, which was recently published in the Journal of Clinical Psychiatry. This was a randomized, double-blind, placebo-controlled trial in patients with MDD who are treated with either AUVELITY or placebo twice daily for 6 weeks. The primary endpoint was the change from baseline in the total depression severity measured by the Montgomery-Åsberg Depression Rating Scale total score at week 6. The key secondary endpoints designed to measure rapidity of outsets were the change in MADRS at week 1 and at week 2. I will draw your attention to the gold line, which represents the AUVELITY Group. As is shown in the graph, improvement for patients treated with AUVELITY was significantly faster and greater in magnitude than in the placebo group. The improvement of a placebo is statistically significant at all time points, starting with week 1. The table on this slide summarizes the magnitude of the improvement. For the primary endpoint, which is the change in MADRS at week 6, the AUVELITY Group has a near 4-point advantage of our placebo group. So the improvement is not just statistically significant, but very clinically significant. Just to give you some context, generally in depression trial, a separation of 2 points on the MADRS between the active component and placebo is considered to be a clinically significant difference. When looking at the key secondary endpoints at week 1, AUVELITY separates by more than 2 points from placebo, and that is, again, both statistically but also clinically meaningful. And then at week 2, the placebo-corrected difference with AUVELITY is nearly 3.5 points. So these results truly highlight the rapidity and the robustness of the clinical effect. Next slide. Shown on this slide are the percentages of patients achieving remission over time. Remission is the holy grail of antidepressant treatment. Achievement of remission is essentially a depression score in a patient that is at that time, not significantly distinguishable from that of someone who does not have depression. It is defined in the -- on the MADRS scale, the score of 10 or less. As demonstrated on this graph, already at week 2, the proportion of the patients achieving remission is higher in the group receiving AUVELITY compared to group receiving placebo. The separation between AUVELITY and placebo in terms of remission rates continues and increases over time. The rate of remission with AUVELITY is more than double the rate with placebo at week 6. Again, this demonstrates a very robust clinical response. Next slide. In terms of safety, in the trial, AUVELITY was safe and well tolerated. The most common adverse events in the AUVELITY Group were dizziness, nausea, headache, somnolence, dry mouth, and sexual dysfunction. The rates for the individual adverse events were low, especially when compared with placebo. Finally, AUVELITY was not associated with psychotomimetic effects, which are the dissociative symptoms unpleasant, which are present with other glutamatergic medications like Spravato, and it was -- AUVELITY was also not associated with weight gain, which is an important negative side effect of other antidepressants. Next slide. So in conclusion, AUVELITY has demonstrated rapid, sustained, substantial and statistically significant efficacy in major depressive disorder as compared to placebo. AUVELITY demonstrated significant efficacy in major depressive disorder compared to placebo as early as week 1 after treatment. I really need to highlight that this is a really outstanding result, especially when compared with other antidepressants, which even when efficacious take much longer. The achievement on remission rates, which, as I mentioned before, is really the holy grail of treatment in major depressive disorder were significantly greater with AUVELITY compared to placebo, starting as early as week 2 and then continuing for the entire duration of the study. The treatment difference for AUVELITY compared to placebo was substantial at all time points. AUVELITY was well tolerated. It was not associated with psychotomimetic effect or weight gain. And on balance, due to its novel mechanism of action, targeting both the glutamate system and the sigma-1 receptors and due to its rapid and robust antidepressant efficacy that was demonstrated in this and other clinical trials. I truly believe that AUVELITY is a welcome, new and important treatment for patients with major depressive disorder. Thank you very much for your attention.

Thank you, Dr. Iosifescu. We will now turn it over to Lori, who will discuss our commercial plans.

Thank you, Herriot, and good morning, everyone. We are thrilled with the FDA approval for AUVELITY. AUVELITY is a potential game changer for the millions of patients living with major depressive disorders, and we are excited to finally bring this product to market. Launch preparations started well over a year ago. We are prepared and ready to execute. Before I discuss our commercial strategy and launch readiness, I'd first like to reiterate earlier commentary on the devastating prevalence trends and the potential opportunity AUVELITY has to help those patients living with major depressive disorders. Major depressive disorder is highly prevalent. 21 million U.S. adults were diagnosed with MDD in 2020. As mentioned previously, studies estimate that depression prevalence may have risen last year to as high as 32.8% or 85 million U.S. adults. MDD is considered the #1 leading cause of disability worldwide. Of those who are on therapy for the treatment of MDD, an overwhelming majority are not satisfied with their treatment experience. In 2022, Axsome partnered with the Depression and Bipolar Support Alliance, DBSA, to quantify and better understand patient treatment experiences and expectations along with treatment-related impacts on those taking antidepressants for major depressive disorder. This was a large study of 385 U.S. adults and a key finding highlighted that 78% of respondents were not satisfied with at least 1 of their current MDD treatments. Further insights also highlighted that despite being on therapy, 68% still reported symptoms, 52% reported having difficulty being productive as a result of depression, and 48% had trouble with side effects. Perhaps one of the most insightful results was that 82% believe that people would depression deserve better medications than what is currently available. Last year, in an effort to support the depression patient community, Axsome launched a patient-focused disease education campaign called Talk Depressettling. Talk Depressettling provides a platform for patient empowerment, support and education for those impacted by major depressive disorder. The campaign was launched via digital and social media and has reached more than 11 million unique individuals. Results from survey questions asked on the website showed that 78% of all registrants were neutral to very disappointed with their depression treatment experience, and 69% were planning to talk to the doctor about it. Results from the support survey and engagement with our Talk Depressettling campaign, further highlight the high unmet need for better therapeutic options for patients. As I mentioned before, we are extremely excited to bring AUVELITY to market. Our launch focus will be threefold. First, we will drive fast HCP adoption by strategically targeting, optimizing engagements using our proprietary Digital Centric Commercialization platform, and we will reach potential prescribers through a combination of personal and nonpersonal promotion. Second, we will empower patients by creating awareness of AUVELITY through a targeted digital and social media campaign and by providing educational tools and support. And third, we will enable patient access by providing comprehensive and robust patient support services and by educating payers on the clinical benefit provided by AUVELITY. As you heard in Herriot's review of the label, AUVELITY is indicated for the treatment of major depressive disorder in adults and is a potential game changer for those living with MDD. AUVELITY is the first mechanistically novel oral treatment for MDD in over 60 years and is the first and only NMDA receptor antagonist approved for the treatment of major depressive disorder. AUVELITY demonstrated rapid, strong and sustained efficacy in clinical trials and is the first and only oral antidepressant approved by FDA for rapid-acting efficacy starting at week 1. Achievement of remission was demonstrated as early as week 2 and AUVELITY's magnitude of effect was statistically significant and clinically meaningful at week 1 and week 6. AUVELITY demonstrated sustained efficacy at week 6 across multiple scales and was generally well tolerated and not associated with psychotomimetic effects or weight gain. AUVELITY's clinical profile has the potential to address many of the unmet needs associated with current treatments that were highlighted by Dr. Iosifescu. Our sales force launch strategy will focus on high potential prescribers and utilize our Digital Centric Commercialization, or DCC, platform. At launch, our 165-person sales force will target 25,000 HCPs. Our 25,000 targets capture greater than 70% of the addressable market for AUVELITY and are a mixture of psychiatrists and mental health focused or MDD specialized PCP. We estimate that our DCC enabled sales force will be able to achieve the same productivity as our traditional 250 rep sales force. Axsome DCC platform is a seamlessly integrated infrastructure of systems and tools supported by sophisticated AI and machine learning analytics. The intent behind the DCC platform is to enable efficient and effective engagements with both HCPs and patients. DCC allows for easy identification of the right targets, either HCPs or patients, identifies the best way to engage face-to-face, remotely, digitally, socially, et cetera, and provides recommendations on the appropriate messaging. This approach is different than the broad stroke approaches traditionally used in pharma promotion, and we believe creates both an efficient and effective engagement with our core audience by optimizing every touch point. We are in the process of finalizing the WAC price for ability and expect to provide it in the coming weeks. Our intention is to price AUVELITY in a way that ensures broad access for patients and that takes into account the value supported by the innovation AUVELITY brings to patients with MDD. Antidepressant prescriptions largely flow through the commercial channel. Due to consolidation in recent years, 5 PBMs or payers manage 80% of MDD prescriptions. Through our highly experienced payer team, we have had permitted pre-approval payer discussions for well over a year now and intend to start working with payers to discuss the clinical profile and benefits of the product in the coming weeks. In order to ensure that patients have affordable access to AUVELITY, along with ensuring physicians have an easy experience prescribing AUVELITY, we have enabled a comprehensive suite of tools and services in our patient support program, AUVELITY on my side. Our patient support services will include sample programs, a savings program for eligible patients, and prior authorization support among other tools. All programs will be available immediately upon launch, and I look forward to informing you more about our patient support programs after launch. As previously mentioned, we are excited to bring this innovative new product to market and are prepared for a full commercial launch in early Q4. All new sales force team members who were hired contingent upon approval, will officially start in the coming weeks and will immediately commence training. I look forward to sharing more with you and reporting on our progress during the next earnings call. I will now turn the call back to Mark to lead the Q&A discussion.

Thank you, Lori. And with that, operator, can we please have our first question.

[Operator Instructions] Our first question comes from Charles Duncan with Cantor Fitzgerald.

Great day for patients and for Axsome. Congratulations. My first question is for Dr. Iosifescu. I'm wondering, Dr. Iosifescu, if you could -- if you had to [ mail ] just one aspect of the clinical profile that you're most compelled with and may drive adoption? Would it be speed of onset, would it be a response rate magnitude of effect or the remission effects that you've seen and highlighted? And then secondarily, do you think that the lack of being able to prescribe to pediatrics, at least initially will impact that adoption rate.

Charles, this is Herriot. Dr. Iosifescu is not available for the Q&A portion. But let me take a crack at answering some of those questions.

Yes. What he told you?

Yes. So I think as you heard from his prepared remarks and I think this reflects also our view. It's really the culmination of all of those aspects of the product, which is unique. So it's rapid-acting. It does have a very substantial magnitude of effect. You get remission quickly and at high rates, and it's also very well tolerated. So it's really the culmination of all of those factors, which make it a unique approach. In addition to that, the fact that this is a totally new drug class. It hits the glutamatergic system, which now the drug currently does. So the vast majority of patients we know do not respond to have an adequate response to current antidepressant drugs, which work via other mechanisms of action. So it's really a confluence of all of those attributes, which make it compelling. And with regards to the lack of an indication in pediatric patients, that is normal, all drugs that are launched initially or launched in the adult population. And as you know, sponsors are required to develop or at least test the drug in pediatric patients. And so we do have a pediatric study plan in place.

Okay. Very good. That's helpful.

Charles, it's Lori. I just wanted to jump in. We're very excited here. So everybody wants to talk. I -- we've done extensive market research with HCP. So coupling with what Dr. Iosifescu has conveyed, and Herriot and all of us. I just want to give you kind of a quick overview of some of the comprehensive market research that we've done. And with symptom improvement happening at week 1 and then remission happening by week 2, that to position the combination of those 2 is incredibly differentiating in the marketplace right now. And if you think about the high unmet need that remains in the market, 2/3 of patients don't achieve remission, physicians are now moving towards remission as the goal of treatment. We're pretty excited about the clinical profile of the product.

Very good. And if I could ask you a follow-up, Lori or Herriot. I guess I'm wondering, I know we'll have to wait for pricing and it makes sense that you're nailing that down. But is there a trade-off between broad access and then and capturing the pharmacoeconomic value and differentiation of the product? Or do you think that you can achieve kind of both goals with premium pricing?

Yes. So I mean we're not -- we will communicate price in the coming weeks or we hope to in the coming weeks, and thanks for the understanding on not having that finalized right now. I do believe that it's possible to achieve both. I don't know if your insinuation around premium pricing is meaning that we're going to price extremely high. I think there is a broad understanding with payers that if you bring clinical benefit to the marketplace, you have to figure out what that fine line is to make sure that you have broad access for patients, because in our mind, making sure that patients are able to get on the product is very important to us.

Yes, I didn't mean to insinuate extremely high pricing because that's not what I anticipate you folks will do. Last question regarding robust IP, Herriot, you mentioned it earlier. Is there any one element of the IP for 37 versus 40 that you want to point to? And do you think that any prescriber would right-minded prescriber would try to prescribe the 2 drugs as generics? Or do you believe that you just -- it's clear to be that you won't be able to achieve the clinical profile of AUVELITY with that strategy.

Yes. So with regards to that last question, AUVELITY is a proprietary formulation, which is designed to provide a distinct pharmacokinetic profile. And we've shown now in a dozen clinical trials or a dozen or more clinical trials, which for the basis for the NDA. But this has resulted in a favorable efficacy profile in MDD, and also a favorable safety and tolerability profile. As is documented now in our package insert, the complex pharmacokinetic interaction between the 2 components is actually nonlinear. And so what that means is that any attempt to get at that specific profile that might -- will might be magnified with regards to any small changes in dose. So we're very comfortable with the profile because we have demonstrated it in clinical trials and that has resulted in the FDA approval of the product, which now tells clinicians exactly how to dose the product in a safe way -- for -- and also in an efficacious way for patients. The -- that ties into, into the robust IP, which you mentioned, which go out to -- at least 2037 to 2040. This has been a growing patent portfolio, which now consists of several different families of patents. And I would also add that, that patent family continues to grow.

Congratulations on this news.

Our next questions come from the line of Joon Lee with Truist Securities.

Congrats on the approval. This question was intended for the doctor from NYU, but since he isn't here, at what point in the MDD treatment would you deploy AUVELITY as a second line, third line or later, Herriot and Lori, what is your expectation based on talking to some of the prescribers. And also, how much Spravato is currently in use? And would that now switch over to AUVELITY -- or is that -- is taking share from Spravato not part of your strategy? Then I have a quick follow-up.

Sure. I'll start and then maybe Lori can jump in. The AUVELITY clinical development program looked at various lines of treatment. So as you know, our clinical studies did look at dosing patients frontline, also second line and various lines of treatment, including patients with treatment-resistant depression. We've reported out those results. And what's nice is that you see a very consistent efficacy profile regardless of line of treatment. We do want to point out that the label that has been approved is a broad one. So it's just for MDD. So that encompasses any way that a clinician might want to treat a patient with MDD. So now with regards to how it might be used in a real-world setting, as is well documented, roughly 2/3 of patients do not respond adequately to current treatments. And MDD is also highly treated, roughly 2/3 of patients are treated. So you do have a lot of patients out there who are in need, and we're very happy to provide clinicians a new mechanism of action and a new way to treat those patients and the clinical data so that they can make their own decisions as to where we want to place it in terms of lines of treatment.

Yes, I couldn't agree more, Herriot. Thanks for that, and Joon, thanks for the questions. I'll just quickly touch on the Spravato versus AUVELITY. I -- Herriot said it best. Spravato has a completely different indication than AUVELITY has. And so we do not believe that we will be playing even remotely close to where Spravato places.

I have a couple of still on check the box kind of question. Can you confirm that AUVELITY has no REMS, no DEA scheduling and that is -- is it rapid-acting on label? Or is it that it's static separating at week 1, which they can interpret however they want?

Yes, we can confirm there is no REMS. We can confirm also that there is no DEA scheduling, so it's not scheduled. And then we can also confirm that it is on label that it is rapid-acting. As you know, the definition of rapid-acting is that the drug works at 1 week. And so that it is in our label and the clinical trial section that it starts working at 1 week.

Well, congrats and all the best on the launch.

Our next questions come from the line of Myles Minter with William Blair.

Huge congratulations from me, milestone event for the company and for patients so congrats. My question is just on the clinical data in the label. I just was going back and looking at the GEMINI top line data that the company presented versus what's actually in the label. And it does appear that at 6 weeks, there's a slight difference between what you presented as a company and what the FDA has put in the prescribing label in terms of the MADRS delta versus placebo. Still looks clinically meaningful to me, but just wondering what reanalysis went on there and how they sort of came to that number versus the top line data number that you've been messaging out there.

Yes, it's the same data. The difference is the [ LSMEANS ] versus an arithmetic mean.

And then just on the safety portion of the label, I mean, it does look like it's a combination of new dextrome and well future and labels here with some issues that appears slightly elevated. I think I see some embryo-fetal toxicity. I think that that's in the bupropion label, but this has become a warning to precaution. So just wondering where a lot of these sort of elevated safety concerns have maybe come from? Is it due to the PK of this compound as described in the label? Or is it more just the FDA taking a little bit more of a cautionary stance?

Myles, thanks for the question. We have not seen any elevated safety concerns. So the -- now the label with regards to things like embryo-fetal tox, which we did not see actually in our studies. The -- but the label does reflect whether or not certain nonclinical studies have been conducted or completed. And some of those studies are actually post-marketing commitments. And so the label -- the future label will reflect the results of those studies.

Okay. Okay. Congrats on the approval here.

Our next questions come from the line of Marc Goodman with SVB.

Yes. Herriot, now that this is all done, maybe can you tell us what took so long? What was the FDA's issue? We know that we have Relmada and Sage and your company all trying to come up with new mechanisms to the market fast-acting. I'm just curious if this whole fast onset was a question mark for the FDA of how to put it into the label and versus an indication and stuff? And second question is, what are your post-marketing commitments. You just started to mention that just in the previous one.

So Marc, thanks for the question. With regards to the process from a natural review perspective, as we've stated previously, it was very straightforward. And now when we filed our NDA, unfortunately, we filed it right at the beginning of a historic pandemic, which affected and disrupted companies as well as all kinds of government organizations. So we're -- look, we're grateful that an understanding of the FDA meeting the time that they needed in order to take action on our application. With regards to the PMCs and the PMRs, they're pretty standard ones. So for example, one of them is to do a maintenance study, which is a standard requirement for antidepressant drugs, which are approved initially. So we're going to do that. We did mention that some of the PMRs do include some follow-on nonclinical studies, which clearly were not required at the time of approval. And we'll be doing those. So nothing out of the ordinary.

Do you have a discussion about actually getting a label that Fed approved for with fast onset? Or was that always the plan that it was going to be in the label?

So as you can see for yourself, the label does have that but onset of action was prespecified. So that's something that we did look for and it made it into the label. So I think it speaks for itself.