Prothena Corporation plc (PRTA) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by and welcome to the Prothena conference call about PRX004 Phase I study results. [Operator Instructions] Please be advised that today's conference may be recorded. [Operator Instructions] I would now hand the conference over to your speaker today, Ms. Ellen Rose, Head of Communication. Please go ahead, ma'am.

Thank you, and hello, everyone, and welcome to Prothena's investor conference call to review the positive results from the Phase I study of PRX004 in patients with ATTR amyloidosis. Please review the press release we issued earlier today, which is available on our website at prothena.com. On today's call, Dr. Gene Kinney, our President and Chief Executive Officer, will provide introductory remarks. Dr. Wagner Zago, our Chief Scientific Officer, will then speak about ATTR amyloidosis, its underlying pathophysiology and key elements of PRX004's preclinical research. Today, we will also be joined by 2 physicians with expertise in treating ATTR amyloidosis. Dr. Ole Suhr, a senior professor in the Department of Public Health and Clinical Medicine at Umeå University. Dr. Suhr will review the Phase I study results and was a principal investigator in the study with expertise in treating patients with ATTR peripheral neuropathy. Dr. Suhr will be followed by Dr. Dan Lenihan, Director of the Cardio-Oncology Center of Excellence, Cardiovascular Division at Washington University in St. Louis. Dr. Lenihan is well-known for his extensive experience in the care and treatment of patients suffering from ATTR amyloidosis with cardiomyopathy, and he will provide additional context on the patient journey and remaining unmet medical need. Dr. Radhika Tripuraneni, Prothena's Chief Development Officer and ATTR Program Head, will then highlight our next steps for the program. Following these comments, Gene will offer some concluding remarks, and we will then be joined by Tran Nguyen, our Chief Operating Officer and Chief Financial Officer, before opening the call for Q&A. Before we begin, I'd like to remind you that during the course of today's presentation, we will be making forward-looking statements that are subject to certain risks, uncertainties and other factors that could cause actual results to differ materially from those to any forward-looking statements. For a discussion of the risks and uncertainties associated with our forward-looking statements, please see our press release issued today as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements. And with that, I'd like to turn the call over to Gene.

Thank you, Ellen, and thank you all for being on our call today. We're very excited to be sharing with you the positive results from the Phase I study of PRX004 in patients with ATTR amyloidosis. I'd like to thank Dr. Suhr and Lenihan for joining us on the call today. As Ellen mentioned, Dr. Suhr was an investigator in the Phase I study, and we are extremely grateful to both him and Dr. Lenihan for joining us today. As many of you know, the Prothena pipeline reflects our deep understanding of protein dysregulation and the contribution of these toxic proteins to the cause and progression of disease. We have extensively researched how to optimally target these proteins through our empirical and unbiased discovery approach. This approach results in molecules that specifically and selectively target the toxic or pathogenic protein species in order to alleviate their detrimental effects while, to the best extent possible, leaving the native or healthy form of the protein unaffected. We are applying this expertise to develop new medicines for a number of failed neurodegenerative and peripheral amyloid diseases, including ATTR amyloidosis. Recently, after decades of our own investigation as well as the work of others in this space, we've been gratified to see the results from multiple clinical studies across several indications, demonstrating that antibodies targeting the appropriate epitope with the optimal binding strength and in the context of the right study design, the right patient population and appropriate endpoints can result in meaningful clinical benefit. I'm excited that we're able to add to this growing body of evidence by discussing with you today the results from the PRX004 Phase I study. PRX004 is an investigational monoclonal antibody for the treatment of ATTR amyloidosis. It is a first-in-class amyloid depleter with a differentiated mechanism of action that is designed to remove the amyloid deposits in vital organs that cause this disease. Despite significant progress in the understanding of ATTR amyloidosis, an urgent unmet need remains, specifically for patients with cardiomyopathy who are at high risk of early mortality due to amyloid deposition in vital organs. As you will hear on today's call, PRX004's mechanism of action is uniquely suited for this defined population. As Dr. Lenihan will discuss later, these patients are in need of meaningful treatment options, are readily identifiable and are generally treated by specialty cardiologists and amyloid specialists. These facts support our plan to efficiently progress PRX004 into a late-stage clinical study designed to assess the impact of PRX004 on survival in this targeted patient population. Focusing now on the results from our Phase I study. Today, you will hear that in addition to demonstrating favorable tolerability, PRX004 treatment also improves clinical assessments of both neuropathy and cardiac function. Specifically, PRX004-treated patients demonstrated a slowing of mean neuropathy progression, approximately 86% relative to what would have been expected based on the analysis of published historical data in this progressive disease. Finally, I'd like to thank the patients, their caregivers, investigators and clinical study site teams who participated in this study, particularly given the challenging 2020 conditions. With that said, I'll now turn the call over to Wagner who will get us started by providing an overview of ATTR amyloidosis and PRX004's novel mechanism of action. Wagner?

Thank you, Gene. I'll briefly talk about 2 topics today: First, the underlying pathophysiology of ATTR amyloidosis; and second, how we used this understanding to develop PRX004 as the first anti-ATTR amyloid immunotherapy that specifically depletes amyloid. Due to its differentiated mechanism, we believe that PRX004 has the potential to offer a novel treatment approach for ATTR patients, particularly for those at high risk of early mortality, where a significant unmet medical need remains. Transthyretin, or TTR, is an abundant and important protein produced mainly by liver cells. Once it adopts is normal structure, TTR serves as a transport carrier for thyroxin and retinol-binding protein and also has been proposed to have neuroprotective effects. The normal TTR protein is assembled from 4 identical subunits into a homotetramer. This TTR tetrameric structure is critical for TTR to exert its physiological functions. TTR's instability caused by PON Mutations in hereditary forms or by other factors in wild-type forms leads to the association of the tetramer in monomers that can be sowed, aggregate and deposit as amyloid in a variety of organs. Importantly, amyloid deposition is the cause of organ dysfunction and failure in both hereditary and wild-type ATTR. In ATTR, amyloid deposition can impact multiple organs leading to a variety of clinical manifestations. The most commonly affected organs are the heart and peripheral nerves. At the cellular level, amyloid intercalates intracardiac tissue, insulting cardiomyocytes, physically pushing them out of shape and interfering with electrical conduction and muscle contraction. In the heart, amyloid deposition causes the myocardium to stiffen and work inefficiently, leading to progressive restricted cardiomyopathy and congestive heart failure. In nerves, deposited amyloid between cells and nerve bundles causes neuropathy, characterized by loss of sensation, reflex and muscle weakness. It is believed that amyloid begins accumulating many years prior to patients becoming symptomatic or diagnosed. Currently, there are 2 therapeutic approaches that share a common principle reducing TTR from entering the pathogenic pathway. This would, at least in theory, slow the formation of new amyloid. This is why therapies classified as stabilizers or silencers tend to do by either stabilizing the normal TTR tetramers or suppressing the production of the protein synthesis. However, simply preventing the process -- however, simply preventing the protein from entering the pathogenic pathway is not adequate for patients who are at high risk of early mortality due to the substantial existing amyloid deposition in their vital organs. Instead, what is needed is a mechanism that clears pathogenic amyloid. PRX004 has been developed to meet this requirement. PRX004 is designed to target both wild-type and hereditary forms of ATTR amyloid that causes organ dysfunction and failure. The primary mechanistic goal is to clear the amyloid in order to improve organ function. We call this a depleter mechanism of action. This ability to deplete amyloid, especially in cases where rapid clearance may be a determinant of survival, uniquely positions PRX004. Turning now -- turning now to how PRX004 was designed, similar to how we develop other anti-amyloid immunotherapies in our portfolio, we use a combination of our understanding of the normal protein structure, computation antibody design technologies and empirical and unbiased screening process. Our scientists work within collaboration with the academic laboratory of Dr. Chakrabartty at University of Toronto, who solved the NMR structure of the TTR protein and determine epitopes that become uniquely exposed when TTR dissociates. Through a detailed screening process, we targeted 1 such epitope as a core interface between the protein monomers. This epitope is hidden when the protein is normally folded but becomes exposed when TTR dissociates intramonomer and remains exposed to the misfolding and aggregation process, inclusive of deposited amyloid. This approach led to the specificity of PRX004 to pathogenic TTR while leaving the normal protein function intact. The exact position of this epitope is illustrated in this 3-dimensional structure where the PRX epitope shown here in red is fully accessible in a monomer but hidden if in a tetramer. I will now briefly summarize some of our preclinical research on PRX004. PRX004 was extensively studied preclinically. This slide highlights some of the key attributes that support its depleter mechanism of action: First, starting on the bottom left side, we show that PRX004 is able to prevent amyloid formation. In this in vitro experiment, we see that PRX004 potently inhibits amyloid formation in a concentration-dependent manner as demonstrated by the downward directional change in the graph; second, in the middle panel, are examples of ATTR amyloidosis autopsy issues, demonstrating that PRX004 specifically binds to the amyloid in the tissue from hereditary and wild-type patients. PRX004 binds to amyloids, no matter whether it is deposited. And here, you see binding in multiple organs, including heart, nerve and GI tract. The brown staining in these pictures is, in fact, the detection of PRX004 bound to the amyloid, and you can appreciate the high amyloid levels that are present in these arms. Third and most importantly, PRX004 was designed to be able to deplete amyloid following binding. As evidenced by results from these in vivo studies as depicted in the graph on the lower right, PRX004 administered systemically exits the vasculature, binds to the ATTR amyloid, promotes the engagement of phagocytes and clears amyloids via phagocytosis. This particular mechanism of action is best illustrated in this video that will appear on the box at the left and shows how PRX004 depletes amyloid. In this in vitro experiment, we monitor how phagocytes react to amyloid deposits in 2 conditions: In the presence of an irrelevant IgG control, or in the presence of PRX004. In each panel, you will find a large formation of amyloid and a number of phagocytes. Let's see first what happens when a nonspecific control antibody is added to the amyloid. In this case, even though phagocytes had a chance to come in contact with amyloid, they don't recognize and initiate phagocytosis. This inability of phagocytes to naturally degrade amyloid might be one reason why amyloid deposits are not cleared in ATTR amyloidosis disease. On the other hand, let's see what happens if amyloid is now in the presence of increasing concentrations of PRX004. In this case, when PRX004 occupies its amyloid target, the phagocytes subsequently touched the surface of that amyloid and in engulf it rapidly. PRX004 provides the phagocytes a new sensory capacity to detect amyloid. As you can see, almost immediately after that engulfment, the amyloid fluoresces red. That red fluorescence confirms that amyloid is directed to a clearance pathway inside phagocytes. Finally, given the central role of the positive amyloid in ATTR disease, it was critical to understand how PRX004 would interact with amyloid in patients. I'll speak briefly about the work we did to model the amyloid occupancy of PRX004 and how that pertains to the different dose levels we tested in this Phase I study. First, understanding the binding kinetics of PRX004 allows us to predict the dose-dependent occupancy of amyloid in patients. What you see on the left is the outcome of our preclinical model built from data from an assay that use patient-derived samples to measure PRX004 binding. This model predicted that doses of PRX004 of 3 milligrams per kilogram or higher would saturate or occupy more than 90% of amyloid deposits in the tissue of patients. This model gave us the initial guidance for dose selections, but we also used the Phase I study to validate our assumptions in patients. To do this, we utilize a measure of the binding of PRX004 to non-native TTR species in the plasma of patients using our proprietary assets. Accounting from PRX004 binding properties and assay conditions, we are able to confirm our preclinical model and accurately assess amyloid occupancy. This is illustrated in the graph on the right, demonstrating that those levels of PRX004 equal to or greater than 3 milligrams per kilogram are sufficient to achieve saturation of amyloids in tissue and, therefore, are equivalent for the purpose of pulling efficacy assessments. With that, I am now very pleased to turn the call over to Dr. Suhr, who will review the results from our Phase I study.

Thank you, Wagner. I am pleased to join you today to review the positive results of the Phase I study of PRX in patients with ATTR amyloidosis. The Phase I study was an open-label, multi-centered, 3+3 dose-escalation and long-term extension study. The study was designed to determine the safety, tolerability, pharmacokinetic and target engagement properties for PRX in patients with hereditary ATTR amyloidosis. In the dose-escalation phase of the study, the patient received PRX004 intravenously once every 28 days for 3 months. 6 dose levels was evaluated: 1.1 (sic) [ 0.1 ], 1.3 (sic) [ 0.3 ], 1, 3, 10 and 30 milligrams per kilogram. Patients who completed the dose-escalation portion of the study and who are eligible could enroll in the long-term extension portion of the study. The neuropathy impairment score on these, which is a clinical endpoint commonly used in ATTR interventional study, was included as an exploratory endpoint to characterize the clinical efficacy. We assessed the recent patients at the dose levels of PRX004 will be predicted to saturate ATTR amyloid in tissue. As Wagner discussed, based on the PK/PD model, both labels greater than or equal to 3 milligrams per kilogram were predicted to saturate amyloid and therefore, cohort 4, 5 and 6 were considered equivalent and efficacy assessment in these patients were prudent. There were 21 patients enrolled in the Phase I study, and they all completed the dose-escalation portion. 17 of those 21 patients subsequently enrolled in a long-term extension portion of the study. The 4 patients who elected not to enroll in the long-term extension did not meet the eligibility criteria but had no safety or tolerability concerns. This long-term extension portion was ongoing when the COVID-19 pandemic began. As a result of the pandemic, patients we started visiting the long-term extension. And this portion of the study was ultimately discontinued. I can tell you from my own experience in Sweden, that it was not permitted for these patients to come in for their infusions. As a result, the 7 patients in Cohort 4, 5 and 6 of the Phase I study that received all infusions through 9 months were considered evaluable for efficacy. This slide highlights the baseline demographic of all 21 of the patients enrolled in the study. Of the 21 patients, 11 patients have peripheral neuropathy and cardiomyopathy, 7 have peripheral neuropathy only and 3 patients have cardiomyopathy only. Patients with ATTR amyloidosis experience a spectrum of symptoms. And it's quite common for them to present with both cardiomyopathy and peripheral neuropathy. I will note that the 7 patients who were evaluable for efficacy had similar baseline characteristics. Turning to safety. PRX was found to be generally safe and well-tolerated following monthly intravenous infusion at all dose levels tested in the study, up to and including 30 milligrams per kilogram, the highest dose level tested. There were no dose-limiting toxicity or serious treatment-emergent adverse events leading to death. All serious events were deemed unrelated to study drug. Overall, 223 infusions were administered during the course of this study in 21 patients. Up to 17 infusions were given to any single patient. One subject withdraw from the study due to pregnancy. 2 subjects had transitioned positive antidrug antibodies. However, there were no clinical secrete in these subjects and no change was noted on PK. There were no clinical significant safety trends in laboratory data or other assessments observed in the study. In terms of the PK results, exposure to the drug indicated an increase in a dose-proportional manner and PRX demonstrated PK profiles consistent with that of an IgG1 monoclonal antibody. The half-life of PRX004 is approximately 31 days. Before turning to the efficacy results, I'll highlight 2 common scales used in clinical study to assess neuropathy impairment, the NIS and the mNIS+7. The NIS, which was used in this Phase I study is a 244-point scale that include assessments of motor strength and weakness, sensation and reflexes. mNIS+7 is a 304-point scale that includes the same motor strength and weakness and reflex assessment. The primary difference on the mNIS+7 is the QST or quantitative sensory testing component that repletes -- replaces the sensation measures in NIS and provides a greater dynamic range, 80 points versus 32 to evident change in the sensory components. For both scales, the highest score indicated greater impairment. Neuropathy impairment was assessed with NIS for the 7 evaluable patients at baseline and after 9 months of treatment. The expected natural history of neuropathy in patients with ATTR amyloidosis is a progression of approximately 1 point per month on NIS. More specifically, over 9 months, one would expect NIS worsening as represented by an increase of 9.2 points. This progression is calculated based on 2 publications described the change in NIS in untreated and placebo-treated patients, including a manuscript assessing the influence of ATTR polyneuropathy which I co-authored. Turning to PRX004 Phase I study, all of the [ evaluable ] patients had slower neuropathy progression than expected. PRX patients demonstrated a new increase from baseline in NIS of 1.29 points at 9 months compared to the calculated expected mean increase in NIS of 9.2 points at 9 months. At the patient level, the change in NIS for each of these available patients was more favorable than the published historical data. In addition, in this highly progressive disease, it was encouraging to see 3 of 7 patients demonstrate improvement in neuropathy with a decrease of NIS of 3.33 points at 9 months. These positive results were observed in patients with or without concomitant use of stabilizer therapy. For the 2 patients who received PRX alone without concomitant stabilizer therapy noted on this graph in orange, there was a mean change in this of 0 at 9 months. You can also see that in the [indiscernible] of patisiran, the drug approved for the treatment of hereditary ATTR amyloidosis with peripheral neuropathy, the mean increase in NIS was 2.6 points at 18 months. We also looked at the global longitudinal strain, or GLS, which is a key measure of cardiac systolic function, where decreasing this measure indicates improvement. Each of 7 evaluable patients who received PRX004 through 9 months demonstrated improvement in cardiac systolic function. The mean decrease in GLS was 1.21%. For the 3 patients whose NIS improved, the mean decrease in GLS was 1.51%. As with NIS, these positive results were observed in patients with or without concomitant use of stabilizer therapy. And for the 2 patients who received PRX alone, the mean decrease in GLS was 2.16%. Here again, we note that in the APOLLO study, patisiran-treated patients had a mean increase on GLS of 0.08% at 18 months. We also see on this slide, that in the placebo-treated arm, the mean increase in GLS was 1.46% at 18 months, which illustrates the normal progression of this placebo-treated patient population. Overall together with the NIS results, it's encouraging to see improvement in cardiac systolic function in these patients treated with PRX004. In addition, we also measured a New York Heart Association or NYHA Class. At baseline, 6 of the 7 evaluable patients in NYHA Class A -- Class I and one patient was Class II. At the end of the study, all of these patients were stable at their last assessed time point, meaning that the last New York Heart Association assessment was unchanged from their baseline assessment. You can see on this slide further details on New York Heart Association Class for these 7 patients. In summary, this Phase I study represents the first clinical results of a therapy for the potential treatment of ATTR amyloidosis with a novel mechanism of action designed to deplete amyloid in the affected organs. All 6 dose labels tested in this study were found to be safe and well tolerated with a total of 223 doses administered through the study, where patients received up to 17 doses. For the 7 evaluable patients, we observed benefit from neuropathy and cardiac systolic function at 9 months. The patients in the study did better than I would expect based on my clinical experience, and change in NIS was more favorable than expected based on natural history data. Here, you can see a summary of those clinical assessments. Taken together, these results support the potential of this depleter mechanism to provide a new treatment option for patients and supports further clinical investigation. Personally, I'm encouraged by this finding and believe there remains an unmet need in treating patients with ATTR amyloidosis, that could be addressed by a depleter mechanism such as PRX004 that directly clears amyloid and has a more rapid impact on affected organs. And now to talk about how patients with ATTR are diagnosed and treated and also the unmet medical need, I will turn the call over to Dr. Lenihan. Dr. Lenihan?

Thank you, Dr. Suhr. Appreciate the invitation to speak about this. The etiology of ATTR amyloidosis is transthyretin amyloid deposition in organs, which is derived from either mutated or wild-type forms of the protein. The organ dysfunction and failure as a result of this amyloid, particularly when the heart is impacted makes ATTR amyloidosis a fatal disease. The clinical manifestations of this disease are dependent on where the amyloid is deposited, known as organ tropism. Clinical severity is believed to be related to the amount of amyloid deposition in affected organs. Over time, the heart becomes severely impacted by the deposition of amyloid causing it to stiffen and work inefficiently with morbidity and mortality primarily caused by progressive restrictive cardiomyopathy leading to heart failure. Patients face a long and complicated journey to accurate diagnosis as a result, often initially presenting with very advanced cardiac disease. If a patient is experiencing symptoms that they first discuss with the primary care physician, their symptoms are often initially attributed to other conditions. This can go on for months or years. What I see most commonly, however, is that patients are admitted to the hospital for cardiac symptoms as the initial event on the path towards a diagnosis. They are commonly experiencing diastolic heart failure, and this initiates referrals to specialists for further evaluation. By the time patients are admitted to the hospital, they are often very advanced, likely already NYHA Class III or IV. Ultimately, when amyloidosis is suspected and after accurate diagnosis, cardiologists will often lead management of these patients, and there is typically an interdisciplinary team. Confirming an ATTR diagnosis requires multiple clinical assessments. AL amyloidosis must be excluded as the different course of treatment would be indicated for patients with this disease. AL amyloidosis is an analogous peripheral amyloid disease with similar clinical presentation that also results in a restrictive cardiomyopathy. AL is a more rapidly progressive disease with shorter overall survival compared to ATTR. Typically, diagnosis requires some combination of clinical exam, heart tissue, biopsy or more recently, nuclear scintigraphy. Blood tests, echocardiography and genetic sequencing inform the extent of disease progression and the potential hereditary nature. Clinical examinations, including NYHA classification that is used is typically -- informs the overall prognosis of the patient. Tafamidis is the only 1 approved therapy for patients with ATTR cardiomyopathy. While this has been a recent advance, an urgent unmet medical need remains for patients with moderate to advanced cardiac disease who are at the highest risk of early mortality. As you can see from the Phase III study results, Tafamidis provided little benefit in these NYHA Class III patients. Further, Tafamidis has not been studied in patients with NYHA Class IV. And this is the most common presentation for patients is -- in either of these classes of heart failure. In addition, survival benefit with Tafamidis was not observed until after 18 months. Very often, moderate to advanced cardiac patients cannot wait that long. The high level of cardiac amyloid deposition in these patients leads to a severe clinical presentation and early mortality. Silencer therapies are not approved for the treatment of ATTR cardiomyopathy. While there are clinical studies to investigate silencers for this indication, they exclude high-risk patients in NYHA Class III in all patients in Class IV. This moderate to advanced patient population represents a large portion of patients with ATTR. One final and important point I'll make is that despite some progress being made to increase awareness of ATTR, it is still very underdiagnosed. A tremendous unmet need will remain for the moderate to advanced patients, generally defined as those in NYHA Class III and IV. You don't need to look for these patients. They are the ones regularly admitted to the emergency department. Therefore, given the current treatment landscape, a therapy with a mechanism such as PRX004, that is designed to specifically target and clear amyloid out of tissue, has the potential to improve survival in patients who are at high risk of early mortality due to amyloid deposition. I find the results from this first clinical study of PRX004 that show improvements on neuropathy and cardiac function, very encouraging and certainly warrant further investigation. With that, I'll turn over the call to Radhika. Radhika?

Thank you, Dr. Lenihan, and thank you again to both Dr. Suhr and Dr. Lenihan for your time and perspective today. As Dr. Lenihan mentioned, patients with ATTR with moderate to advanced cardiomyopathy are at particularly high risk of early mortality. By the time that these patients are diagnosed, amyloid has been accumulating in their organs for many years. These patients struggle to carry out any sort of basic physical activity. Bringing groceries into that house from the car or walking up a single flight of stairs can leave them short of breath. At diagnosis, these patients learn that they have less than a 50% chance of survival in the following 2 years. Patients diagnosed with ATTR, who are NYHA Class III and IV are estimated to represent more than 30% of the ATTR cardiomyopathy patient population, but there is also a growing belief that a segment of the patients diagnosed with HFpEF, or heart failure with preserved ejection fraction, have ATTR. If you consider the 4% to 13% of patients with HFpEF who may be -- who may have ATTR, together with the more than 30% of ATTR CM patients diagnoses as NYHA Class III or IV, this represents a patient population of somewhere between 130,000 and 490,000 patients globally. And proven survival in these moderate to advanced patients represents an urgent medical need. We believe PRX004's depleter mechanism of action is uniquely [ suited to ] [indiscernible] that causes heart attacks. Our confidence is informed by our experience with other peripheral amyloid disease, which also results in a restrictive cardiomyopathy. AL amyloidosis, like ATTR, is a rare and fatal peripheral amyloid disease. Mortality in both diseases is driven by the amyloid deposition that causes organ dysfunction and failure. AL is a more rapidly progressing disease caused by amyloid light chain. For patients who are categorized as Mayo Stage IV, median overall survival is approximately 6 months. Birtamimab is designed to specifically target amyloid light chain that deposits in vital organs. What you see here is an analysis of the data from the Phase III study that demonstrated a rapid and greater than 50% relative risk reduction for all-cause mortality favoring birtamimab in Mayo Stage IV patients. Birtamimab and PRX004 have a similar mechanism of action. Accordingly, the survival benefit in the Birtamimab study informs PRX004's potential benefit in patients with moderate to advanced cardiac disease due to amyloid deposition. Looking ahead, based on these very encouraging results, we're planning to advance PRX004 into a late-stage study in moderate to advanced ATTR cardiomyopathy patients. This is an area of urgent need, which directly aligns with PRX004's differentiated depleter mechanism that targets the amyloid that puts patients at risk of early mortality due to organ dysfunction and failure. We look forward to sharing additional details about these plans in 2021. Finally, I'd like to echo Gene's thanks to all those who have made this study possible, especially to the patients, their caregivers, investigators and the clinical site teams who participated in the PRX004 study. Now I'll turn it back to Gene for some concluding remarks before opening the call for Q&A. Gene?

Thank you, Radhika. I'll briefly summarize by reiterating that we are excited about the unique opportunity offered by PRX004 to change the treatment paradigm for patients with ATTR amyloidosis. PRX004's novel depleter mechanism of action is in keeping with our scientific approach to targeting clear toxic disease-causing proteins while leaving the normal form of these proteins to do their job. In terms of the broader landscape, awareness of ATTR amyloidosis is growing and diagnosis is improving, but as Dr. Lenihan noted, patients are still diagnosed late in their disease course when they have significant amyloid deposition and cardiac dysfunction. In these patients, stabilizers have failed to show a meaningful benefit. This is not entirely surprising given that this mechanism does not address the deposited amyloid. Silencer therapies are not currently being studied in these high-risk patients. As Radhika noted, moderate to advanced patients in NYHA Class III and IV, represent a significant patient population that is in urgent need for adequate treatment. These patients are easily identified as they are seen in specialty academic and amyloidosis centers. This supports our plan for an efficient development path in a late-stage study to assess PRX004's impact on survival. In addition to the favorable safety and tolerability profile, we've seen very encouraging effects on neuropathy and cardiac function. These positive results from our Phase I study give us confidence to proceed into further development. Looking ahead, we believe that PRX004 has the opportunity to establish a premium position in a rare-disease space with blockbuster potential. Before opening the call to Q&A, I'd like to highlight some of our upcoming milestones in our broader pipeline. As I described at the beginning of this call, our programs stem from a deep scientific understanding around the biology of protein dysregulation. This expertise and focus have enabled us to build a robust pipeline focused on neurodegenerative and rare peripheral diseases. We are entering a time where this cumulative knowledge and the convergence of scientific learnings and advances in clinical trial design are translating into observations of clinical efficacy across multiple trials. These exciting advances open the door to deliver transformative therapies for some of the most devastating diseases affecting society today. With the results we reviewed today, we are happy to add PRX004 to the list of examples where our innovative science has translated into positive clinical results for patients. At Prothena, we are extremely well-poised to advance and extend these learnings throughout our pipeline. As we look ahead to 2021, we expect to significantly advance programs in our Alzheimer's disease portfolio, including our wholly owned anti Abeta antibody. For our anti-tau antibody that is part of our worldwide neuroscience collaboration with Bristol-Myers Squibb, we expect to file an IND, triggering a possible U.S. license option payment of $80 million. Next year, we also expect Roche to initiate a late-stage Phase IIb study of prasinezumab in patients with early Parkinson's disease. Prothena will earn a $60 million clinical milestone payment upon first patient dosed in this study and further details on this study are expected to be announced in the first half of 2021. And finally, as Radhika had discussed, we look forward to sharing additional details on next steps for PRX004 with you next year. So at this time, we'll open the call for questions. Operator?

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

Congratulations on these very interesting results and I'll just ask a few and then hop back in the queue. First of all, with regard to those patients that had improved neuropathy impairment scores versus the overall patient population, I'm wondering if you could provide us any insights on what differentiates those patients, why that particular responder rate, and do you think that this could be used in the future for the design and conduct of a clinical trial?

Yes. Thank you, Charles, for that question. So let me just say, I think Dr. Suhr mentioned, as he talked about the demographics, that those 7 evaluable patients really didn't differ with respect to any meaningful demographic changes relative to the overall population. So we think they're pretty representative of ATTR patients. Maybe I can ask Radhika, if you want to speak to that in any further detail?

Yes. I mean, there appeared to be no difference in the demographics of those patients, the genetic mutation in addition to any other baseline clinical characteristics. So nothing that was clearly identifiable when we looked across these 7 patients.

Okay. That's helpful. And then with regard to next steps, I know that you're going to outline that and discuss it next year, but can you provide some additional color on what you anticipate the size and timing? I think that Radhika was pointing to some effect sizes that might suggest a sample, a certain sample size, but what would you anticipate the next step to be with this program?

Thanks again, Charles. So I think what we're focused on is thinking about these at-risk patients, right? And obviously, the patients, as you heard from Dr. Lenihan, that really have a critical unmet need, remain the patients that are at high risk of early mortality due to the deposition of amyloid in these vital organs such as the heart. And so we see that patient population as a population where this depleter mechanism of action is particularly well suited. And obviously, that would be something that we would be focused on. Clearly, in that population, we'd be focused on survival-based endpoints. So we think that's important. And obviously, we'd be focusing a future study on an effect size that we think is meaningful from a patient population perspective. I think maybe, Tran, did I hear you had a comment?

Yes. I was just going to say, I mean, I think you could think of kind of a proof-of-concept trial that's in the 100- to 200-patient population. There are other ways to potentially expedite that, and we might get to higher patient numbers if we were to go into a Phase III, but we're balancing those decisions. And so I think that gives you a little bit of perspective of what to expect next year.

Okay. And last question is regarding COVID. If I made the simplifying assumption that there wasn't herd immunity or broad vaccination program by, say, roughly mid-year next year and perhaps even overly risk-adverse assumption about then, when you consider, say, the kind of infusion timing for this study for the next step, are you concerned about the ability to conduct this study or do you think that these data will help drive patients and investigator interest?

Yes. So there's a couple of questions kind of in there, Charles. So first, I think these data are helpful with respect to starting to understand the potential for this type of mechanism of action. And I think that's always helpful when you think about gearing up for next studies. And maybe I'll come back and ask Dr. Suhr to speak about his experience on that. I will say just with respect to COVID, we don't expect there to be anything unique here relative to any clinical study. I think that COVID is something people are thinking about with respect to inclusion of patients. It's certainly around inclusion/exclusion criteria, how you think about bringing patients into study and controlling for COVID and obviously, how to ultimately incorporate the thinking around -- obviously how to ultimately incorporate the thinking around vaccination once that's more widely available. Those are kind of operational details that we think about across all of our programs, particularly those starting in 2021, but maybe let me just circle back...

And can I add one thing to -- I mean given the grievousness of the moderate to advanced patient population that we'll be focusing on that only our mechanism is probably most appropriate for, that also has to play into the variable thinking about the impact of COVID too, if it was to be a more prolonged situation. But clearly, there's been a lot of momentum on the vaccine side. So I'm a little optimistic there that things will look much better in '21 than in '20. But that being said, again, I think you have physicians' and patients' attention due to the patient population we're focused on and the fact that survival -- early mortality is an issue in these patients and that's... [Audio Gap]

And that's how these data may be viewed. Yes. So in terms of thinking about next studies and how you feel? [Audio Gap]

Well, I think this is a systemic disease. I think it is I mean the most encouraging about the study is that both neuropathy and cardiomyopathy [indiscernible] signs were so good as they were. So that is something which I think is very important to remember. And ultimately, a depleter mechanism should have better efficacy on the heart because most people think that the removal of the heart will have the potential actually to cure the disease -- or the removal of the heart will have the potential actually to cure the disease or make the patient a much better situation. Whereas when it comes to neuropathy, you have a more dysfunction of the nerves and therefore, regaining full nerve capacity is probably out of reach, whatever treatment you find. So I think that's an important message for the study that all parameters goes in the same direction.

That's great. And maybe Dr. Lenihan, you kind of spoke to how these patients present oftentimes in an emergency department setting. I mean, what's your sense in terms of their urgency for care relative to thinking about the ongoing COVID situation?

Yes. Thanks for the question. I think it's a very difficult one to answer because I don't believe anybody really knows any answers about the future. I will say that when COVID first started, there was general -- the general implication is to just keep patients away from any kind of hospital or clinic setting. And then over time, the chronic medical conditions, they still existed during that whole time frame. And then as it became apparent that they weren't being treated that patients now really have to come for ongoing evaluations. So these patients really fit in that category because most of the time they're admitted to the hospital. And that's not is not a elective -- an elective reason for admission. These are people that got very sick and had to come to an emergency room, regardless of their COVID status. So I think that we're trying to work through being safe for all of our patients, but generally, I feel like we're doing that. And then we're enrolling in clinical trials at this point. And I think, especially at the clinical trial that has a potential benefit for therapy is critically important to continue that. So for example, in patients with cancer, they're still getting their treatment for their cancer at this point. So I think you're just trying to be more careful in terms of exposure.

That's great.

But if I might make a remark about COVID-19, I do ask that this patient population are also the first at least in Sweden, who will get vaccinated. So I that will help to enroll patients because they will be vaccinated quite quickly.

That's an excellent point. It seems like COVID could actually increase the acute need in this already high unmet need patient population. I'll hop back in the queue.

And our next question comes from Jay Olson of Oppenheimer.

Congrats on these results. And I had 2 of them. First one is since tafamidis doesn't seem to benefit New York Heart Association Class III patients, and Class IV patients weren't studied. Could you just comment on where PRX004 with its novel depleter mechanism could potentially fit into the treatment landscape? And then separately, if you could also comment on how the diagnosis of ATTR should continue to evolve over time, especially for patients who have heart failure with preserved ejection fraction when there's a treatment available that might actually benefit these patients?

Yes. So 2 great questions. Thanks for those. So first, let's start with where we think this depleter mechanism of action is particularly well suited. And I think you mentioned it in line with how we're thinking about it as well, which is there's a lack of therapies right now that have shown to benefit these more moderate to advanced cardiac patients. And I think, particularly, you can think about the New York Heart Association Class III and IV patients there. I think based on the mechanism of action, the encouraging Phase I results we shared with you today and also our experience with another "depleter mechanism of action" that is birtamimab in AL amyloidosis and the robust survival benefit seen in the more advanced cardiac patients, the at-risk patients in that study. We believe that this mechanism is particularly well-suited for that group of individuals. And given that, that remains not only a meaningful unmet need but also a sizable portion of the overall ATTR amyloidosis patient community, we think that, that's an important place to move to. On the part of diagnosis and how diagnosis will evolve if, in fact, we have a successful therapy for these patients, maybe I can ask Dr. Lenihan to speak to that. I think that might be something that he thinks about on a regular basis.

Thanks, Gene, and thanks for the questions. The -- yes, I believe that this is a very relevant question on 2 fronts. But the first front is that patients who are being treated with tafamidis, the ones that benefit are the ones that are either asymptomatic or minimally symptomatic. Anybody who's highly symptomatic, it really takes roughly 18 months' worth of tafamidis to notice a significant change. And in the population that was more symptomatic, there wasn't really a documented benefit. And actually, they did have a trend towards increased hospitalization. So I think that for significantly symptomatic patients, tafamidis, although it's all that we have, is really not particularly effective. The general push from a tafamidis point of view is to find patients before they become symptomatic based on specific testing. So I think that the place where tafamidis really is strong is in people where you detect the disease at early state. And so PRX004 is ideal in that sense because it will take care -- it could have an important improvement mechanism on patients that are highly symptomatic that have a lot of amyloid infiltration already. So I think that, that's a really exciting place. Right now, we have nothing to offer them. And then the second question is more along with how do I think things about diagnosis are changing. I think it's really about raising awareness of the possibility because whenever we evaluate patients for aortic stenosis, for example, if we think about it carefully, it ends up that somewhere between 10% and 15% of those patients actually have amyloidosis as a coexisting condition. And then if we look at patients that are admitted to the hospital for diastolic heart failure, the rate of -- or the percentage of patients that end up with the diagnosis of amyloidosis is surprisingly high, depending on which population you look at. And that could be somewhere in the range of 10% to 15% as well. It's curious, if you look at all of our heart failure trials done across the world, the ones that have shown a benefit with certain therapies are all in systolic heart failure. And you could imagine that one of the reasons why we haven't documented any real benefit for typical heart failure therapies and people with diastolic heart failure is perhaps that a portion of those, maybe a substantial proportion of those patients would actually have had amyloidosis. And those treatments are not effective in that population. So it's a very interesting question. I hope that we raise awareness of the diagnosis of amyloidosis in years to come, but it's still not really thought of.

And our next question comes from Michael Yee of Jefferies.

Congrats on this data. I had 2 questions. One was trying to understand the Slide 22 with the improvement in cardiac systolic function via GLS. We were looking at data and it suggests perhaps a 1% increase in GLS is about a 5% decrease in mortality. Just wanted to think about how you would predict what type of magnitude of benefit you could see in either a longer study or in Class III patients and what that might mean for an overall cardiac mortality benefit, how would you think about that and the benefit you're seeing here on Slide 22? And then when you think about your next study, in Class III patients, I guess. How do you think about the design of that study, what you want to see? And maybe just talk a little bit about that.

Thanks for the questions, Mike. So let's start with GLS and kind of linked to mortality. I mean I think I think from our perspective, we would be careful to say that GLS is a measure of systolic function, which we think is important and meaningful in the context of ATTR amyloidosis in those patients. Given the amyloid deposition as you think about kind of longitudinal strain, it makes good sense that it's a sensitive measure given what amyloid is doing when it deposits in the heart. And maybe I'll come back and ask Dr. Lenihan to speak about that a little bit as well because he's published in this space pretty extensively. I think we -- I think we'd be careful to say that in terms of predictors of survival, I don't know that we think that there are biomarkers that one could employ in a Phase I study that would be directly predictive of survival, right? So I think a measure of systolic function was important. I think it's meaningful with respect to the AL patients, but I'm not sure we want to go and say that this is a direct surrogate efficacy measure of survival. I think NIS, on the other hand, is a direct measure of neuropathy, and it is a functional outcome measure that measures neuropathy directly on a clinical level, and we're obviously very encouraged by the NIS results for exactly that reason because it really substantiates that through the mechanism of action of depleting amyloid. You can see these clinical benefits. And I think what's particularly exciting stepping back for a moment about the overall data set from our perspective is that we are looking at clinical benefit when we talk about the neuropathy scores. And obviously being able to evidence that in a Phase I study gets us to a proof of biology, proof of concept, if you will, that's quite exciting. So we're happy about that. I think in terms of exactly how well GLS change is linked to survival. Maybe I can ask Dr. Lenihan to speak a little bit about GLS in the context of AL amyloidosis, and why it's a reasonable mechanism to look at?

Yes. Again, that's a pretty detailed question. I do think that we are continuing to learn about global longitudinal strain or GLS and how it could inform our practice in cardiology. I do think that the data that Prothena has on PRX004 is really interesting and very -- it's certainly something that we're highly encouraged by. We're still trying to establish how reliable GLS is in terms of monitoring for cardiac disease. And I think that we're gradually gaining confidence in it and further reliable information about how an improvement in GLS would actually reflect an improvement in function. So I think that the answer is still not firm on that whole process, but the data that was shown in this Phase I study is very encouraging. And I look to -- looking at that in more detail going forward. And I do find it to be very encouraging.

I guess it was related, right? Gene, because for the Phase II or the next study, the goal is to show that the improvements in neuropathy are a proof-of-concept and proof of biology, right, for a depleter mechanism. And that, that would lead to improvements in cardiac benefits and survival, which is what you're implying you'd like to ultimately do for cardiomyopathy patients. And so what do you need to see in a Phase II on cardiac types of endpoints since we -- this is not a CV study, right? But ultimately, that is what you want to show?

Yes. So ultimately, we'll be looking at survival-based endpoints, like, we think that to be obviously what's most appropriate here in this patient population. I'd point also to the data that Radhika showed. In our AL amyloidosis program. Remember, AL amyloidosis is kind of an analogous peripheral amyloid disease, very close to ATTR. It is caused by different proteins, but ultimately, the etiology is the same. It's amyloid deposition in vital organs, including the heart that leads to a restrictive cardiomyopathy and ultimately can lead to mortality in patients. And there, when you look at the more severe patients, now these patients are categorized a little bit differently. So these would be considered Mayo Stage IV patients. Based on literature, you'd expect the median survival of those patients to be somewhere around 6 months. In our study, what we found was that on standard of care treatment, the median survival was just around 8 months, but we had a very rapid and robust survival benefit when we targeted amyloid with a depleter mechanism of action. This would be birtamimab in that study, which ultimately gave us a better than 50% relative risk reduction in all-cause mortality. So we think that also adds into our thinking about how this type of mechanistic approach can play into this space. And of course, on a biology level, it makes perfect sense. If what's driving these patients to a severe phenotype and ultimately to present in the emergency department is a relatively robust level of amyloid deposition in the heart, than what's needed particularly quickly if patients are at risk of early mortality is to remove or deplete that amyloid so that the cardiac function can be restored to an extent that these patients can survive. And that's, again, I think, something that we can leverage in terms of learning across our portfolio, and we think provides strong analogous evidence on top of the data that we're talking about on cardiac systolic function that we saw in the Phase I study here with PRX004, that adds to our confidence.

And our next question comes from Kennen MacKay, RBC Capital Markets.

Congrats on the data today and the update. So these 7 long-term extension patients were all relatively low on the NYHA Class score, 6 in Class I, 1 in Class II. Can you just remind us how many patients in the Phase I study were Class III or IV at baseline, and how do those more severe patients responded to treatment? Just given you're comparing the data to the Class III, IV patients in the birtamimab study and given tafamidis has sort of a dichotomous benefit in early stage, but not late stage, just trying to understand what data we have in these more severe patients before starting a Phase III trial there?

Yes. So great question, Ken. And I'll ask, maybe Radhika, here to speak to this, but I'll just say that, obviously, this is a first-in-human Phase I study, we had not included the most severe patients, but maybe Radhika, do you want to speak to whether we had any NYHA Class III patients in the study?

Yes. No, we did not have any NYHA Class III or IV. Those patients were formally excluded from the study.

But again, Ken, I'd say here, again, we can leverage some comfort from our AL amyloidosis experience where really from a safety perspective from -- in terms of how the antibody interacts with the amyloid we really didn't see any distinction on a safety basis between more severe, more mild patients. And in fact, if you think about the mechanism here, the idea is if you're this antibody, if you're PRX004 in the case of AL amyloidosis, birtamimab. You're hunting amyloid because it's in an amyloid structure, right? It doesn't matter where it's deposited or even how much is deposited or what organ it's in. So the idea would be, we think, from a biology perspective, from a mechanism perspective, that should be relatively undifferentiated.

And our next question comes from Bert Hazlett with BTIG.

Yes. Congratulations on the results from me as well. And again, my question is I -- my question is with regard to the doses, I think you've spoken about the PK/PD modeling, the saturation that you affect with these -- with the molecule. Are there any differences among the dosing or the doses that lead you to focus on one of the doses as opposed to the others with regard to what you see in this Phase I study?

Yes. Thanks for that question, Bert. It's a good question. And obviously, I think Wagner did a pretty nice job of laying out how we both had established in a preclinical PK/PD model and then subsequently confirmed that through our assessments in the Phase I study, that the expectation that doses at and above 3 milligrams per kilogram would be saturating, i.e., above 90% occupancy at the level of tissue in an in vivo setting. I think -- so to answer your question, why might you go, for example, to a dose higher than 3-milligram per kilogram. And I think there, one would start to think about the mechanism, right? So what you're thinking about with the PRX004 mechanism is optimization or coding of the amyloid and the recruitment of phagocytes, as Wagner showed in the videos today. And I think what -- when you think about that, then obviously, you layer on top of that, a patient population that may be at risk for early mortality. And so the idea would be you wouldn't want to tiptoe into that system and start to remove amyloid slowly, you want to make sure that you had maximum impact. So to the extent that you could dose at a higher level I think you'd be inclined to do that, particularly in an at-risk cardiac population. And I think the question then becomes one of a safety tolerability question, which is are you afforded the ability to do that based on your tolerability profile. And so we were very happy to see that the safety profile was generally safe and well tolerated as was laid out by Dr. Suhr. Wagner, do you want to comment any further on the idea of kind of optimization and why that might be advantaging when you have a high amyloid load?

Yes. Thanks, Gene, and thanks for the question, too. This is an important point. I think we have -- we had our initial expectations based on in vitro data that were confirmed in the Phase I. So we are happy that the 3 doses were essentially confirmed that they would reach the same level of occupancy in the amyloid or reaching 90% or more of occupancy. If you think in the cardiomyopathy space, though, there is a viability in terms of the amount of amyloid that's deposited in organs and from the organs that we've seen that we inspected the amount of amyloid, the heart certainly has the highest load. It's quite impressive the amount of amyloid that can deposit in that organ. So as Gene said, just to be sure, to be ensured that we have coverage of all the patients' populations with all the different amounts of amyloid if the end is the safety profile [indiscernible] allows, which it is the case, for this program. Then you might want to think that to cover all the bases that you could go a little higher than what your saturation point is expected. So I think we were going to have discussions in the future about what the doses would be, but at least for this program, we can -- based on this data so far, ensure that safety is not going to be limiting. We think the doses that we tested.

Yes. I mean, this goes back to our program with birtamimab in terms of our therapeutic window, as Wagner was just saying. And you want to -- again, you want to get rid of the amyloid as fast as you can to restore function, especially in vital organs such as the heart. So if you have the therapeutic window in a population where early mortality is the biggest issue. You want to hit it as hard as you can as fast. There -- doesn't mean that in neuropathy, we wouldn't think about a 3 mg per kg dose that's subcu-able.

Our next question comes from Tazeen Ahmad of Bank of America.

Congrats on the early data. Gene, I just wanted to ask you about the IV form of dosing that you've chosen. Is the way that it's dose critical to the type of potency that you have seen so far? And do you think that in the future, there could be the potential for shifting formulation to something that might be perceived as something a little bit more user-friendly? And then I just have a couple of follow-ups.

Yes. Thanks for that question, Tazeen. So let's start with -- starting with IV. So we think with just over 30-day half-life, an IV formulation is reasonable, particularly when you start to think about moving into a patient population at high-risk for early mortality with looking for a potential survival benefit. So we think with that kind of profile, IV would certainly be reasonable, could ultimately you think about going into other formulations? Well, certainly, I mean that's always something that one can think about. So that would be the -- I think Tran just made mention of this. If, for example, somewhere in the clinical development plan, you wanted to move into neuropathy and maybe target a lower dose level like 3 milligrams per kilogram, then that could be a dose level that would be particularly suitable for a subcutaneous administration, for example, but I think right now, thinking about survival benefit in a severe patient population, we think an IV presentation is reasonable.

Right. We could always think of life cycle management formulations such as continuous dosing. I mean, there are definitely technologies out there that we can think about, but to echo what Gene just said, this is -- clearly, these patients are focused on surviving, given the early mortality here. So we have the physician and the patient's attention. So actually getting that monthly care may not be at the beginning, it actually might be good to their standard of care.

Okay. And then as it relates to survival benefit, how long do you think, Gene, it would take to show that benefit given that these patients are advanced? I would imagine it would take a lot less time than what you would have needed to see, for example, with AL amyloidosis, but just wanted your thoughts on that?

Yes. So look, it's 2 factors, right: I mean, one is what's happening on the control side and how quickly are you recognizing those events? And so for example, going back to AL amyloidosis and birtamimab in that Mayo stage IV patient population, which are the higher at-risk patients with respect to a mortality event. As I mentioned, in that study that we ran on the control side, which those patients were receiving standard of care, we saw median survival of just over 8 months, but literature would suggest about 6 months, but interestingly, somewhere just under half of those patients, a meaningful number of patients, we actually saw a mortality event occur within the first 3 months. And over that time period, we saw a very robust effect of birtamimab. So we believe that being able to intervene in the amyloid process and actually being able to deplete amyloid from organs like the heart. If that data obviously holds -- one; it points to the idea that you can see a very rapid impact so then it really just becomes a function of, do you have a signal with which to evidence that benefit, i.e., do you have enough events happening on the placebo arm to be able to actually realize that benefit. So those are...

And we're encouraged by the GLS improvements, too. So I think all of that fits together well with what Gene just said.

Okay. And then maybe my last question would be how much discussions have you had with FDA on the trial design for the next step, which as you mentioned at the beginning, would be a potential pivotal for cardiomyopathy patients. Is it your understanding that you would actually have to show a survival benefit in that study or is FDA willing to accept the biomarker data?

We think it will from a...

Go ahead, Tran.

I would just say from a tafamidis perspective, you've seen how Phase III is conducted, and there are other trials that are being done with 6-minute walk, but we think, ultimately, in terms of the patient population that we're targeting that we believe other mechanisms aren't targeting. We think ultimately, it will be survival that wins the day here. And so as we get more details clearly around the nuanced trial design, we'll share that next year.

Okay. Have you met with FDA already or will you be meeting with them?

So I mean, it's always best practice to have interactions with regulatory counterparts at FDA. So that being said, we'll give you the update next year when we initiate the trials.

And ladies and gentlemen, this does conclude our question-and-answer session. I would now like to turn the call back over to Gene Kinney for any closing remarks.

Great. Thank you, and thank you all for joining us this morning. I'll take this opportunity to wish you all a wonderful holiday season. I look forward to seeing many of you in January and throughout next year as we have updates on our programs to report. So thank you very much.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.