Good morning, welcome to the Alkermes conference call. My name is Brandon, and I will be your operator for today. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session during which you can dial star one if you have a question. Please note this conference is being recorded, and I will now turn it over to Eva Stroynowski, Co-Head of Investor Relations. Eva, you may begin.
Thank you, welcome to the Alkermes plc conference call to discuss the results of our ENLIGHTEN-2 phase III study for ALKS 3831. With me today are Richard Pops, our CEO, and Craig Hopkinson, our Chief Medical Officer and Senior Vice President of Medicines Development and Medical Affairs. We will be making forward-looking statements based on our current expectations relating to, among other things, the future clinical development of ALKS 3831, its therapeutic value and commercial potential, and our regulatory filing strategy and timelines. These forward-looking statements are neither promises nor guarantees and are subject to a high degree of uncertainty and risk. Please see our press release issued today and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in the forward-looking statements.
We undertake no obligation to update or revise the statements provided on this call as a result of new information or future results or developments. After our remarks, we will open the call for Q&A. Now, I would like to turn the call over to Craig.
Thank you, Eva, good morning, everyone. We are extremely pleased today to announce positive top-line results from the ENLIGHTEN-2 pivotal phase III study of ALKS 3831 in patients with schizophrenia. Put simply, the study was an unequivocal success. Before I get into the details, I will start with some background. ALKS 3831 is an investigational novel antipsychotic drug candidate designed to provide the robust antipsychotic efficacy of olanzapine, but with a differentiated weight and metabolic profile. It is a once-daily bilayer tablet composed of olanzapine and samidorphan, our proprietary opioid antagonist. Olanzapine is widely regarded as one of the most efficacious atypical antipsychotics, as evidenced by the landmark CATIE study. However, there are limitations to its use due to the substantial weight gain and metabolic consequences that many patients experience. Yet, even with these liabilities, olanzapine remains the third most prescribed antipsychotic for schizophrenia because of its powerful efficacy.
We designed ALKS 3831 to provide the antipsychotic efficacy of olanzapine while mitigating its associated weight gain. Following positive results from a 300-patient phase II study, we met with the FDA to establish the registration criteria for the program. FDA requested two studies. The first, which we called ENLIGHTEN-1, was a dedicated study designed to prove the antipsychotic efficacy of ALKS 3831 in an acute setting. The study's primary endpoint evaluated reduction in positive and negative syndrome scale scores, or PANSS, a conventional endpoint used in schizophrenia studies, and we completed that study successfully last year. The second study required by FDA, ENLIGHTEN-2, was a head-to-head comparison of weight gain for ALKS 3831 versus olanzapine over a six-month period, similar to the phase II study we had previously conducted.
In phase III, the FDA set a higher bar and wanted two co-primary endpoints in order to establish clinical meaningfulness. One focused on the mean change in weight, and the other on the proportion of patients gaining an excessive amount of weight at a level specified at 10%. Both studies are now successfully completed. Together, they support a differentiated product profile of strong antipsychotic efficacy with a meaningfully improved weight profile for ALKS 3831 compared to olanzapine. Looking ahead, we'll meet with the FDA to review the data from the ENLIGHTEN development program and plan to submit an NDA to the agency in mid-2019. Let's move now into the results for ENLIGHTEN-2. ENLIGHTEN-2 was a multi-center, double-blind, randomized phase III study that evaluated the weight gain profile of ALKS 3831 compared to olanzapine over six months as measured by two co-primary endpoints.
The mean change in body weight from baseline and a categorical endpoint evaluating the proportion of subjects with 10% or greater weight gain at six months. In order to achieve a positive study, each of the co-primary endpoints had to achieve a P value of less than .05. A total of 561 patients with stable schizophrenia were randomized in the study, and 538 patients who had at least one post-baseline weight assessment were included in the full study population. The results of the study were clear and strong, with ALKS 3831 demonstrating clinically meaningful and statistically significant improvements for both the pre-specified co-primary endpoints at six months. Looking at the mean change from baseline first, patients in the olanzapine group had a mean percentage weight change of 6.59% versus 4.21% for the ALKS 3831 group. This difference was statistically significant with a P value of .003.
Stated another way, this represents a 50% higher mean change for olanzapine as compared to ALKS 3831. The mean reflects the entire patient population, and a shift of this magnitude is meaningful. When considering the overall profile of olanzapine, shifting the mean does not tell the whole story. We know that there's a substantial subgroup of patients that will gain extreme amounts of weight. The categorical co-primary endpoint evaluating the proportion of patients who gained 10% or more of their baseline body weight at six months was designed to assess the benefit of ALKS 3831 on reducing the risk of a severe weight gain.
At six months, the proportion of patients who gained 10% or more of their baseline body weight was 29.8% for olanzapine versus 17.8% for ALKS 3831. Expressed in terms of an odds ratio, the olanzapine group had two times the risk of this level of weight gain as compared to the ALKS 3831 group. This was statistically significant with a P value of 0.003. In addition to meeting both co-primary endpoints, the ENLIGHTEN-2 study also met its key secondary endpoint. At six months, the proportion of patients with 7% or more weight gain was 42.7% for olanzapine versus 27.5% for ALKS 3831. Expressed as an odds ratio, the olanzapine group, again, had two times the risk of gaining 7% or more of their baseline body weight as compared to ALKS 3831, and this had a P value of 0.001.
Beyond the 10% and 7% categorical cutoffs, we had conducted additional analyses focused on the proportion of patients in the study who experienced weight gain of at least 2%, 5%, and 15% of their baseline body weight at six months. We observed a similarly favorable profile for ALKS 3831 compared to olanzapine at each of these categorical cutoffs. These data clearly demonstrate a meaningful and favorable shift of the entire weight distribution curve for ALKS 3831 compared to olanzapine, both in terms of mean weight gain and the proportion of patients at the tail of the bell curve experiencing extreme weight gain. In addition to this, the shape of the curves matter. Consistent with our phase II study, the weight gain curves for ALKS 3831 and olanzapine treatment groups began to separate after week four and continued to diverge for the remainder of the study.
The ALKS 3831 weight curve stabilized at week six and remained flat for the rest of the six-month treatment period. This is the profile we were hoping to see, and we believe demonstrates the clinical value of ALKS 3831 for patients. Overall, 64.2% of patients treated with ALKS 3831 completed the study, compared to 63.8% of the patients who received olanzapine. All patients who completed the study were eligible to roll over into an open label long-term extension study for an additional 12 months of treatment with ALKS 3831, and 76% have done so. The most common adverse events reported in the ALKS 3831 treatment group were weight gain, somnolence, and dry mouth. The most common adverse events reported in the olanzapine group were weight gain, somnolence, and increased appetite.
Serious adverse events occurred in 3.6% of the ALKS 3831 patients and in 2.5% of the olanzapine-treated patients during the treatment period. Today's top-line results are the first of what we expect to be a number of important findings to emerge from the ENLIGHTEN-2 study as we continue to analyze this extensive data set. Given the size and scope of the study and the multiple additional parameters assessed throughout the course of the six-month trial, including antipsychotic efficacy, metabolic parameters, including basic laboratory assessments, and an evaluation of weight circumference and subgroup analyses, we plan to present the detailed results from the study at medical meetings in the spring.
Before I turn the call over to Richard, let me take a moment to offer my sincere thanks to the patients and investigators participating in our studies, as well as the caregivers that play a key role in supporting our efforts to advance patient health. With these results, we are now on the cusp of another NDA submission, a significant achievement and a direct result of our highly experienced, dedicated employees who are driven to improve patients' lives. I'm honored to be part of this team and offer my gratitude to the employees across the organization who have enabled us to reach this goal. With a novel pharmacologic approach designed with the real-world needs of patients in mind, we believe that ALKS 3831 has the potential to have a profound impact on the treatment of schizophrenia. With that, I'll now hand the call over to Richard.
Well, thank you, Craig. That was excellent, and congratulations to you and your team been working so hard on this. This is obviously an important result for the 3831 development program, for the patients who stand to benefit from it, and for the company. First, from the perspective of the 3831 program itself, it completes our registration package. We'll now plan to meet with FDA and proceed to file. From the inception of this program, we established clear standards for what would constitute data showing meaningful differentiation from olanzapine and real clinical significance. We wanted to see statistically significant effects on two endpoints, which served to define the overall weight distribution, mean weight change, and the proportion of patients gaining more than 10% of their baseline weight.
In addition to that, we wanted to see a flattening weight gain curve for 3831 to be convinced that the pharmacology was stable and therefore the weight difference could grow over time as compared to olanzapine alone. We needed a clear positive outcome to confirm findings from earlier studies, and that's exactly what we got. Clinical studies in psychiatry are challenging. This was particularly true in the case of ENLIGHTEN-2, given its large sample size, six-month duration, active olanzapine comparator, and the inherent complexities of clinical studies in the treatment of patients with schizophrenia. Yet, the profile of ALKS 3831 revealed itself consistently once again. It's gratifying and noteworthy to be able to point to positive data from two large phase III trials in the ENLIGHTEN program, along with the large phase II weight study.
Throughout, ALKS 3831 has performed consistently with what we designed from the outset, the proven efficacy of olanzapine with a favorable weight profile. The second point is that this is really important for patients. We have a tremendous amount of experience in the field of schizophrenia and have a clear sense of the unmet needs. Our long-acting injectables provide important benefits to patients, and we expect them to continue to grow in their use and in their impact. The vast majority of the market consists of oral agents, and the current offerings fall short. Patients need highly efficacious oral medicines, but efficacy alone is not enough. These medicines must have an acceptable tolerability profile. That's the crux of what we're trying to address and where we believe 3831 has the potential to offer a new treatment option for patients with schizophrenia.
We believe strongly that an oral medication with this profile can become a leading agent in this class, with potential utility in other indications as well. Finally, this result has important implications for the company. We have a growing proprietary psychiatric franchise based on VIVITROL and ARISTADA, and a distinctive commercial capability honed in complex treatment system with government payers. We've been anticipating our next wave of growth driven by our late-stage pipeline, and 3831 is our next important potential value driver. With the registration program completed successfully and the clinical profile of 3831 established, we see the potential to build on our already significant presence in psychiatry in a way that can be synergistic for all of our medicines.
VIVITROL, ARISTADA, and 3831 were designed to address real-world challenges that physicians and patients and their caregivers experience, and they're the result of our patient-centered approach to new drug development. We're thrilled with the outcome, and we look forward to bringing forward this potential new treatment option to patients. With that, I'll turn it back to Eva to run the Q&A.
Thanks, Rich. We'll now take your questions. Brandon, if you can open up the line.
Yes, thank you. We'll now begin the question and answer session. If you have a question, please press star one on your telephone keypad. If you'd like to be removed from the queue, please press the pound sign or the hash key. There may be a delay before the first question is announced. If you're on a speakerphone, please pick up your handset first before dialing. Once again, if you have a question, please press star one on your telephone keypad. From JP Morgan, we have Cory Kasimov. Please go ahead.
Hey, guys. This is Matthew on for Cory and congrats on the data, and thanks for taking my questions. My first question is on the commercial potential of 3831. Beyond the trial statistics, what does your market research say about the level of weight gain differential that docs see as clinically meaningful?
Hey, good morning. I think it's a really important question because it reveals the distinction between the data necessary for regulatory approval and the real-world data that I think physicians have expressed interest in. We've been doing a lot of work, obviously, with physicians over many years in this regard. First of all, you should know that there's a tremendous interest in using olanzapine in the treatment of schizophrenia and other diseases, but a reluctance based on the weight gain. Showing a meaningful change in the weight gain profile of an agent with olanzapine's efficacy is considered to be something that's very attractive.
We feel that the profile now that we've established in the clinical trial by showing a change in the mean, in the tail, and importantly, the flatness of the curve, we're shifting olanzapine now to being back more like a weight-neutral agent that they're comfortable using. We're quite excited about the profile. Craig, do you want to add anything to that?
No, I completely agree with Rich. I think what really makes these data compelling is the shape of the curve, because yet again, we saw early separation between olanzapine and 3831. We saw flattening of the curve reaching significance from week six onwards, and maintaining that flatness of the curve for 3831 and continued divergence throughout the study between the groups. I think when you look at the published literature, these results really place it into the realm of agents like brexpiprazole in terms of weight gain that they saw across their clinical programs.
Great. Thank you. I'm curious what you can tell us about the different patient subgroups in the trial. Any baseline characteristics to point to that may be predictive of weight gain on either of the co-primary endpoints?
What I can say is that the baseline characteristics of the study, the study was extremely well balanced. We specifically looked at a number of subgroups as part of the primary analysis. In each of those subgroups, the same benefit held across subgroups. We looked at baseline BMI coming into the study. We looked at age, we looked at race, and all of those held in terms of the overall result.
Awesome. Great. Thanks for taking my question.
From Bank of America, we have Jason Gerberry. Please go ahead.
Good morning, and thanks for taking my questions. I guess first one, maybe Rich, your thoughts in terms of what you think now that you have got data in hand might translate into a different product label or package insert label claims versus the Zyprexa molecule. My second question, just to come back and kind of confirm. On the curves for weight gain, it sounds like you are seeing a plateau at six months on ALKS 3831. I imagine just based on what we have seen in other meta-analyses trials on Zyprexa that is continuing to move upward. I would have thought that around we would have seen closer to maybe 8% weight gain on the olanzapine arm. Anything surprise you in terms of the performance of the comparator arm in the trial?
Morning, Jason. I will answer the second one first, just to be clear. We saw flattening of the ALKS 3831 data at six weeks, not six months. That is really important. That is statistically significant flattening. We actually saw separation beginning at four weeks, consistent with our phase II. I think when you see the data presented, you will be struck by how consistent the data are from the phase III study with the phase II study. With that said, you are right. I think that we saw a little bit less weight gain in the olanzapine arm than we would have modeled or what we saw in CATIE, but it was still enough to drive the significant separation.
It was fine in that regard. What was interesting about our discussions with FDA on the registration program was rather than their asking us to run two replicate efficacy studies for approval, they asked us to run the one efficacy study and the second study, ENLIGHTEN-2, with the primary endpoints being weight. Those will be in the label, right? That is the labeled primary endpoint, and we expect all those data to be in the label.
I am sorry, just to follow up. At the end of the treatment period, which is six months.
Right
You are still seeing a flat curve from six weeks out to six months?
Correct.
Okay.
That's Craig's point. When we talk to clinicians, the basic statistical nuances of mean shifts and tail shifts are one thing, what patients want to know, and doctors want to know is, what's the profile? What does it look like? I've said many times, if we had won on both endpoints, yet our curve was still ascending at six months, ultimately to converge with the olanzapine curve, this drug would have no clinical utility, and payers wouldn't pay for it. What we're saying is we have a fundamentally different drug now than olanzapine, but we've captured its efficacy. That's why we're so pleased with the outcome.
Got it. Thank you.
From Cowen, we have Chris Shibutani. Please go ahead.
Yes, good morning. I believe that there was an analysis of looking at patients who were early weight gainers, those who gained weight during the first week. Will you be able to provide any commentary about identifying those patients and perhaps how those patients behaved?
Yes. that was one of the analyses we looked at. as I said earlier on, as we looked at each of the subgroups, the overall results held. There really was no additional benefit in those patients who were early weight gainers in terms of the overall result, which really reinforces the fact that we made the right decision in designing the study, not specifically looking to enrich for early weight gainers. Once again, those patients benefited, but to the same degree as the overall population.
Chris, I'll just add to that in phase II, recall, no one had ever run a study like this before. we employed that stratification or that analysis to determine whether early weight gain in the first week was a harbinger of significant weight gain later on. it turned out in phase II that two-thirds of the patients were early weight gainers. discussing with our team of clinical trialists, they basically said everyone gains weight. we dispensed with that in phase III, and as Craig said, it was the right decision. all comers, we now analyze everybody benefits. in post-hoc subgroup analyses, we don't see a different stratification based on early weight gain.
Great. if I could follow that up on the safety profile commentary, was there any particular pattern in terms of the time course when patients were taking 3831 or olanzapine that you saw some of the safety events, particularly with regard to any treatment-related discontinuations?
Not at first pass, Chris. These data are pretty fresh. We'll be looking at a whole lot of additional analyses. In terms of the overall safety profile, this is very consistent with what we've seen previously with 3831.
I know that you'll be planning to share more data at a medical meeting, but can you broadly comment whether any other aspects, for instance, metabolic profile from this, were as you expected, or are there any notable findings there? Then, of course, on the efficacy side, should we assume that the efficacy of both 3831 and olanzapine at the six-month point were comparable and in line with expectations? Thank you.
Yeah. Let me start with your second question first. In terms of the efficacy, obviously, we measured efficacy utilizing PANSS scores. These patients came into the study as pretty stable patients. What we saw was early separation from baseline for both olanzapine and 3831. We saw improvements in PANSS scores with statistical significance in separation from baseline pretty early on in the study. We'll be obviously presenting that full data set in the spring. In terms of the additional endpoints, we've got obviously a wealth of data still to come. The metabolic data are interesting, and there's a number of different aspects that we plan to share with everyone in the spring when we present the data. Yes, there's more to come.
Okay. Thank you very much. We'll look forward to those.
From Evercore ISI, we have Umer Raffat. Please go ahead.
Hi. Thanks so much for taking my question. I have three, if I may. First, can you go over the impact that metformin has on olanzapine weight gain? Also, to what extent is that actually used in clinical practice? That was first. Second, on weight gain as an AE, I remember phase II had a few patients that were counted as adverse events on weight gain. I was curious what that was in this phase III. Finally, also, could you please remind us about the dose used for both the olanzapine in the study as well as for ALKS 3831? Thank you so much.
In terms of the adverse event profile, could you maybe just repeat the three questions again?
First one was the use of metformin-
Metformin
impact on weight gain.
Yes, we know that metformin. It's more sort of anecdotal use. There's not a whole lot of wealth of data to support the use of metformin in this population. We also know it's not indicated for use in this population. Essentially, I think there's variable results. In terms of its use, we don't think it's widely used. Once again, there's really no well-controlled data to support metformin use in this population, and it's outside of its indication. The second question?
Let's go to the last question first, the question about the dose used in the study. 10 mg of samidorphan with 20 mg of olanzapine.
In the-
In ALKS 3831 arm, and then olanzapine 20 mg.
Yeah. Essentially, patients coming into the study were titrated up to 20 mg of olanzapine and 10 mg of samidorphan. After one week of coming into the study, patients could be down-titrated for up to the first four weeks of the study, after which all patients had to remain stable for the remainder of the study.
What was that? The majority of patients did stay on that 20 mg dose.
Yeah. Absolutely. The majority of patients as in our previous studies tolerated the 20 mg of olanzapine and remained on 20 mg throughout the study.
Umer, you were a little hard to hear. Your second question was around the weight gain AE. Do you mind repeating that?
Sure. In phase II poster, I remember there was an AE disclosure of weight gain. I was curious, was there an adverse event line item by weight gain and what that was?
Yes, both groups had a weight gain. As I said, that was one of the most common adverse events reported for both groups. We saw a higher numerical incidence in the olanzapine arm than in 3831, obviously, we'll be presenting those data as well.
Got it. Thank you very much.
Okay.
From B. Riley FBR, we have David Buck. Please go ahead.
Yes, thanks. Can you talk about what the main reasons for discontinuation were and whether there was a difference in weighting between the two groups? Secondly, if you hit the timeline of a mid-2019 submission to the FDA, what's your sense of whether they will be in AdCom as part of the review? Thanks.
Starting off with your safety question. Obviously, in terms of overall safety, 64.2% of patients who received 3831 completed the study versus 63.8% of patients who received olanzapine. The most commonly reported adverse events in the 3831 arm were weight gain, somnolence, and dry mouth. The most common adverse events in the olanzapine arm were weight gain, somnolence, and then increased appetite.
The second question was on.
Well, I guess just was there a differential in terms of discontinuation by adverse event, reasons for discontinuation?
Not really, no.
Okay.
Your second question on the AdCom, obviously this is an NCE, the pattern has been recently that all NCEs go to an AdCom. At this point in time, we'll be preparing for that. Once again, there's no real pattern, especially with this division as to whether they will be requesting an AdCom for this program. I don't know, Rich, if you wanted to add.
My only thing is if the NCE is samidorphan, it's been reviewed by FDA in the context of the 5461 submission, it's not clear. I think if they have scientific questions they want to ask in AdCom, they'll have an AdCom, if not, they won't.
Great. Maybe if I could sneak in one more. Was there anything in the design of the phase IIIs that was controversial, needed to be sort of discussed before setting up ENLIGHTEN-1 and ENLIGHTEN-2?
No. We had a very open dialogue with the agency in planning this program. We reached full agreement on the designs of the studies. Most recently, reached full agreement with the agency on the statistical analysis plan for the trial before we locked the study.
Thank you. From Credit Suisse, we have Vamil Divan. Please go ahead.
Hi, this is Uy Ear for Vamil. Just a couple of questions. I don't know if you're able to share with us, what is the mean baseline in both groups? You indicated they were both balanced. Also, I think you indicated that the bell curves for both arms shifted, and I was just wondering what proportion of the bell curves overlapped. Thank you.
In terms of the baseline BMIs, patients came into the study very well-balanced with a baseline BMI of about 25.45 across the study arms, and very little difference between the two groups. In terms of the bell curves, I think what's really impressive is when we looked at the categorical endpoints in the study, and we looked at a number of them. We had the 10% categorical endpoint where we significantly shifted the curve with highly statistical outcome. Our secondary endpoint was 7%. We also looked at a 2%, 5% and 15%. In all of those categorical measures, we reached statistical significance between olanzapine and 3831. Not only did we shift the mean weight curve significantly to the left, but you're also seeing in terms of any categorical cut point that we took, that we saw significant separation between the two groups.
Okay. Thank you. From Piper Jaffray, we have Danielle Brill. Please go ahead.
Hey, good morning. Just a quick one for me. Did you evaluate any inflammatory parameters, and can we expect those to be presented at a medical conference as well?
No. We did look at a number of metabolic parameters, but, to my knowledge, we didn't collect any inflammatory markers.
Okay. Thank you.
Okay. From Leerink Partners, we have Marc Goodman. Please go ahead.
Hi, this is Roanna on the line for Marc Goodman. Just a quick question for you. I'm wondering if you could put the data a little bit more in context by giving us a sense of what the weight gain was for olanzapine at six months in pounds, and also if there is maybe a slight plateauing of olanzapine. I know you mentioned there was separation, but I just want to gauge what the difference was compared to 3831. Thanks.
Yeah. Expressed in pounds, the olanzapine group gained an average of 11.2 pounds and 3831, seven pounds.
Okay.
Okay. From Jefferies, we have Biren Amin. Please go ahead.
Yeah. Hi, thanks for taking my questions. I've got several. What was the treatment difference in patients gaining more than 15% body weight, given this is probably a patient pool with a significant unmet need? I guess that's the first question. Second question, Richard, how should we look at difference in treatment arms? Because I think, in the phase II, you looked at weight reduction from olanzapine, whereas in the phase III, it's higher weight change to 3831. I guess the last question is how should we think about potential pricing for 3831? Thanks.
Maybe I'll take your first question. In terms of, as I said, the categorical cut points that we looked at, we reached statistical significance across every single one of those cut points. At this point in time, we're not actually disclosing more data than that. We'll be presenting the full data set in the spring. I think, once again, what's really exciting to us is, no matter whether you looked at 2%, 5%, 7%, 10% or 15%, we saw statistical separation between olanzapine and 3831 in terms of the categorical endpoint.
Biren, I want to just make sure you understand the objective of the medicine and development program. 15% is a retrospective look at a patient who has gained excessive amount of body weight. The point of the experiment is to show that this medicine is very different than olanzapine and trends more toward the weight-neutral agents than toward olanzapine. The idea is not to wait for somebody to gain 15% of body weight and then see whether you can reverse it with 3831, because it won't do that. It's to build the case that this is a differentiated medicine that should be used in every patient. This is a better, safer approach to deliver the efficacy of olanzapine in a differentiated new medicine. Your second question, I didn't completely understand. We measured the same things in the phase II as you measured in the phase III.
You can express them as changes in different ways, but it's exactly the same measurement. We're looking at weight over time, and you'll see those plots. As I mentioned before, when you see the phase II plot side by side with the phase III plot, you'll be struck by the consistency of the ALKS 3831 effect. In terms of pricing, it's too early to make a decision on pricing. I will say this is a market that we're in every day. The idea of working in strict payment systems with institutionalized and highly bureaucratic systems and patient populations that are often disadvantaged at price points that are very different than oncology or orphan drugs, this is where we live every day. We feel quite comfortable here.
Great. Thank you.
All right. We have time for one more question.
From Stifel, we have Paul Matteis. Please go ahead.
Great. Thanks. Appreciate you taking a few questions. I guess one, I'd be curious if you agree with this statement, Rich, I think in the real world, many analysts and investors assume that ALKS 3831 might be used as sort of a switching agent in a patient on olanzapine who maybe takes a drug for a month or two and gains some weight, then you use this to try to flatten the curve. To that point, I guess, do you agree with that, and do you plan on generating any switching data to show that the drug works and what might be a real-world context? Then I just have one follow-up. Thanks.
I'll let Craig as a clinician answer that first, I'll give you my point of view, which is derived from talking to clinicians. Craig.
I think the most important aspect of the entire program that we've seen so far is that what we see in terms of the profile of ALKS 3831 is that we see early separation from olanzapine. You see complete flattening of the weight gain curve. Our view is that the patients that benefit from this are the patients that come onto therapy early and remain on therapy. ALKS 3831 is not a weight loss agent, I think ultimately, the clinically correct approach here would be for physicians to place patients onto ALKS 3831 and not step through olanzapine first, where they put on significant amounts of weight early on that they're never going to lose again.
My view, Paul, is that it's not really the way that schizophrenia patients are treated in the U.S., sadly. It's more of a comment on the poor status of care for these patients. It's not like they're frequently going to the doctor, testing their medications, titrating mood. You have an opportunity to initiate treatment on patients, often in the acute setting. You want to put them on an agent that they're going to be tolerant and continue to take. The ALKS 3831's going to be very useful in that setting. Second thing is that we know that there's just a tremendous amount of use of olanzapine in the community right now, albeit reluctantly, because people know the risk they're putting patients under. The efficacy of olanzapine in the community is well established in schizophrenia as well as in bipolar disease.
We detect from physicians a real reluctance to use it for a long period of time and a reluctance even to initiate on it, because if it's well tolerated, it's difficult to shift. People don't want to shift them off of an efficacious medicine. The final point I'll make is that sadly, every patient that's going to go on ALKS 3831 will have failed multiple generic medicines. That's just the state of care of schizophrenia in the United States. The idea that we're going to be getting newly diagnosed patients and putting them on a brand new medication is just not true. With that said, this is a population denominated in millions, and there's plenty of opportunity for new patient starts.
Okay, thanks, Rich. That's helpful. Just one follow-up. On the question that Umer had on the weight gain adverse event versus weight gain on the primary endpoint. I would just love to clarify that. In what context in this study is weight gain on 3831 or olanzapine codified as an adverse event versus incorporated into the primary endpoint? Maybe just lastly, I was wondering if you could just comment on your expectations for scheduling on the heels of the 5461 panel and discussion around samidorphan. Thanks again.
Let me give some context around the adverse event. What was really interesting from the data was obviously we had the primary efficacy endpoint, which is a weight endpoint, and obviously, we presented those data to you. In terms of the adverse events, once again, you saw a differential in terms of olanzapine versus 3831 in terms of the treatment emergent adverse event of weight increase, where we saw 36% of the olanzapine patients that reported this adverse event versus 24% on 3831. Once again, in a study that is designed to specifically look at weight gain where patients are consented, that they know that we're going to be following up for full weight gain. I think it's pretty interesting that you're seeing that differential even in the safety profile.
I think we should clarify, that's a patient-reported.
Yeah
AE. There's no threshold for it. You could gain a pound and report it. It's a spontaneous report.
Absolutely.
I think the final question was on scheduling.
Well, if there were any bright spot of the 5461 panel, it was the presentation by FDA on the abuse liability of samidorphan as a single agent. It was very clean, very clear, because it is indeed an opioid receptor antagonist. We don't expect this drug to be scheduled.
Thank you, ladies and gentlemen. This concludes today's conference. Thank you for joining. You may now disconnect.
All right. Thanks, everyone. Please reach out to us if you have any additional questions.