Altimmune, Inc. (ALT) Earnings Call Transcript & Summary

Good day, ladies and gentlemen, and welcome to the Altimmune, Inc. MOMENTUM Pemvidutide Phase II Obesity Trial Week 24 Interim Analysis Conference Call. [Operator Instructions] As a reminder, this call is being recorded. I would now like to introduce your host for today's conference call, Rich Eisenstadt, Chief Financial Officer of Altimmune. Rich, you may begin.

Thank you, operator, and good morning, everyone. Thank you for participating in the conference call to discuss the results of the week 24 interim analysis of the MOMENTUM pemvidutide Phase II obesity trial. Members of the Altimmune team joining me on the call today are Vipin Garg, our Chief Executive Officer; Scott Harris (sic) [ Scot Roberts ], our Chief Scientific Officer; Scott Harris, our Chief Medical Officer; and Dr. Louis Aronne, Professor of Metabolic Research and Professor of Clinical Medicine, Weill Cornell Medicine, the principal investigator of the MOMENTUM obesity trial. On today's call, we will also discuss the results of our 12-week Phase Ib safety trial of pemvidutide in subjects with obesity or overweight and Type 2 diabetes. Following the prepared remarks, we will hold a question-and-answer session. A press release summarizing the results of the Phase II trial that was issued this morning can be found on the Investor Relations section of the company's website along with the slide set that will be used in today's presentation. Before we begin, I would like to remind everyone that remarks about future expectations, plans and prospects constitute forward-looking statements for purposes of safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Altimmune cautions that these forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those indicated. For a discussion of some of the risks and factors that could affect the company's future results and operations, please see the risk factors and other cautionary statements contained in the company's filings with the SEC. I would also direct you to read the forward-looking statements disclaimer in our press release issued this morning and now available on our website. Any statements made on this conference call speak only as of today's date, Tuesday, March 21, 2023, and the company does not undertake any obligation to update any of these forward-looking statements to reflect events or circumstances that occur on or after today's date. As a reminder, this conference call is being recorded and will be available for audio replay on Altimmune's website. With that, I will now turn the call over to Dr. Vipin Garg, Chief Executive Officer of Altimmune.

Thank you, Rich, and good morning, everyone. We appreciate you joining us today for a discussion of the results of 24-week interim analysis of the MOMENTUM pemvidutide Phase II obesity trial and full results of our 12-week Phase Ib safety trial of pemvidutide in subjects with Type 2 diabetes. We are also pleased to be joined by Dr. Dr. Louis Aronne, principal investigator of the MOMENTUM trial, who will participate in the discussion of the data. With that, I'll turn the call over to Scott Harris, our Chief Medical Officer, to go through the results of the 2 trials. Scott?

Thank you, Vipin, and good morning, everyone. We are excited about the 24-week interim analysis results of the MOMENTUM trial and the full results of the 12-week Phase Ib safety trial of pemvidutide in subjects with Type 2 diabetes. For the presentation of these 2 trials, I will use the slide set that was posted this morning to our corporate website, as noted by Rich Eisenstadt in his opening remarks, and ask Dr. Aronne to provide his thoughts as I move through the deck. The 2 trials provide a comprehensive overview of the impact of pemvidutide in weight loss, lipids and glucose homeostasis both in patients with and without diabetes. I will start today's presentation on Slide 3, which describes the MOMENTUM trial design. This is a Phase II 48-week trial of pemvidutide with a planned enrollment of approximately 320 subjects with overweight or obesity. Subjects were randomized 1:1:1:1 to 1 of 4 treatment arms, either pemvidutide 1.2 milligrams, 1.8 milligrams, 2.4 milligrams or placebo, stratified by sex and baseline BMI with lifestyle intervention standard for our obesity trials that included a 500-kilocalorie caloric restriction and 150-or-more moderate intensity minutes per week. No dose titration was used at the 1.2 or 1.8 milligram doses, while a short 4-week titration was used with the 2.4 milligram dose, as was used in our most recent trials. This was considerably less than the 4- to 5-month titrations employed with other GLP-1-based agents. It is important to note that dose reduction was not allowed if subjects experienced intolerability, a significant point that I will discuss later. An interim analysis was performed in 160 subjects that have completed 24 weeks of treatment, with the final analysis of the full population at week 48 expected in the fourth quarter of 2023. As shown in Slide 4, the next slide, the key eligibility criteria included men and women 18 to 75 years of age with body mass index, or BMI, equal to or greater than 30 kilograms per meter squared or 27 kilograms per meter squared with at least 1 obesity-related comorbidity. Subjects were required to have at least 1 unsuccessful weight loss attempt and were excluded if they had Type 1 or Type 2 diabetes. Obesity studies have traditionally over-enrolled with women, so a minimum of approximately 25% of male subjects was established. Next slide. The primary end point of the study was the percent change in body weight from baseline. Key secondary end points included the proportion of subjects achieving weight losses of 5%, 10% and 15% of body weight, changes in waist circumference, serum lipids and blood pressure. Safety end points included serious or severe adverse events, adverse events leading to discontinuation, gastrointestinal adverse events, heart rate and glucose homeostasis. Slide 6 shows a concert diagram of the disposition of subjects in the study. 11 of 39 or approximately 28% of subjects in the placebo group discontinued treatment before week 24 compared to 29 of 121 or approximately 24% of subjects in the pemvidutide treatment groups. Withdrawals in the placebo group were primarily the result of withdrawal of consent. A review of the data shows these subjects were largely experiencing only a minimum amount of weight loss and may have discontinued their participation in the study because of the lack of drug effects, whereas the majority of subjects who discontinued treatment in the pemvidutide arms was due to the adverse events, particularly at the highest dose of 2.4 milligrams. Almost all of these withdrawals occurred by week 16 irrespective of cost and few withdrawals occurred after that week in the trial. I have more comments on these data when we discuss the safety findings of this trial later in the presentation. I'll now turn to Slide 7, which shows the baseline characteristics of the 160 subjects included in the interim analysis. These characteristics were similar to the demographics of the full study population that we reported in November with a median age of approximately 48 years, median BMI of approximately 36 kilograms per meter squared and median body weight of approximately 100 kilograms. Approximately 75% of the subjects were women and approximately 20% were of Hispanic ethnicity. It should be noted that the mean systolic and diastolic blood pressures were near the normal range, and many subjects were receiving concomitant antihypertensive medications at trial entry. Now let's look at the week 24 efficacy data, which we consider extremely promising as we move forward to later stages of development, Slide 8. This slide shows the primary end point of the study that present weight loss achieved by subjects at 24 weeks of therapy using an efficacy estimand. A double-digit weight loss of 10.7% was achieved at the 2.4 milligram dose and a weight loss of 9.4% was achieved at the 1.8 milligram dose. A 1% weight loss was observed in subjects receiving placebo, resulting in a placebo-adjusted weight loss of 9.7% at the 2.4 milligram dose and 8.4% at the 1.8 milligram dose. The weight losses at all 3 doses were highly statistically different from placebo. For context, a mean reduction of 10.7% in body weight corresponded to an average weight loss of over 24 pounds in just 24 weeks. Weight losses achieved over time are shown in the right-hand graph. We believe this data is on track to achieve 15% weight loss at 48 weeks and see an even greater potential weight loss were subjects to continue for 68 or 72 weeks, the duration of treatment in the semaglutide and tirzepatide Phase III clinical trials. I would also note a clear dose response with continuing increases of weight loss through 2.4 milligrams. Slide 9 shows the percent of subjects achieving predefined weight loss targets at week 24 of treatment. Approximately 50% of subjects achieved 10% weight loss and approximately 20% of subjects achieved 15% weight loss at the 1.8 and 2.4 milligram doses. As in the prior slides, with the exception of the 15% target at the 1.2 milligram dose, all of these results are statistically different from placebo. We consider this an impressive magnitude of weight loss at only 24 weeks of treatment. Slide 10. The impact of baseline body weight on the weight loss achieved at week 24 is shown on this slide. Subjects in the MOMENTUM trial who weighed less than 115 kilograms at baseline, which represented 75% of the full study population, achieved an 11.9% reduction in body weight at week 24 or 11.1% after adjusting for placebo. The cutoff of 115 kilograms was prospectively defined based on published analyses of semaglutide in which subjects weighing more than 115 kilograms lost approximately 30% less weight compared to the full study population. As you are aware, while the benefit of the 2.4 milligram dose over the 1.8 milligram dose was not apparent in our initial trials, we made the decision to move forward with that dose in view of the possibility that a similar effect of body weight, which would necessitate a higher dose of pemvidutide, might be observed in our trials. We are extremely pleased by these results and foresee an opportunity for higher doses than 2.4 in future trials to achieve even greater efficacy, particularly in subjects with more severe degrees of obesity.

So Scott, I'd like to make a few comments. This is Dr. Aronne. Number one, I think these are really impressive results for this stage of development. And we can see that in as little as 24 weeks, we have significant weight loss approaching 15% in up to 1/4 of the subjects in the trial. And 15%, we're seeing, is a real milestone because the majority, more than 90% of the risk of Type 2 diabetes is gone if you get to 15% or greater weight loss. Secondly, I think that the 1.2 and 1.8 milligram doses can be administered without dose titration. And as you mentioned earlier, we may need back titration down to a lower dose in the future and future trials, which is a strategy that we employ clinically all the time. And the importance of having a GLP-1 compound that doesn't need titration is that in primary care, primary care physicians are very confused by these titration protocols. And so having something that's a single dose, and maybe if somebody needs it you increase the dose, I think that will dramatically increase uptake of these compounds in primary care. And again, the idea of starting with either a 1.2 or 1.8, depending upon the weight of the patient, you see here that based on the weight of the patient, 115 kilos or less, you get greater weight loss, maybe those people will take a slightly lower dose to start. People who are over 115 kilos would start with a higher dose. Now those are the kinds of strategies that we are now thinking through in the development of medications like pemvi.

Thank you, Dr. Aronne. I'll move on now to the next 3 slides, which show 3 important markers for cardiovascular risk: waist circumference, serum lipids and blood pressure. Slide 11 shows an impressive reduction in waist circumference, a marker for central obesity and visceral fat at week 24. If you recall, we also saw impressive reductions in liver fat, another component of the visceral fat compartment, in our 12-week trial of subjects with nonalcoholic fatty liver disease, or NAFLD. Please keep in mind that a 10% reduction in waist circumference represents a 4-inch change in waist size and 4 belt holes. That is especially impressive at week 24. Slide 12 shows the effects of pemvidutide on serum lipids. We observed a greater than 16% reduction in total cholesterol, 12% reduction in LDL cholesterol and a 25% reduction in triglycerides at the 2.4 milligram dose. It is particularly reassuring that the reduction in LDL, which was observed in our earlier trials, has been maintained through week 24, and we believe these reductions will be maintained through the entire 48-week trial.

So here's another differentiating point about pemvi. These are very impressive reductions in serum lipids. This may be due to the glucagon effect and the fact that there's a dramatic reduction in liver fat that has been previously reported, which is different from the previous compounds, currently available compounds. The reduction in total and LDL cholesterol here is dramatically greater than with the GLP and the GLP-1/GIP combined product. So the impact of this on cardiovascular outcomes, I think we know what a reduction in LDL cholesterol can do, and here, we finally are seeing the improvements that we need to dramatically improve cardiovascular health.

Thank you, Dr. Aronne. On Slide 13, the reductions in systolic and diastolic blood pressure through week 24 of treatment are depicted. Importantly, these improvements in blood pressure occurred without increases in heart rate which have been problematic for various GLP-1/glucagon dual agonist or GLP-1/GIP/glucagon triple agonist in development. Dr. Aronne, I know you had some comments on that.

Yes. I think that the reduction in blood pressure here is really impressive. It far outweighs the miniscule increase in heart rate so that when you look at the product of the blood pressure and the heart rate, it's clearly down. So this is important when it comes to the risk of the combined compounds. If you think about the other compounds, they couldn't reduce blood pressure enough. They may have had higher pulse rates. Here, we see extremely favorable response in the heart rate, blood pressure product.

Thank you again, Dr. Aronne. The next slide, Slide 14, shows the adverse events observed in the trial. One subject experienced an SAE of severe nausea and vomiting requiring rehydration at the 2.4 milligram dose level. With respect to adverse event discontinuations, we believe these rates can be mitigated if dose reduction is allowed as was implemented in the Phase II and Phase III trials of semaglutide and tirzepatide where high rates of dose reductions to maintain tolerability were reported. Furthermore, the adverse event discontinuation rates in our Phase II MOMENTUM trial are quite similar to those of the Phase II tirzepatide trial in subjects with Type 2 diabetes in which nearly 25% of subjects discontinued treatment at the 15 milligram dose of tirzepatide due to adverse events. We're well aware that this was mitigated by dose reduction to very acceptable levels in Phase III, and we anticipate the same with pemvidutide as well. I'd also point out to the AWARD-5 trial with dulaglutide where 21% adverse event discontinuations are reported, and we know that that's a very acceptable dose in primary care right now. So it's been dealt with not only in clinical trials but also in the clinic as well, and we'll have Dr. Aronne make some comments about that. I want to point out, in comparison to that Phase II tirzepatide trial that I just discussed, the trial with 25% adverse event discontinued, when we compare to that trial, the rates of serious and severe adverse events in our trial were actually lower than that trial, even though dose reduction was not allowed in our trial but employed in the other trial. The actual incidence and severity of nausea and vomiting adverse events in our trial were actually similar to those we reported in prior trials. In fact, the incidence and severity of lower GI adverse events, such as diarrhea and constipation, were lower than what we observed in prior trials. The observation that the adverse event discontinuations occurred predominantly after the 4-week titration period indicates that a longer titration may benefit the 2.4 milligram dose at the higher doses, but we currently do not believe that dose titration will be necessary at the 1.2 or 1.8 milligram doses. Thus, as mentioned, pemvidutide is uniquely positioned to be dosed without dose titration at the 1.2 or 1.8 milligram doses or titrated to higher doses to customize therapies for individual patients' needs. We observed a fivefold elevation of ALT in a single subject receiving pemvidutide at the 2.4 milligram dose. Subject history and blood tests suggested an intake of 4 or more alcoholic drinks per day, an intake that would have disqualified the subject from enrolling in the trial in the first place. And in consideration of this level of intake, the subject was withdrawn from treatment. The subject has since had at least 1 recurrence of ALT elevation off treatment. We have now dosed approximately 500 subjects with pemvidutide with the rate of occurrences of elevated ALT in both placebo and pemvidutide arms that is consistent with the rate of 1 in 200 subjects experiencing fivefold elevations of ALT that has been reported in trials of semaglutide and tirzepatide. Dr. Aronne, I would be interested in your comments about the safety profile of the compound and tolerability.

Thanks, Scott. I think that the compound is quite tolerable. It's at least as tolerable as tirzepatide definitely and more tolerable than semaglutide. We've had no dropouts at our site to the adverse events. Our research staff is expert at titrating people. I mean we do this all day long. And I think that that's teachable. Once you start using these compounds, you know not to push too hard. And in this case, our research staff felt that this was more tolerable than what they've been using in the past. When you think of the process of developing these compounds, you need to find out how well they work, so you tend to have to have a structured forced-dose titration regimen at the beginning of the trials. And eventually, you learn that you may need back titration. You may need to pause treatment. You may need a longer dose titration upward as you go along. And I think that's what we're seeing here. So I see this as no different -- I mean when you look at the results, the AEs in the Phase II diabetes trial were actually better than the tirzepatide trial at the same point in time. So I think that this is very well tolerated and very favorable compared to the other GLP-1 compounds that are out there.

Thank you, Dr. Aronne. These are excellent comments. Let me now turn to Slide 15, which shows that glucose homeostasis, as assessed by fasting glucose and hemoglobin A1c, was maintained in both parameters consistent with the maintenance of glucose homeostasis reported in earlier trials. The MOMENTUM trial is now the largest clinical trial experience we have to date confirming the adequate control of blood glucose over extended period of slides. In summary, as shown in the next slide, which would be Slide 16, an absolute 10.7% and placebo-adjusted 9.7% reduction in body weight were noted at 24 weeks at the 2.4 milligram dose and an absolute 11.9% and the placebo-adjusted weight loss of 11.1% in subjects with body weight less than 115 kilograms. Excellent effects were also noted at the 1.8 milligram dose where absolute 9.4% and placebo-adjusted 8.4% weight losses were observed. Approximately 50% of subjects lost 10% or more body weight within 24 weeks and robust reductions in waist circumference, serum lipids and blood pressure were observed, all of which could be cardioprotective. The overall AE profile with respect to GI intolerability was unchanged relative to our earlier trials, and we believe a path forward is possible by allowing dose reductions or more prolonged titration at the 2.4 milligram dose, which could improve tolerability in our future trials. We continue to believe that the 1.2 and 1.8 milligram doses can be administered without dose titration, but we also see a path forward by employing higher doses to drive even greater degrees of weight loss, particularly in subjects with greater degrees of obesity. In contrast to other glucagon-containing compounds in the incretin class of agents, we did not observe the increase in heart rate that had been reported for the other compounds. In addition, glucose homeostasis was maintained. We also believe that patients with more severe degrees of obesity might derive even greater benefit from doses of pemvidutide above 2.4 milligrams. Dr. Aronne, did you have any comments?

Scott, I agree with you on all the points you're making. We have to look at anti-obesity medications the way we look at drugs for other fields. Let's look at hypertension. I've written that obesity is the new hypertension. And what did I mean by that? I meant that in hypertension, we have 100 drugs in 10 therapeutic categories. And some people need beta blockers. Other people need calcium channel blockers or ACE inhibitors. We need multiple agents that work in somewhat different ways to address all the different variations on obesity that we see. And obesity is a burgeoning field, just like hypertension in the 1980s and lipid-lowering agents and statins in the 1990s. So having drugs that work in different ways and may have different titration schedules and different suitability for different patients is really critical to the development of this very, very important field of medicine. And I'm very optimistic about the differentiating aspects of pemvi. The fact that we don't need a dose titration at a therapeutically effective dose, that's great. The reduction in liver fat, which we've been trying to get, makes this ideal for NASH and NAFLD. Reduction in blood pressure without an increase in heart rate, the reduction in LDL cholesterol, all of these, which can reduce cardiovascular risk. So I'm very enthusiastic about this compound for a number of reasons. One last thing, people may not be aware of this, but we see hypoglycemia in some of the patients where we're using the pure GLP-1 agonist, in patients who don't have Type 2 diabetes and occasionally in people who do have Type 2 diabetes, and it limits our ability to use them. So we are thrilled to see a compound that has maybe less of a glucose-lowering effect than those other compounds.

Thank you again, Dr. Aronne. I'm going to now move ahead to the discussion of the results of the Phase I Type 2 diabetes safety trial, starting on Slide 18. As you will see, the results of this study support the weight loss achieved in the study population traditionally seen as more refractory to treatment. This was a 12-week, randomized, placebo-controlled study of pemvidutide in subjects with overweight or obesity and Type 2 diabetes mellitus. 54 subjects were randomized 1:1:1:1 to the same treatment arms as in the MOMENTUM trial and stratified by the presence or absence of metformin use at baseline. As in our prior Phase I trials, such as our Australian first-in-human and NAFLD trials, caloric restrictions or lifestyle interventions were not employed. Slide 19. Key eligibility criteria are shown on this slide. Men and women 18 to 65 years of age with BMI 28 or greater were eligible to participate in the trial. Subjects were required to have Type 2 diabetes on a stable glucose control regimen for at least 3 months. Other than diabetes, the demographics of the study population were similar to the MOMENTUM trial. Nearly all of the subjects were using metformin at baseline. The concert diagram for this study is shown on Slide 20. Note that there were no treatment discontinuations. Again, no treatment discontinuations in this trial due to adverse events. The next slide, Slide 21, shows the weight loss achieved by the subjects who participated in this trial. The absolute weight loss achieved at the 2.4 milligram dose was 7.7% which, adjusted for placebo, was 8.5%. And again, this was at only 12, not 24 but 12, weeks of treatment. This is impressive weight loss for a population with diabetes which usually achieves 30% to 40% less weight loss than a population without diabetes and obesity trials. In fact, this level of weight loss exceeds the 4% placebo-adjusted weight loss observed at 12 weeks at the same time point in subjects with diabetes in the tirzepatide SURPASS trials. Again, surpassed the weight loss achieved by tirzepatide at week 12 in these trials. The next slide, Slide 22 shows the glucose homeostasis obtained in subjects with diabetes as assessed by fasting glucose and hemoglobin A1c at the 12-week time point. These results show no significant differences between pemvidutide treatment groups and placebo, and any trends that you might see reflect the wide variation in the data points, which is expected for a still small study. For example, note the increase at week 12 in the hemoglobin A1c in the treatment group. That would be otherwise interpreted as worsening glucose control in the placebo and probably represents the variation that we're seeing in the glucose at the 2.4 milligram dose. Now supporting this conclusion, we also performed a pooled analysis of fasting glucose results in subjects who had diabetes in this trial with the subset of subjects with diabetes in the Phase I NAFLD trial, and this continued expanded analysis demonstrated no differences in pre- and posttreatment fasting blood sugars in any dose group. Adverse events in this study are shown on Slide 23. There were no adverse events leading to discontinuation in this trial. More importantly, no hyperglycemia adverse events were reported, further supporting the conclusion that glucose homeostasis was maintained as described in the previous slide. Gastrointestinal adverse events, in fact, were extremely low with no nausea reported at the 1.2 or 1.8 milligram doses and a total of 23 in total mild and moderate events combined at the 2.4 milligram dose. In summary, on Slide 24, an absolute 7.7% weight loss and 8.5% placebo-adjusted weight loss was noted in subjects with diabetes after only 12 weeks of treatment, a level of weight loss greater than the weight loss achieved at 12 weeks in subjects with diabetes in the tirzepatide SURPASS trial. Glucose homeostasis was maintained in this population with diabetes. It was also maintained in a pooled analysis of this trial with the diabetics in the NAFLD trial, with no significant changes in fasting glucose or hemoglobin A1c over the treatment duration and, importantly, no hyperglycemia adverse events were reported. Rates of GI adverse events were low, and there were no discontinuations due to adverse events. Dr. Aronne, did you have any final comments?

Yes, Scott. So while this is preliminary, very small number of subjects, I think that the weight loss results are very impressive, and they surpassed SURPASS at the same time point, 12-week time point, so very exciting to see that. I think that when it comes to using a combined GLP-1/glucagon agonist in people with early diabetes, I think it's going to take time to see the reduction in A1c. I think the fact that it doesn't go up, phenomenal, no hypoglycemic events. That's phenomenal. But I think that it's going to take greater weight loss in order to see that reduction in A1c to balance out the glucagon -- low adverse event rate and no discontinuations, although the trial was very small up to this point. So I think that people in diabetes trials tend to be more dedicated to the trial. They're more concerned about their health. They tend to stick with it a little bit better than what we see in some obesity trials. And I think that this tells us that the 1.2, 1.8 are going to be well tolerated without dose titration in many populations like NAFLD, maybe early Type 2 diabetes, prediabetes and in other situations.

Thank you, Dr. Aronne. This completes the formal presentation of the 2 trials. I will now turn the microphone over to Vipin for his closing remarks. Vipin?

Thank you, Scott, and thank you, Dr. Aronne. To summarize, we are excited about the week 24 interim analysis results of the MOMENTUM trial and full results of our Phase I Type 2 diabetes 12-week safety trial. The weight losses achieved in these 2 studies were impressive and bode well for the effects that could be achieved at the completion of 48 weeks of therapy and beyond. The impact of baseline weight, which was also observed with semaglutide above 115 kilogram, suggests we have the opportunity to further improve upon the robust efficacy by exploring dose levels beyond 2.4 milligram. We might also enhance tolerability and efficacy by permitting dose adjustment, either up or down, to suit each individual subject with regards to side effects and weight loss goals. Pemvidutide's combination of significant weight loss, reductions in LDL cholesterol and reductions in liver fat, together with the optionality for dose titration, has the potential to be the treatment of choice, especially for patients with obesity that are at risk for liver disease, dyslipidemia and other related conditions. Operator, that concludes our formal remarks, and we would like to open the line to take questions. Could you instruct the audience on the Q&A procedure?

[Operator Instructions] Our first question coming from the line of Seamus Fernandez from Guggenheim.

So maybe just as a starting point, Dr. Aronne, I'd love to just get a sense of the patients that you think are most appropriate for pemvidutide based on these results, which patients you would target with an agent like this just as a starting point. And then separately, as a follow-up, it seems like this would be a uniquely positive profile potentially for all NASH patients, even the diabetic patient population. But just wanted to get, Dr. Aronne, your reaction to that. We're not seeing any meaningful changes in HbA1c even at the highest, 2.4 milligram, dose at 12 weeks, obviously. But just wanted to get a better sense for the breadth of the utility. And then I have a couple of follow-up questions for the team.

Sure. The NASH patient with early Type 2 diabetes would be the exact patient, I think, that could be targeted with it. Obviously, people with NASH without diabetes, but I think that what this is telling us is we're not worsening the diabetes, maybe the patient would need another treatment, an SGLT2, metformin or something more aggressive than that. But the point is that getting a reduction in liver fat is critical for that patient. And so this could turn out to be a very good target population for these patients. And I hear, my office is next to the liver people here at Weill Cornell, and the idea that you're going to treat someone's NASH or NAFLD and not get them to lose weight doesn't make sense. I mean the agents that are being developed that are not -- maybe you work on fibrosis or something specific, but I think that liver fat is where it's at. When it comes to the liver problems associated with obesity, I think that this drug is ideally suited for that. So really, where I see this thing of immense value is in the primary care setting where we would be able to give very simple instructions to primary care physicians of how to manage this. And I think that, that, to me, is going to be one of the important steps in bringing the use of anti-obesity medications into the primary care setting. How do you simplify the titration regimen is to not need titration. That's the best way to do it. And I see other targeted populations as well that could do well, but I think this is going to be a very useful therapeutic.

Great. And then just a couple of follow-up questions for the team. You mentioned that there's a clear opportunity to manage whether it be with a sort of sequential titration, potentially even pushing the dose higher from here. Can you just help us understand the sort of ability to down-titrate for patients who may be experiencing some tolerability issues and then, separately, the magnitude that you think the dose could be sort of pushed up to what would be kind of an incremental target dose that you think could have incremental or further utility from here?

Yes. Well, thank you so much for the question, Seamus. So I want to first talk about the dose reductions in the semaglutide and tirzepatide trials, and this is public information. Only 65% of subjects in the semaglutide STEP program were taking the 2.4 milligram dose at the end of treatment. Now there were treatment discontinuations, but it implies that in the range of about 18% of subjects had to have dose reduction in order to make that dose tolerable. And when they report their adverse event discontinuations, after allowing dose reduction, it would have been much higher had they not allowed dose reduction. In the tirzepatide trials, and I can refer to the SURPASS trial, that information is published by FDA, 11% of subjects could not get to the 15 milligram dose. And in fact, 15% of subjects actually dropped their dose. So the adverse event discontinuation they're reporting reflects the allowance for dose reduction. We didn't think we needed it in our trial, and we didn't allow it. But clearly, in this population, at the 2.4 milligram dose in particular, it would benefit by doing that. And also, we believe that the 2.4 milligram dose could be titrated over 4 weeks based on our experience in earlier trials, but that didn't seem to be as well tolerated with that short titration in this trial. So obviously, we would have to go to a longer titration. With the tirzepatide Phase II trial, their adverse event discontinuation rates were 24.5% at the 15 milligram dose. That was in a Phase II trial, a trial with the same phase of development. They did what we did as they applied their development tools and they developed their profile, which had a very acceptable profile at the 15 milligram dose that involved dose titration while we believe that the 1.2 and 1.8 milligram doses would be ideal for primary care without dose titration and to the extent that those doses could also be reduced and even improve their tolerability even further than what we're seeing in this trial, a longer dose titration with 2.4 over a longer period of time. We actually haven't worked out what that duration would be, but we know it's been as long as 16 to 20 weeks in the semaglutide and tirzepatide programs. But we have the doses at this time. 2.4 could easily be reduced to 1.8, 1.8 to 1.2. As you know, we have the 0.6 milligram dose in the titration scheme of the 2.4 milligram doses. We're looking at all of those for dose reductions. With regards to increasing the dose, we have the data in-house to go to higher doses and can implement that program. So we'll move ahead currently with doses we have right now. We think they're well tolerated. We think we're in an ideal position right now to move ahead, very similar to where tirzepatide was at, at this stage of development. And we think the 2.4 milligrams is a very effective and highly tolerable dose. Now in parallel, we can also conduct studies if we wish, and we envision that this would be very effective if we wanted to pursue a higher dose, to go to doses higher than 2.4 that we can implement. And we can make some announcements of that design as we go forward, but we think it could be very effective if more weight loss is needed to go to those higher doses in development in another study.

Great. And then just one final question. On the fasting plasma glucose change at the 2.4 milligram dose versus the change in HbA1c, Scott, can you just talk a little bit about that in the diabetes safety study? Just wanted to get a better understanding of that, and if there were sort of extended excursions if that happens early, just a little bit more color on the 2.4 dose in the diabetic safety study.

Right. Well, thank you for the question, Seamus. So what we're referring to, and that would be on Slide 23, I believe, but you'd have to go back and check the deck or the glucose data, which showed a slight absolute but nonsignificant increase in blood sugar at the 2.4 milligram dose. It was 128.2 and 140.6 with a very wide standard deviation. Now that's not significant, reflects the small numbers of subjects, particularly since there were some discontinuations to the 2.4 milligram dose, which made it even a smaller number. Now if that was real, we will look at the increase in the hemoglobin A1c of 6.6 to 7.0 in the placebo group and conclude, if we use the same logic, that placebo was causing a worsening on blood sugar. But nonetheless, as I mentioned in the formal part of the presentation, we took these patients, we pooled them with the diabetic patients in the NAFLD study, enlarged the population, which means you're going to get lower variability. And the net effect was absolutely no change. I can quote you the numbers. In the pooled population, which was comprised of now 20 subjects at 2.4 milligrams, the fasting blood sugar for the pooled population was 141.4 at baseline and actually dropped in the pooled population to 135.1. So we believe that there is maintenance of blood sugar at all doses, including the 2.4. Substantiating that, there were no hyperglycemic adverse events, which is more meaningful than anything else, because that's the doctor's identification of worsening blood glucose control. So as Dr. Aronne pointed out, this was a 12-week trial. We didn't expect to see a change in hemoglobin A1c at only 12 weeks. We saw a signal for that, as Dr. Aronne mentioned, in our NAFLD trial at 24 weeks as we get more weight loss over longer periods of time. But as this is combined GLP-1/glucagon therapy and we don't have the unopposed GLP-1 effects that you have with semaglutide and tirzepatide, we did not feel, and we continue to maintain, that we would not see a hemoglobin A1c change at week 12. But we do think we would see it at week 24 and later time points.

And our next question coming from the line of Yasmeen Rahimi from Piper Sandler.

Congrats for the data. And before I go into my questions, I just want to really thank you both, you and the physician, for your very thoughtful and well-articulated commentary that you have provided us throughout this entire call that I'm certain it's very helpful to all of us analysts and all of the investors listening. In regards to my questions, I guess the first one I want to ask you is, given what you've seen with the 2.4 mg dose group, is there an opportunity to go back into the MOMENTUM trial and maybe amend a protocol where you are allowed to maybe control for dose down titration? That's one. And then two, I would like to maybe focus my thoughts around the 48-week data. So now especially to our doctor, based on the curve that you're seeing where plateau is really nowhere at near size, how do you predict not only weight loss to fall but also what would this continued weight loss -- let's say, we do get to that threshold that you outlined to us, what would that impact be on many of the other markers, such as LDL-C, glycemic benefit, et cetera, that was reported? And then I'll jump back into the queue.

Right. Well, Yasmeen, as I mentioned during the formal part of the presentation, almost all of the discontinuations have occurred by week 16, so they're pretty much done. We're seeing a trickle now and not really GI related that happened here and they're for odd different reasons. So I think we're through that period of susceptibility for adverse event discontinuations where down titration would mitigate them. I don't think it would be necessary to ponder because we're no longer seeing them in the trial. All of the subjects are now easily through week 16 and beyond that point. I'd ask you, however, to restate the second question. I'm not sure I fully understood the question. Could I ask you to restate it?

Yes, of course. But before we get to it, I just want to clarify, for the full 48-week full results, we're going to have the entire cohort. So I guess, have all full cohort finished 16 weeks of treatment, and therefore, there is no opportunity to change that? Is that what you're saying? And then I'll restate my second question.

That's correct, Yasmeen. All subjects are now through week 16. So making that change to the protocol would not impact the adverse event discontinuations. I would also add that they're not going to go up and really go up further at this time, they're all front-end loaded into the study. So I think that by the time we report out this study, we will be in approximately the same range because they all occur earlier in the trough.

Great. My second question was, what do we expect at week 48, not only in weight loss but the impact of, let's say, the threshold that you're going to define? I think you said 15%. But was that placebo adjusted or not? I wanted to get your thoughts on 48-week weight loss as well as the docs? And then secondary, what would that impact be on some of the many metabolic parameters then we will see further reduction? Like, what should we expect in that setting?

Right, Yasmeen. So the 15% weight loss is an estimate. It has wide intervals, depends on how you look at the data. It could be both placebo-adjusted and absolute. It's certainly in that range when you look at the curves. When you look at the other parameters, waist circumference is going to continue to improve. There's a potential for improvement of lipids, although I think our base case right now is that they're going to at least be maintained. As Dr. Aronne mentioned, they're very impressive right now. We don't foresee them going down any, but it's possible they could potentially continue to improve. Regarding the hemoglobin A1c, this is a nondiabetic population. I think you're going to need large numbers of subjects in order to see that kind of change over the course of time. As you're aware, in the STEP program, they had 1,500 subjects in that program in order to see a change of 0.5. That's a lot of people to see a very small change, and this study is much smaller than that. So it's possible we may see a signal there. I would doubt that it would be statistically significant at these numbers.

Yes, I think the other important point there, Yasmeen, is we certainly expect the response rate for different buckets of weight loss to improve over time, of course. And that means that more subjects will be experiencing the 10% and, importantly, more subjects will be experiencing the 15% weight loss. And with that 15%, we see big effects on A1c and lipids and all of that. So I think that's the obvious interpretation of what will happen. As Scott said, the shape of the curve is something that will be debated over time. But I think that it's pretty clear that the weight loss is continuing in a pretty substantial way. And we see obtaining that goal by the end of the 48 weeks as easily accomplished.

Dr. Aronne, did you have any comments to make on that point?

No, I agree. I fully expect that we will see -- remember that the people in this trial were not picked out because they had problems with their lipids or their blood pressure. So I think that in future trials, as we have people with hypertension and significant hyperlipidemia, that we could potentially see bigger changes in these parameters. So I think that that's entirely possible, and I believe that these will be maintained over the long run. I think when you look at what it takes to really have an impact on health, the idea we're getting now is that 15% is where there's just an enormous impact on all the complications we associate with obesity from the hypertension, lipids, diabetes prevention, NAFLD, cardiovascular improvement, heart failure, sleep apnea. I mean the list goes on and on. So I see with a 15% weight loss, which, by the way, I think there's no question that we will reach 15% and potentially more than that, I think that we're going to have really great improvement in these parameters.

And our next question coming from the line of Corinne Jenkins with Goldman Sachs.

Maybe a couple for me. First, given some of the dose and protocol optimization you'd like to implement based on these results, do you think you'll be ready to move forward with an optimized Phase III dose after the full 48-week readout next year?

Yes. Thank you, Corinne. Look, we certainly think we have a Phase III program. We have no doubt about that. We're going to take a look at the whole program, look at dose increases, see if that's valuable to implement at this point and whether we'd want to run that trial in parallel. So we do think that we have the opportunity to go into Phase III, but we'll look at our opportunities for increasing the dose specific to obesity and decide what we want to do. But based on the current results, this, we believe, would be a Phase III-ready program. Whether we actually do that or not, we'll have to determine after we take a better look at the potential for higher doses. Also, we would look at the opportunity to do longer in Phase III, we're actually going to a longer duration of treatment if we dose-titrated at 2.4 milligrams. We think that probably that's an adjustment that we would like to make and certainly what the tirzepatide program did. As you recall, in that Phase II study I described, they titrated only over approximately 6 weeks. They later did another Phase II trial where they titrated longer, and they finally, in Phase III, actually took the step within Phase III to go to 20 weeks. And they didn't have that data before they moved into Phase III. They implemented it in a Phase III. So if we wanted to go to a longer titration at 2.4 milligrams, the regulatory precedent tell us that we could do it. So we have that optionality, and we'll make that decision.

Yes. One thing I want to add, Corinne, is that our goal has always been to have multiple dosage approved. We think there's benefit to that because, as you heard Dr. Aronne and as well as we've talked to many of the KOLs, they want flexibility. They want the ability to both go up as well as go down. So we think all of our doses that we are working with, 1.2, 1.8, 2.4, and perhaps even at the higher dose, we would like to pursue them and really get approval for all of those dosage because we think, ultimately, in clinical practice, it's important to have that flexibility.

Okay. And to clarify, so you might begin looking at higher doses between now and only get to 48-week readout or you'll wait to get those data before moving forward with the higher dose?

A higher dose can be added on to the Phase III program as an add-on. So we can start our Phase III program with the existing 3 doses. It gives us plenty of opportunity to achieve the efficacy that we are looking for. But if we do need an extra dose for heavier subjects, then that can be added on as part of the Phase III program.

Okay. Helpful. And then Scott, I just wanted to clarify on your last comment around getting to 15% weight loss. Over what time frame do you see that as achievable based on the data we've seen thus far?

Well, as Dr. Aronne mentioned, we think that's achievable at 48 weeks. We think that if we were to follow patients all the way out to 68 weeks, 72 weeks, as done in the semaglutide and tirzepatide programs, we'd get even more weight loss. But we do think that's achievable at the 48-week time point by the end of this trial.

And our next question coming from the line of Roger Song with Jefferies.

Great. Congrats for this positive data in a large Phase II global study. So a question from us, the first one is for the weight loss. So you did some interesting analysis for those patients with less than 115 kilograms at the cutoff. Just curious, why did you make that cutoff? Is that based on the historical precedents, your competitors? Or is that something you see maybe meaningful for those patient baseline? And another follow-up question leading to this is, is it possible you can make some prediction for different weight loss at the baseline and to make some adjustment for your dose given you have some dose optimization strategy? I haven't heard something like a weight-based dosage.

Yes, Roger, the 115 kilograms was not arbitrary. It was prospectively defined. We knew about it ahead of time. We talked about it with a number of people such as perhaps yourself, analysts, investors. That's in the public domain with semaglutide. It's based on an FDA analysis. There is summary basis of approval for Wegovy where they saw that at 115 kilograms, these subjects lost about 30% less weight. It was probably due to the fact that they had lower concentrations and they had bigger body size. It looked like Novo was addressing this by going to higher doses in future trials. But that was prospectively defined. We had it as a prospective point in our trial. So this was not picked arbitrarily. It wasn't cherry-picked. It wasn't post hoc. It was prospective. And we thought it might be possible based on the overall similarities of this compounded size and other characteristics of semaglutide. We didn't know it for certain. In fact, we talked about -- people said, "well, why are you moving ahead with the 2.4 milligram dose when the 1.8 looks like it's already achieved the best effect?" And the answer we gave was that we weren't really certain what was going to happen in heavier people. So we used the 2.4 milligram dose. We implemented it, and we were rewarded. It was more effective in that population. But now it gives us the opportunity to go even higher doses, particularly in those people above 115 kilograms. So the analysis was planned. It gave us the results that we could have anticipated. It was prospectively defined. And as mentioned, the population below 115 kilograms was actually 75% of the population. And in that population, the placebo-adjusted weight loss was 11.1%. It was pretty spectacular. So it was even quite good at the 1.8-milligram dose with no titration in that population. As Dr. Aronne mentioned, what an option for lighter people in primary care not to have to use dose titration in order to achieve that level of weight loss is pretty spectacular. You are seeing what we're seeing right now, which we haven't fully laid out, but we're certainly looking at very carefully. It is a strategy based on body weighted baseline. It's certainly implemented in many drug programs where if someone is up to 115 kilograms, you give them 1 dose. If they're greater, you give them more. We could also look just using higher doses with longer titration in the whole population to see if that would be beneficial for people less than 115 kilograms. But I think you're looking at the program the way we are right now that there could be a baseline body weight-adjusted strategy going forward. I think the important point is that we have much more information about the program. It's allowing us to lay out the program. It's allowing us to look at new studies, the potential for going to higher doses to get better efficacy. I think we have a great product profile for people less than 115 kilograms in the primary care setting. I think we saw higher adverse event rates at 2.4 than we would have anticipated. We hadn't seen that before in earlier trials. It's behaving differently in this population. But look, this is exactly why you do a Phase II. This is what they saw in the tirzepatide program. They are able to very effectively manage that going into Phase III when they put in longer dose titrations. We think we have a great compound here. We think we're getting great tolerability. Moving forward, as we make those adjustments, we're really proud of these results, and we really think it's the basis for thought and creatively moving ahead to a product profile that could be spectacular by the time it matures.

Maybe Dr. Aronne has some comments on this.

Well, so I was one of the principal investigators on the SURMOUNT-1 trial of tirzepatide. And we did a post-hoc analysis looking at the response rate in different BMI categories. We didn't look at it by body weight but by BMI category. And what we saw was that in the BMI of 35 to 40 range, the mean weight loss using the efficacy estimand was 22.5% weight loss. But in the BMI of 35 to 40 range, it was 25%. And then BMI 40 and above, it went down to 22.5%. And my impression, and obviously, we need to do a lot more analysis, is that people at the high BMI range were dose limited. So there's an example of something that's out there now up to 15 milligrams, but maybe we need 17.5 or 20 milligrams. So I think this idea of extending these doses in people with a high BMI is entirely plausible and likely to be the way to get better efficacy. And I think that the results that we're seeing here with pemvi fit exactly with what we've seen with tirzepatide.

Got it. Yes. Really appreciate all the comments, understanding we do need this flexibility of balancing the tolerability and the efficacy. Great. So maybe just a quick one as our last question. In terms of the impact to diabetes plus obesity patients, when do you expect to see we can lower the HbA1c or the fasting glucose by the pemvidutide as an acceptable kind of the direct impact? And also to the company, what will be your next step for those patients with both diabetes and obesity?

Yes. Roger, thanks for the question. We never thought that we would see it at 12 weeks. And it's difficult to see in a nondiabetic population, as you know, because there's no room for improvement. As we saw in the NAFLD trial, we think we'll start seeing it at 24 weeks. We definitely think we'll see it at 48 weeks when we do that kind of formal, larger diabetes trial potentially in Phase III.

And our next question coming from the line of Liisa Bayko from Evercore.

Congratulations on the data today. I wanted to just probe a bit on the shape of the curve. How are you interpreting the shape as you think about it reaching 15% weight loss? It looks as though, if you look at the last 2 data points, maybe the slope is starting to become a bit less and starting to show slightly less week-over-week weight loss. Can you maybe comment on just the shape of the curve?

Yes, Liisa. We've taken a look at that curve and recognized that, ultimately, the curve will be determined at 48 weeks when we look backwards with more data. The efficacy estimand is a modeled approach. It kind of estimates where you are at the 24-week time point. And a little change in that 24-week time point, this curve would slope dramatically downward. So you have to kind of look at the variability around that point. And we've looked at that. And depending on where you put that point within that confidence interval, this could be a very vertically downward curve. So based on that, and we've taken a look at that, we're pretty confident that we can get out to that 15% weight loss at that 48-week time point. It's just difficult to tell, and it's going to be much better looked at retrospectively when we have all the time points. These models, looking forward from the earlier time points, they're tough for estimating the shape of the curve. We're showing it. We're sharing it. We also think that we can get to that 15% figure that we talked about earlier.

And can you remind us how you're handling missing data for the purposes of this trial?

Right. So there are 2 ways of doing it, and I don't want to spend time doing it. As you know, there's a traditional approach, which is where you hard impute data. And there are ways of doing that, and that's been done in the Phase III programs. But in this stage of development, people have used the efficacy estimand. And instead of imputing data, what you do is you use a technique called the mixed model for repeated measures, or MMRM. And what it does is it takes the data up to the point that a subject discontinues, and it utilizes the background of the patients, their weight, their gender and the like to estimate where they would have been at the 24-week watermark in this case where they would have been on a weight loss had they continued in the trial. This is standard. This is not something invented by Altimmune. It's been used by FDA for years, and it was implemented in the tirzepatide program and the semaglutide program. And in the tirzepatide program, it was called the efficacy estimand. So what it is, it's a way for handling data that doesn't exist. It's a way of handling missing data. It's a standard technique, and we've employed it the exact same way as the other sponsors.

Okay. Excellent. Obviously, this is just like some of the patients, right? Have you looked at now patients who are in earlier stages of the study before 24 weeks? And if you have, does that seem to track here with the same kind of slopes and weight changes?

Yes. Yes. I would tell you that the data in this study, we've seen it as performing extremely well. It's very predictable. It's a well-conducted study with very good statistics. And if you look at the people who discontinue early, they're tracking exactly where the other population is. So in other words, they're not dropping out because of a deviation from efficacy. If you pick a patient, you look at their weight at baseline, you look at their gender and you predict where they would be, they fall right on the curve with the other patients. So the model is performing extremely well.

Just to be clear, Liisa, we are not looking at the other patients continuing in the study. The only analysis we have done is the 160 subjects. We're not taking any blinded looks on the rest of the data.

Okay. So then when we go to the 48-week readout, which will be the next readout, you will have an update, in a way, to these numbers with the rest of the patients?

Exactly. Exactly. We anticipate the readout at week 48 will look very similar to this. Is there a possibility we could read out into some other things that we have in the study? It's possible. As you know, in an interim analysis, there's really no time to accrue all of your data. But I would imagine we'll at least have the same top line results at week 48. We could have more. We'll have to make that decision when we get out to that time point.

Okay. And then just final question for me, as you think about Phase III, is this something you are prepared to take on, on your own? Are you really looking to find a partner before then to help support a global Phase III obesity study? Or how are you thinking about the next steps?

Yes, Liisa. Really, our strategy hasn't changed. We're going to be preparing for Phase III. We obviously have to meet with the FDA at the end of Phase II meeting. So we want to be ready to execute Phase III in the first half of next year. And we're prepared to do all of that on our own. Obviously, based on this data, we'll also explore opportunities to bring a partner onboard, and that would just sort of play out in parallel as we prepare for these studies. And we're also going to be starting our NASH biopsy trial later this year or in the middle of this year. So I think all of that is on track, and it's going to proceed as we've been talking about.

And our next question coming from the line of Mayank Mamtani from B. Riley.

Appreciate the level of detail here. Congrats. So first question, for Dr. Aronne quickly, the placebo weight loss seems like a bit on the lower end. I understand attributed to the higher withdrawal concentrate. But was there anything different about protocol in terms of lifestyle modification, exercise? And also for the drug arms, if you did assume there was dose reduction interruptions, could you put a number on where the discontinuation rate would be, for example, for the 1.2, 1.8 mg dose? And then I have a couple of quick follow-ups.

So as far as the weight loss, I think the weight loss is at least equivalent to what we've seen with sema and, in certain aspects, tirzepatide. Although you can't tell where it's going to wind up at the end. So I think that the weight loss, I don't see this as being less effective, if that's what you're implying, Mayank. I think it's at least as effective as those agents. And it's just going to take time to work out, to get all the data together for the 48 weeks to see where they fit. When you do these trials, you have to pick the doses and pick the delivery method and do the trial. I believe that the Phase III data is going to look significantly better, as we've seen before with both sema and tirzepatide. It's very difficult in Phase II when you have compounds like this to make the right guess. And so that's why you do a Phase II trial and then go to Phase III. So we will know exactly what to do in Phase III to get the best possible results.

And then on the glucagon-related effects, Dr. Aronne, what specifically are you looking for in the 48-week results, kinetics-wise, in terms of magnitude, that will give you confidence of the longer-term cardiovascular benefit?

Well, I think, number one will be the improvements in all of the risk parameters that we've discussed. So if someone has a reduced blood pressure, reduced LDL cholesterol, reduced triglycerides, all of the other factors, reduced waist circumference, I would be confident that, that will improve cardiovascular outcome. And obviously, the FDA, at some point, will likely want us to prove the safety. That's pretty standard. So I do think that, that will come in time. But I'm pretty confident we're going to see that with this magnitude of weight loss and with the improvement that we're seeing in the cardiovascular parameters.

Got it. And just one final question for the team. Is there an opportunity, Scott, to amend your Phase IIb NASH protocol based on your learnings from the dosing here and if you plan to also have additional Phase II trials before you embark on a SURMOUNT or a STEP like Phase III program next year?

Yes. Thanks for the question, Mayank. So obviously, there's learnings from this trial that we're going to apply to the NASH trial. And it's going to affect dose selection, for example. We got similar levels of liver fat reduction at 1.8 and 2.4 milligrams. And if you just simply stop at that point, you'd say, well, let's not develop more than 1.8 for NASH, the liver fat effect is seen. But as Dr. Aronne pointed out, you have to have weight loss for these patients to have an effective NASH drug. And if you get more weight loss at 2.4 milligrams, why wouldn't you use it in the trial. It's not the primary end point of the trial, which is still the biopsy, but it's still a very meaningful secondary end point and very, very important for the target profile and how the docs are going to use the compound. And I'll say, in addition to that, before I get to your second question, we think that pemvidutide is a great drug for NASH because it's going to give the NASH patient what the patient really wants, which is the weight loss. The doc wants the liver fat reduction, but the patient wants the weight loss. And with the weight loss, you get the other benefits of weight loss as well that you forgo if you only concentrate on the liver fat. So to conclude, we'll make that decision. There's learnings all the time in these programs, as Dr. Aronne pointed out. We've learned from this. We'll have a decision very shortly on our NASH program based on this data. Regarding the obesity program, as I said before, this program, we believe, will be Phase III-ready just simply on the doses that we've studied so far. We're going to take a very careful look about running another, say, Phase II program with higher doses in parallel. We think there's an opportunity there for even higher weight loss and to preserve tolerability based on the learnings from this program in the same way that the tirzepatide program adjusted. So I think there's a real possibility we may conduct a Phase II with higher doses. We can conduct them in parallel. We can move to Phase III. We'll make that decision about the Phase III program in the near term about what we do. But I want to emphasize that I think we're Phase III-ready. Whether we elect to go to Phase III with these levels, let the Phase II program in higher doses catch up, we'll determine. But we think this program, as it is right now, is Phase III ready or will be at the end of the 48 weeks.

Got it. Congrats again on the data.

Yes.

Yes.

And our next question coming from the line of Jonathan Wolleben from JMP Securities.

Scott, just wondering if you looked at the weight loss and tolerability for the 2.4 milligram dose in patients who weighed more than 115 kilograms at baseline?

Yes, Jonathan. So as in the tirzepatide program, when you get above 115 kilograms, you take a haircut of about 30%. So it's behaving very similar to that program. And there were no surprises there because you saw the benefit below 115 kilograms. So it's a very good question. Regarding the adverse events, they were much less than the 115 kilogram and greater cohort. And in fact, there were no discontinuations due to adverse events above 115 kilograms. So less weight loss, much better tolerated, opportunity to go to higher doses in that population, particularly if we dose titrate and dose reduce.

That's helpful. And then speaking of the tolerability, the profile in the diabetic study looks stellar. I'm just wondering how do we reconcile the 2 different tolerability profiles from the interim MOMENTUM data and then in the diabetic study? Is there something unique in protocols or populations? Just wondering how we should think about what's going on between those 2 profiles.

Right. I think it's an excellent question. I want to make some comments, but I want Dr. Aronne to add in as well. Up until this time, we've not seen these dropouts, especially at the 2.4 milligram dose. So there's a difference in the population here that we're going to have to understand more, and maybe Dr. Aronne can make some comments. I do think that, as Dr. Aronne pointed out, the diabetic population, it's a more educated population with regard to the trial, greater motivated population, more likely to stay in a trial and to tolerate, and has not experienced adverse events. So I think that the tolerability profile in the diabetic study is really remarkable here. And the weight loss is really remarkable as well. But we think that it's an opportunity here, and it expresses a better profile of the compound. Dr. Aronne, did you have any comments about that?

Yes. In the other trials that we've done when we've seen Phase II, it has informed us on how to fix that in Phase III so, for example, intensive education for all the sites on the protocol and to help them understand, help the clinical research staff, to understand the side effects and how to manage them appropriately. Those are the types of things that we've done before in order to dramatically reduce the number of dropouts due to adverse events. And one of the key ones was having this back titration in dose. But there are clearly other ways to do that. So I think that those number of other changes will make it easier to manage that type of an issue, and we'll reduce the number that we see in the Phase III trials.

And our next question coming from the line of Patrick Trucchio from H.C. Wainwright.

Congrats on the data. Just a follow-up on the commentary around 50% of the subjects that achieved 10% or more weight loss and approximately 20% of the subjects achieved 15% or more weight loss. So I'm wondering if there were baseline characteristics of these patients identified in addition to the 115 kilogram cutoff for those patients who maybe responded better to treatment and if those findings might impact how you would enroll the Phase III trial as well as if that stratification could perhaps provide a readthrough to the potential eventual commercialization in terms of demonstrating which patient groups pemvi may be most appropriate for should it be eventually approved.

Yes. Thank you, Patrick. Let me answer that. So obviously, baseline weight is the most important. It's been seen across different programs, such as the semaglutide program, that women tend to respond better than men. And that's not unique. Why that happens with this class of compounds, we don't know. Those seem to be the primary factors that are involved in the response. We're taking a very careful look at this in modeling right now, but I would say those are the 2 major factors that would predict response.

That's helpful. And then maybe just one follow-up for Dr. Aronne. I'm wondering if you can tell us what you -- based on the data that's been generated today and what you've seen, what would you like to see in a Phase III program from a design perspective, from safety, tolerability and efficacy perspective, that would give you confidence in pemvi relative to these other GLP-1 agents?

Sure. What I would like to see is dosing flexibility, the ability to go up or down depending upon how -- and I recognize we can't do all of this, right? We have to randomize people to a dose, and that's the dose they get. And then we have to see what happens. But what I would like to see is the ability to adjust the dose and have some type of flexibility. And I think that higher doses could be studied at the end of the trial. As Vipin pointed out, I think that having a dose step-up towards the end is entirely possible from other trials that I've seen. And I think I'm enthusiastic about what the Phase III will look like.

And I'm showing we have a follow-up from Seamus Fernandez from Guggenheim.

Great. I just actually have one simple final question for Dr. Aronne. Dr. Aronne, you've seen a lot of products move through Phase III clinical trials, lots of products move through obesity, lots of different incretin. Just from your perspective, I guess, we think we see a drug here and potentially a very good one, where do you come down on the prospects, both in obesity for pemvidutide and in NASH for pemvidutide?

Yes. I guess I wouldn't be working on this program if I didn't think it had a lot of potential. And I think it has unique potential. Many people think that the GLP-1/glucagon combination is really great and that we need that. And I do think that's my personal belief, I've been interested in trying to figure out how to give glucagon to patients who we had taking GLP-1s for 20 years, and there have been a lot of dead-ends. A lot of people have failed. But I'd like to point out that I've done more than 80 trials of anti-obesity medications in my 35-year career. And I have a lot of perspective and a lot of things that haven't worked out. But this is working out. I mean, to me, this has all the signs of something that's going to work. And I mean the only way to know is to do the study, right? That's how this works. You have to do the study. You have to see what the data looks like. And you have to go with it. And you guys, you're all very experienced, and you see what's there. But I personally am enthusiastic about where this is. And I think this will be an important addition to the field. Again, I don't think we need 100 drugs in obesity, but we need more than 2. That's for sure.

Thank you. And I'm showing no further questions in queue at this time. I will now turn the call back over to Dr. Vipin Garg for any closing remarks.

Thank you, everyone, for participating today. We appreciate the opportunity to share our results and outlook with you, and thank you for your continued interest. Have a great day.

Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.