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 48 Data Analysis 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, Gigi, and good morning, everyone. Thank you for participating in the conference call to discuss the results for the week 48 topline data 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; Scot Roberts, our Chief Scientific Officer; Scott Harris, our Chief Medical Officer; and Ray Jordt, Chief Business Officer. A press release summarizing the results of this trial was issued yesterday evening and 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 statement disclaimer in our press release issued this morning and now available on our website. Any statement made on this conference call speak only as of today's date, February -- December 1, 2020 -- or Friday, December 1, 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 exciting results of the 48-week analysis of the MOMENTUM pemvidutide Phase II obesity trial. During our call today, we plan to provide you with a quick overview of the trial design, share the efficacy results with an emphasis on the impressive weight loss data, and conclude with an overview of the safety and tolerability. With that, I'll turn the call over to Scott Harris, our Chief Medical Officer, to go through the results of the trial. Scott?

Well, thank you, Vipin, and good morning, everyone. Today, I have the pleasure of sharing the top line 48-week results of the MOMENTUM obesity trial. For your reference, I will use the slide set that was posted yesterday evening to our corporate website, as noted by Rich Eisenstadt in his opening remarks. Slide 2. Here is our forward-looking statement. I'll now move on to Slide 3, which describes the MOMENTUM trial design. MOMENTUM was a Phase II 48-week trial of pemvidutide that enrolled 391 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 gender and baseline BMI, with lifestyle interventions of diet and exercise that are standard for obesity trials. No dose titration was used at the 1.2 or 1.8 milligram doses, while a short 4-week titration was used at the 2.4 milligram dose. It is also important to note that dose reduction was not allowed as subjects experienced intolerability. Next slide. As shown in this 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 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. Approximately 25% of the subjects were to be male. Next slide. The primary endpoint of the study was the percent change in body weight from baseline. Key secondary endpoints included proportions of subjects achieving weight losses of 5%, 10%, 15% and 20% body weight, and changes from baseline in serum lipids and blood pressure. Safety endpoints included serious adverse events, adverse events of special interest, cardiac adverse events, major cardiac events or MACE, heart rate and glucose homeostasis. Tolerability endpoints included adverse events leading to discontinuation and gastrointestinal adverse events. Slide 6 shows a concert diagram of the disposition of subjects in the study. More subjects receiving pemvidutide stayed on study compared to those receiving placebo, with 74.1% of subjects receiving pemvidutide completing the trial, compared to 61.9% of subjects on placebo. The higher rates of discontinuations in subjects treated with placebo suggests that subjects treated with pemvidutide preferred to remain in the trial. I'll now turn to Slide 7, which shows the baseline characteristics of the 391 subjects included in the 48-week analysis. These demographics were similar to those of other obesity studies with a mean age of approximately 50 years, mean BMI of approximately 37 kilograms per meter squared, and mean body weight of approximately 104 kilograms. Approximately 75% of 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. While not noted on this slide, mean serum triglycerides, total cholesterol and LDL cholesterol were also in the normal range. Now let's turn to the efficacy data at week 48. We're excited about the impressive weight loss we've achieved in this trial. We're going to show the weight loss data in 4 different ways. First, the relative weight loss at 48 weeks. Second, the weight loss curves for each treatment arm. Third, the proportion of subjects achieving 5%, 10%, 15% and 20% weight loss. And finally, waterfall plots of weight losses in individual subjects, which provide useful information about weight loss achieved at each pemvidutide dose. Slide 8. The left side of this slide shows the primary endpoint of the study. The weight loss achieved by subjects at 48 weeks of therapy. As you can see, the weight loss for all pemvidutide treatment doses was statistically different from placebo. Also as noted by the dark blue bar in the chart, a mean weight loss of 15.6% was achieved at the highest dose of 2.4 milligrams. It's important to point out that this level of weight loss has been shown to reverse the key complications of obesity. To put this amount of weight loss in perspective, we're also showing the corresponding mean absolute weight loss for each of the doses in pounds. What you can see is that, at the 2.4 milligram dose, the mean amount of weight loss was over 32 pounds at week 48. Although this is impressive on its own, I should also mention that we saw a weight loss of up to 87 pounds in this trial. Slide 9 shows the weight loss curves for all doses throughout the 48-week study. What is striking is that the 2.4 milligram weight loss curve remains near linear with no indication of plateauing at week 48, suggesting potential for greater weight loss with longer durations of treatment. It is important to remember that this was only a 48-week trial whereas the Phase III trials for the approved incretins assess weight loss after 68 and 72 weeks of treatment, roughly 50% longer than the treatment duration in this trial. As we dive deeper into the weight loss data, let's move to Slide 10, which shows the proportion of subjects achieving predefined weight loss targets at week 48 of treatment. I'll call attention to the 2.4 milligram dose, represented by the dark blue bar, in which the majority of subjects achieved at least 15% weight loss and over 30% subjects achieved 20% weight loss after only 48 weeks. On Slide 11, we're showing waterfall plots of the percent weight loss at each dose for individual subjects that completed dosing. There is an obvious shift towards greater weight loss for all pemvidutide arms relative to placebo. Once again, you can see a large percentage of subjects experienced more than 20% weight loss at 2.4 milligrams. Furthermore, it is important to appreciate that there are many subjects receiving the 1.2 and 1.8 milligrams doses of pemvidutide that are achieving 15%, even 20% weight loss at these dose levels. It is clear from these waterfall plots that all 3 doses could be used for chronic weight management. Now that we've covered the weight loss results, let me shift to our other important efficacy data. Slide 12 shows the mean changes in BMI for each of the dosing arms with the BMI categories on the right. As you can see, we saw more than a 5-point reduction in mean BMI with the 2.4 milligram dose at week 48. A drop in BMI of this magnitude is very impactful. For example, 49% of subjects on the 2.4 milligram dose realized a 1-class reduction in BMI, and that 29% of subjects realized a 2-class reduction in BMI. Importantly, nearly half of subjects that entered the trial with obesity no longer had obesity at the end of treatment. As it is known that the risk for cardiovascular outcomes increases with increasing BMI, these shifts in BMI class have the potential to possibly impact a patient's well-being. Slide 13 shows the effects of pemvidutide on serum lipids. We observed serum lipid reductions of approximately 35% in triglycerides, 15% in total cholesterol, 10% in LDL cholesterol and 31% in VLDL. These are greater reductions in total and LDL cholesterol than achieved by currently approved incretin therapies at 68 and 72 weeks. The 35% of reduction in triglycerides is also impressive. We have not released VLDL data previously, and given that it is metabolized to LDL, we're very pleased to see important reductions also occur in that serum lipid. However, please keep in mind that these reductions, although striking, were observed in the entire study population, which predominantly included subjects with normal lipids at baseline. Therefore, we wanted to understand the impact of pemvidutide on those subjects with elevated baseline levels. These results are shown on Slide 14. In subjects with elevated triglycerides, total and LDL cholesterol, defined as greater than 150, 200 and 130 milligrams per deciliter, respectively, even more striking reductions in these lipids were observed. We achieved a striking 55% reduction in triglycerides and 20% or more reductions in total and LDL cholesterol in this population. The more pronounced reductions in these -- of these lipids in subjects with elevated baseline lipids suggest that even greater reductions may potentially be realized in subjects with severe dyslipidemia. As everyone can appreciate, reducing lipid levels has been shown to result in cardiovascular benefits. For pemvidutide, it is combined effective weight loss and lipid reductions that we believe will bring clinically meaningful benefits to patients. Slide 15. On the next slide, glucose homeostasis as assessed by changes in fasting glucose and hemoglobin A1c at 48 weeks is shown. For both parameters, there were no significant differences in these measures between the pemvidutide treatment groups and placebo, indicating, as in all of our previous trials, that glucose homeostasis is maintained with pemvidutide treatment. As a reminder, these were normal glycemic subjects, and we would not expect to see any material reductions from baseline in these patients. On Slide 16, the reductions in systolic and diastolic blood pressure through week 48 are depicted. On a placebo-adjusted basis, we observed blood pressure reductions of 8.1 and 4.7 millimeters of mercury, comparable to the reductions observed with approved incretin therapies. Importantly, these improvements in blood pressure occurred without clinically meaningful increases in heart rate, which contrasts with other glucagon-containing dual and triple agonists in development where considerable heart rate increases have been observed that may be associated with arrhythmias and major adverse cardiac events. We believe the reductions in blood pressure without clinically meaningful changes in heart rate could have important cardiovascular benefits for patients. I'll now move to Slide 17, which shows the overview of the adverse events observed in the trial. There was 1 drug-related SAE, serious adverse event, at the 2.4 milligram dose level, which was previously reported at the interim analysis of a subject with vomiting. AE discontinuations for the highest dose were 19.6%, of which 15.5% were drug-related, and most gastrointestinal adverse events were mild to moderate in severity, which we believe is aligned with past and current Phase II studies of oral and subcutaneously administered incretin-based agents. There was a low incidence of cardiac adverse events and arrhythmias, which were evenly balanced between placebo and treatment groups. In summary, as shown on Slide 18, robust weight loss of 15.6% was achieved for the 2.4 milligram dose at week 48. This translated to a mean absolute weight loss of over 32 pounds and a maximum weight loss of 87 pounds. Over 1/3 of subjects lost 20% or more body weight on 2.4 milligrams at week 48, and nearly 1/2 of subjects no longer had obesity at the end of the trial. In addition to the impressive magnitude of weight loss, the rate of weight loss was continuing at this dose at the end of treatment, suggesting that greater weight loss could potentially be realized with longer duration of treatment. Substantial reductions in total cholesterol, triglycerides, LDL and VLDL were observed, especially in subjects with elevated lipids, along with decreases in blood pressure without meaningful increases in heart rate. Taken together, we believe these effects could bring cardiovascular benefits to patients. The overall GI adverse events, which are common to incretin-based agents, were mainly mild to moderate in severity. There were no imbalances of cardiac AEs, including arrhythmias and no MACE events or adverse events of special interest. In addition, glucose homeostasis was maintained. I'll now turn the microphone over to Vipin for closing remarks. Vipin?

Thank you, Scott. To summarize, we could not be more excited about the week 48 results of the MOMENTUM trial. The magnitude of the weight loss achieved in combination with the trajectory of the weight loss curve at week 48 for the 2.4 milligram dose is quite remarkable. This weight loss, combined with potent reductions in serum lipids and blood pressure, suggests that pemvidutide has the potential to be an important treatment option for patients with obesity, especially those who are at risk for cardiovascular comorbidities. With these exciting data in hand, we're now in a position to advance our ongoing partnering discussions. In addition, we're planning an end of Phase II meeting with the FDA in the middle of 2024. Operator, that concludes our formal remarks, and we would like to open the line to take questions. Could you please instruct the audience on the Q&A procedure?

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

Great. So just a couple of follow-ups. Maybe first question, as we think about the weight loss at -- the 15.4% weight loss, and placebo subtracted, 13%, looks pretty competitive with Wegovy and sort of approaching that of tirzepatide, just trying to get a better sense of how you're thinking about and perhaps how your partner -- potential partner discussions, you would say are the key aspects of the weight loss dynamics and the sort of ability to titrate this asset going forward, what do you think is the most important aspect here? From our perspective, it looks like the ability to dose higher with this asset is definitely very important. I think separately, in the past, you've commented that this really is a drug for patients with obesity and not for patients with diabetes per se, or not a diabetes drug per se. We're seeing some separation of that view in the market where branded products for obesity specifically are being branded as obesity drugs versus being branded as diabetes drugs, and that may actually be a preference of patients that's been stated. Just wanted to get a better sense of how you're thinking about the importance of -- including the ability to manage HbA1c in terms of its importance to physicians, but maybe separating that to its importance to patients. And I guess that's -- both questions are really kind of more for your CDO than anything.

Yes. Thank you, Seamus. Good morning and thank you for the question. There's a lot to unpack there. Let me just start with the weight loss itself, and then I'll invite Scott Harris to talk about the management of the -- the thought of increasing the dose. And then finally, I'll invite Ray Jordt to talk about the positioning of the product. In terms of weight loss, as you know, we're getting very robust weight loss at the 2.4 milligram dose. And in fact, all 3 doses, if you look at the waterfall curve, it is clear that many patients are losing 15%, 20% weight loss even at the lower dosage. So we think all 3 of these doses are active. Our plan is to proceed with 3 of -- both -- all 3 doses in Phase III and seek approval for all of them. And clearly, 25 -- 2.4 milligram dose will produce a very robust weight loss. So we think we're getting sufficient weight loss at 2.4 milligram dose, a very competitive weight loss. And when you combine that with all of the other features of the product, particularly the lipid, the serum lipid reduction, we think we have a very compelling story. With -- and as you said, there is also always the potential to even go to higher doses. We're not planning to do that right now. Our goal is to take these 3 doses forward, get them approved. And in terms of life cycle management of the product, we can always go and increase the doses, like others are doing. Everybody else is doing the same thing. Scott, do you want to talk about the management? Yes.

Yes, Seamus. So regarding the higher doses, we clearly think there's a pathway to higher doses that we could consider and follow-up programs. The opportunity is clearly there, and that's something that will have to be considered as we develop the compound further. Ray, do you want to take the differentiation question?

Yes, sure. Thanks, Scott. So I think one of the encouraging things with our discussions with partners to date is the aligned vision that we have. So I think what everybody is appreciating is that there are different segments of patients with obesity that have different needs. So I think that's come out loud and clear on our discussions with partners. So we need different therapeutics. I think we've even seen that with Lilly and Novo doing deals with various companies and expanding the portfolio to address these various needs. So when we talk about pemvidutide, the thing that we've been hearing from partners is they want to see competitive weight loss. It is not about a single number, but they do need to see that competitive weight loss number. But the conversations quickly translate to the comorbidities of obesity. And when they look at our reduction in serum lipids, the liver fat, they recognize, and we've had these discussions, that these address some of the largest needs in the obesity population. Dyslipidemia is one of the largest market segments within this patient segment. Further, it's interesting, even before the select data, and obviously, even after, when they look at the lipid profile, the blood pressure, the weight loss, all that in combination, they were quickly having -- leading the conversation to potential cardiovascular benefits and what that might mean for patients. And then lastly, as you can appreciate, with any drug, it's about safety. And we like that our heart rate data, the cardiovascular safety profile that Scott described, and even considering some of the high-risk patients that you might have in this population, that's resonated with partners. So I think the good news was we've had the discussions, we have an aligned vision, and all that remained was to have the data. And now that we have that in hand, we're really excited about just continuing those discussions with partners.

Great. And then as a follow-up, there's a lot of interest in the sort of post-treatment benefits. So an ability for either sustained or somewhat durable or more durable weight loss in an off-treatment setting, is that something that's being looked at in the MOMENTUM study, that there will be, let's call it, 6 months of additional follow-up with patients off-treatment even if it's in a subset, so that we get maybe a little bit more information on that just because I think there have been some speculation that impacting glucagon and the way that glucagon agonism impact visceral fat could perhaps play a role in that sort of, I guess, metabolic reset that has been discussed to some degree as one of the limitations of the current incretin treatment options? Then just a final question, we did get some questions on changes in HDL. Just hoping you could maybe put some context around that, as we look at the overall data set. And again, congrats on the data.

Yes. Thanks for the encouragement, Seamus. The current protocol that we have does not call for follow-up beyond the 48-week treatment period. The question that you're asking about the metabolic reset is important and absolutely there potentially with glucagon and glucagon containing agents. That would have to take a committed withdrawal type trial like a step forward design in order to answer that question. I want to ask Scott Roberts to address your question about the HDL. Scott?

Sure. So we've seen the decreases in HDL and we've been saying for some time that that's really a response to just that metabolic shock, if you will, of losing that much weight so quickly. And we expected that to normalize and would return towards baseline, and that's what we're seeing. If we look at our 12-week data and our 24-week data, and now the 48-week data, we see that normalizing. So that was expected and it's reassuring to see that. The other thing is that we're exploring the possibility that pemvidutide has a specific effect on cholesterol metabolism, in a positive way. This is called reverse cholesterol transport. And it's a means by which the body removes cholesterol from the arteries and disposes of it. And that's something that we think pemvidutide is doing. We're looking at that currently and we hope to be able to report on those results shortly.

Our next question comes from the line of Yasmeen Rahimi from Piper Sandler.

Congratulations to your outstanding data set. Really excited for you. I guess a few little questions. The first one is, I know you had mentioned in the past that you could do some sort of modeling to predict sort of longer-term weight loss numbers. Have you been -- have you had a chance to do those type of modeling analyses to kind of predict what the weight loss curves would look like at a maybe 72-week or even a 2-year mark? That would be fantastic. Secondly, could you maybe comment on, I know investors have been hypersensitized around ALT elevations, whether -- how stringently were they monitored in the study? What did you observe? Were there any patients with elevated liver enzymes that exhibited a reduction? And then the third one, was there an opportunity to look already at MRI-PDFF reductions at a subset of patients that had those analyses? And I'm mindful this is topline data. Really appreciate providing color, and have one last follow-up beyond these 3, but I'll save that at the end.

Thanks, Yasmeen. Yes, in terms of the modeling, we would advise looking at the curves, and arriving at your estimates of what would happen at week 72, we think that's the best we can advice.

Yes, yes. I would just say that it is very clear that the weight loss is continuing at 48 weeks. And I think one can draw their own conclusions from that, that the weight loss should continue. We feel very comfortable saying that, rather than putting a number at it. We know we already have a very robust weight loss and it should continue as we go from 48 weeks to 72 weeks. So we feel very good about that.

Yes. Regarding your other questions, yes, there was stringent monitoring of ALTs. We had an algorithm for following ALTs, all liver enzymes repeatedly and the monitoring was stringent. There was a very low frequency of ALT elevations, and they were distributed equally among -- between placebo and drug. Regarding the MRI-PDFF, as we announced, we would not have that data ready for the topline readout. It was in a subset of subjects participating in a body composition study of MRI-PDFF. And that data is still coming in-house and being analyzed. We have been able to get a snapshot of a little bit of the data. And it appears in that analysis that the rates of liver fat normalization in patients who had elevated liver fat above 5% at baseline is approaching 80%. And again, I want to stress that's just a preliminary data, and we'll have a better readout on that with the body composition data, which should be coming in the near future.

Great. And then maybe one last question. On the heels of the strong data, I'm certain M&A interest is high. So the question to you is, one, what is your wish list in your potential future partner in terms of characteristics and capabilities that they should bring to the table? And then lastly, is a Phase III sign-off needed for next steps, or given that the Phase III designs are pretty straightforward, maybe a discussion could occur or -- even ahead of that regulatory filing?

You mean Phase III sign-off from the FDA?

Yes. Yes. I guess the question is, do you need the sign-off for the FDA to initiate the partnership discussions?

Okay. So let me start on that. And basically, as you said, the Phase III designs or Phase III campaigns, I should call, are pretty well established for the obesity space. The size of the studies, the types of measurements and so on. So I think as far as that is concerned, our goal is to move forward with end of Phase II planning and have an end of Phase II meeting by the middle of next year. That gives us enough time to also continue to progress our partnership discussions and really have a partner lined up by the time we start Phase III. So that plan stays as we've always stated in the past. Obviously, this data will help us a lot in terms of moving those, propelling those discussions forward. You have -- what was the next question? You want to take that?

The partner wish list?

The partner wish list from our perspective. Yes, thank you. Well, we -- obviously, this is a very large indication, primary care market. We're looking for a multinational player that's interested in both obesity and NASH. And the good news is that most of the players we're talking to really are interested in both of these indications. So this is a full campaign moving forward in both of these indications, and we need a partner to pursue them in parallel.

Wonderful. Congrats again.

Our next question comes from the line of Corinne Jenkins from Goldman Sachs.

So I think you saw a pretty notable improvement in the tolerability and discontinuation rate, particularly at the high dose, from the interim readout to this one. So just curious if there was any -- what you would attribute that improvement to? Or if there's any kind of management that you've instated that helps there? And then in terms of like a Phase III study with 3 separate doses, I guess, I'd just be curious how you think about the designing hub, the size of that potential study and how you think about like stats, plan for such a trial?

Scott?

Yes. Thanks, Corinne. Well, when we read out previously on the adverse event discontinuations, it was only, Corinne, in 40% of the subjects. We now have 2.5x the number of subjects, going from 160 to 391. The 391 is the accurate readout of the data. So I would simply say it was a question of getting to the right number, when we finally have the final data set. There was no changes that were introduced in the study, between the beginning of the trial and the end of the trial. The trials were -- the trial was conducted exactly the same way in the first and second half of the study. So what this represents is the fact that, by having the full data set, you get the right number. And the right number was 19.6%. Regarding the Phase III study design with 3 doses, that will have no burden on the size or sample size of the trial. What determines the size of the trials is the FDA requirement that you have about 5,000 patients in your Phase III program, about 3,500 in your active drug arms and 1,500 in your placebo arms. And sponsors have elected to distribute those 5,000 patients in different ways. Some sponsors conducting 4 trials and some conducting 3. But there's plenty of power in the 5,000 patients to analyze 3 doses. And in fact, this is what was done in the tirzepatide program and they ran a program of about 5,000 patients.

Our next question comes from the line of Roger Song from Jefferies.

Great. Add my congratulations to this impressive data. Overall, it's very robust. So a couple of questions, mostly related to the tolerability. So number one is, I believe in the past you have said that you will incorporate dose down-titration in the Phase III. The goal probably is to even further lower the discontinuation due to AE, down to single digit, like other Phase III incretin trial. My question is maybe you can help us understand this will lower the discontinuation, but how this will impact the potential weight loss efficacy or any other efficacy parameters? So that's the number one question. Number two is we have been seeing other dual GLP-1 glucagon drugs having some CV signals, as you alluded. Maybe you can just give us a little bit of details how the arrhythmia, cardiac AE event looks like and heart rate increase in those compounds versus yours? And also, what's your hypothesis that pemvidutide is differentiated from other GLP-1 glucagon co-agonists?

Thanks for the question, Roger. So in terms of the impact of a dose reduction in efficacy, it should not be very great. If you would consider that perhaps half the patients would be or more would be, let's say, would be dose reducing and the difference between, say, the 2.4 and the 1.8 milligram is about 4%, you would see that across the trial that would lead to -- by doing that in that population, of maybe, say, 10% of people, you could see that might lead to as much as a 0.4% reduction in body weight loss, which is not very meaningful in the course of the trial.

And keep in mind that, that dose reduction is typically only temporary. So you reduce the dose, the patient acclimatizes to a new dose and then you come back up. So usually, this is just for a few weeks and you come back up again.

Right. And regarding the cardiac AEs and arrhythmias, Roger, we presented, let's say, at the 2.4 milligram dose 3 cardiac adverse events, I believe there was 1 arrhythmia in that. And we're just not seeing a meaningful number of arrhythmias. That would be 1% of the 2.4 milligram dose, that compares to 11% to 14% in the retatrutide program. So clearly, there is really a differentiation there with regards to that. And we're not seeing meaningful increases in heart rate. We do believe that the increases heart rate that are being seen with other GLP-1 glucagon compounds is related to that heart rate increase. We think it's driving cardiac stress. And we're just extremely happy with the cardiac readout that we have in this trial.

Scot, do you want to talk about the potential mechanism for that?

Sure. It really starts with the design of the molecule. These peptides have to be modified so that they can allow for weekly dosing. And the way that we accomplished that is with a modification called the EuPort domain. And so that EuPort domain works perfectly well, and we've got weekly dosing PK, and that's fantastic. It turns out that there's another benefit to the EuPort domain. And that is that it appears to slow the entry of the pemvidutide into the bloodstream. And so that's measured by a thing called Tmax. It's the time that it takes to get the maximum blood concentration following the subcutaneous injection. And what we know is that our Tmax is very much longer than the other glucagon-containing compounds that are -- that the data is available. For example, some of them are as fast as 14 hours, whereas ours is 72 hours. And so what that means is that the drug enters the bloodstream more slowly, more gently, and you don't get this rush of the drug. And we think it's that rush of drug and the high concentration that results from that, that triggers these cardiac heart rate increases and possibly arrhythmias, as Scott mentioned.

Excellent. Congrats again.

Our next question comes from the line of Liisa Bayko from Evercore.

Congratulations on the data. Can you talk about the use of concomitant background meds, like statins, maybe blood pressure medicines, other things?

Sure, Liisa. So regarding blood pressure medicines, it was about 35%. Across the whole study, it was about 22%. But in actuality, in the subset of patients who had elevated lipids, as we discussed before, interestingly, it goes up to approximately 30%. And those benefits that we described are also being seen -- those additional benefits that are being seen in patients with elevated levels are also being seen in patients with statins, meaning that there seems to be a synergistic effect of pemvidutide with baseline statin therapy. So we're really excited about the potential use of pemvidutide in patients with more severe degrees of dyslipidemia, even those that are taking statins.

Interesting. And were those pretty balanced across the arms?

Yes, absolutely. The -- as you get to smaller subsets, that get a little harder to analyze in terms of balance. But I think the overall conclusion is that, yes, it was balanced, as I've described.

And did you use any antiemetics to help with some of the GI tolerability? Or is that something...

Yes. That's true. That was allowed in the trial. But I would point out that the nausea rates that were seen were actually less than the nausea rates in the retatrutide trial and also in the STEP 8 semaglutide trial. And we think the most meaningful events are not just reporting nausea. The majority of them were mild or mild to moderate. But does the patient perceive that the side effect undercuts the benefit of staying on treatment, and that's the adverse event discontinuation rate. But we think this drug is very tolerable. As was indicated during the call, by allowing dose reduction in the Phase III program, we expect the discontinuation rates to drop down to single digits as they have in other Phase III programs.

Okay. Great. And then just final question for me. As we look at the data, and I know sometimes you're expressing it as patients who kind of completed the study on medicine, patients who've completed the study or sort of like ITT, you looked at it in different ways, how did you handle discontinuations just to kind of tally up the results? Can you just remind us how those were handled? In other words, like patients who completed the study, but they weren't on medicine, how did you calculate -- how did you estimate the weight loss for those patients? Or even patients who kind of discontinued altogether, how did you calculate that?

Right, Liisa. There's an FDA-endorsed technique, which has become the standard of all obesity trials. It's used in all the trials by all the sponsors as their topline readout. It's given different names. We call it, and Lilly calls it, the efficacy estimand. But it relies on a technique called the mixed model for repeated measures. And what it does is it estimates how patients who stopped therapy would have fared had they continued therapy. The easiest way of looking at this is it draws the curve. It's a curve that you see, for example, on Slide 9. And on that curve, if you look at any time point and ask yourself the question, if the patient discontinued therapy, what would the weight loss be on average? And would fall right on that line.

Our next question comes from the line of Mayank Mamtani from B. Riley Securities.

Congrats on the results. So maybe just to summarize, team, if you could just share your thoughts on what target weight loss and discontinuation rate you could get in the Phase III program, which would have those reduction, maybe a bit lower Hispanic population that you had in the higher dose cohort? And I was really interested to hear from Ray, if there's a particular bar on these 2 metrics, it could be ranges that come out repeatedly in partner discussions, and if those ranges tend to be different for injectables versus orals, especially as we digest the Pfizer update this morning? Any thoughts on that would be great. And then I have a couple of follow-ups.

Yes. Thanks. Thanks, Mayank. Let's take your second question first. And then we'll talk about your first question. Ray, do you want to talk about the bar?

Yes. Thank you, Mayank. I think when we've had partnering discussions, there's no specific number that comes to mind. I think it's about the profile of the asset itself. It's the -- all the attributes combined that I think it's most compelling to partners, at least the discussions we've had to date. And what people were looking for, I think, is what we've been communicating, which is that mid-teen weight loss, having the robust reductions in lipids, and safety. And so as we've described the profile of the asset, that's what's been, I think, most compelling and encouraging with the partners that we've had to date in terms of the discussion. So no specific number, I think it's more of the profile that we offer.

Yes. And one thing I would emphasize, Mayank, sometimes we forget how important safety is in this patient population, particularly cardiovascular safety. I mean if you don't have safety, you don't have a drug. So you can get all the weight loss you're talking about, but that's not going to help you. So you need to have competitive weight loss, robust weight loss, we're already getting that, but I think our safety profile really stands on its own, and we're very excited about that. Scot? Any thoughts on the discontinuation rate? Yes, go ahead, Scot.

Yes. Well, a common theme in development in this space is that, in Phase II, we're seeing adverse events north of 20%. In fact, in one program recently, 27% discontinuation rates. But what sponsors do is they use what they've learned in Phase II to get better dosing regimens as they go to Phase III. And this is exactly what happened with the semaglutide program that had towards 30% adverse discontinuation rates in Phase II. And the Lilly program which had about 25% in Phase II and got them down to single digits in Phase III. What they used is by extending the dose titration. That's not something that we need to do because the most obvious factor that we can change here is allowing dose reduction, which was allowed in all of the other programs. And in fact, if you look at the Phase III tirzepatide and semaglutide programs, 30% of patients had either dose-reduced or never got up to the upper dose. So you can see the power of what would happen if we introduce this in a Phase III program. And we have great confidence that making that modification, which is a very simple modification, we'll be in the single digits also in Phase III.

Got it. And then a quick follow-up on your liver fat sub-study analysis data. It seems like something similar you're doing that you did for a subgroup of elevated LDL patients where cholesterol reduction looks very interesting. But there's a general sense of capping out at 1.8 mg dose, the dose-dependents that you have between 1.8 and 2.4 mg is -- that you have in weight loss is not very as clear for other cardiometabolic markers like lipids and liver fat. So could you just comment on whether -- what you're seeing in that sub-study analysis for 1.8 and 2.4 mg on liver normalization, liver fat normalization?

Yes, Mayank, the data is still preliminary. We're just getting it in-house right now. When we have all of the data in, our plan had always been to look at liver fat with the other body composition because it's an MRR-based technique, and it was a sub-study. So we'll have much better -- much greater detail to answer your question in the ensuing weeks.

Got it. And lastly on -- just a quick double-click on nausea rates and how that is sort of connects to discontinuations. I'm more interested in how maybe differently it's being handled now in Phase III and real world, Scott? Any perspective on that would be helpful.

Right. Well in the pemvidutide doses, the drug-related adverse events leading to discontinuation were about 15%, and they were predominantly GI. What we have here are 3 solid doses of drug. And recognize that unlike other approved agents where you have to go through titration phases, the 1.2 milligram dose, which is our lowest dose, does not -- it's effective, being prescribed right from the get-go, same with the 1.8 milligram. So consequently, we've learned in the past couple of years how physicians are dosing these agents, and they tend to themselves start with a lower dose, see how the patient does, go to a next dose, and the next dose. Now that 1.2 milligram dose could create 20%, 25% weight loss in some people, or good enough weight loss. David D'Alessio says the 10% weight loss is adequate. But nonetheless, if the goal is to get the higher weight loss, a physician could then go to 1.8 milligrams or even 2.4 milligrams. We see that's probably the way these drugs will be used in the marketplace based on what we've learned in the last couple of years about the use of these drugs for the treatment of obesity.

Got it. And congrats on the data again.

Great. Thanks, Mayank.

Our next question comes from the line of Jon Wolleben from JMP.

Congrats on the data. Two for me. The first, just wondering, is there any difference between drug exposure between the 3 doses or patient populations, given the doses are all evenly distributed? You see the 1.2 and 1.8 milligrams, at least on the curves, behave pretty similarly, but then a big jump to the 2.4 milligrams. Any rationale for the jump between the 2 low-mid and then the high dose?

Yes. Jonathan, the Phase III trials will be much larger. This trial was 100 patients per arm, and while it was a nice-size study. When we get to Phase III, it will be 400 to 600 patients per arm. We think as we get to larger trials, that 1.8-milligram dose will converge on the 2.4-milligram dose. You can see by the waterfall plots, I believe that's Slide 11, that there were some outliers at the 1.8-milligram dose that may have been dragging down the mean. When you get to a larger study, those outliers have less of an impact. So we firmly believe that as we get to these larger trials, you're going to see the 1.8-milligram dose have greater weight loss than seen in the current trial.

That's helpful. And then thinking about the parallel path between NASH and obesity and how important this is for strategic, with several AASLD and other medical associations already recommending GLPs for obese and diabetic patients with NAFLD and NASH, how much greater opportunity do you think there is with running a dedicated Phase III NASH program versus just an obesity program? And then assuming docs will use it in their obese patients who have fatty liver already. Can you just talk about kind of the trade-offs between running that Phase III and how important that is from a strategic perspective?

Well, as you mentioned, clearly, GLP-1s are being considered as a potential treatment for NASH. What we bring to the table is really quite unique. We're bringing a combination of a GLP-1 or an incretin GLP-1 glucagon and the direct effect on the liver. So it's really the best of both worlds. We've been doing - getting the benefit of the weight loss and we have a drug that's having a direct impact on the liver fat. I think by combining the 2, we think we're going to hit it really both for obesity as well as for NASH. So we really like that scenario as it develops.

And how do you think pem-v would fare in the cirrhotic population with the recent failure of the FGF21s? Is that something that comes into your conversations with strategics?

Well, not so much in strategic conversations because people are still focused on just having a drug for NASH, and cirrhotic patient population becomes kind of the next frontier in terms of what you do, how do you expand the utility of these NASH drugs. So I think as far as the larger market is concerned, people are still focused on NASH and obesity. And that's where most of our conversations are. Clearly, as the program matures, we will look at in the next phase at the cirrhotic population as well. But that's not a requirement for us to get approval in NASH.

Makes sense. All right. And congrats again guys.

Our next question comes from the line of Patrick Trucchio from H.C. Wainwright & Co.

Congrats on the data. I have a couple of questions. First is a follow-up on an earlier question. Do you envision a potential path forward for Phase III development in type 2 diabetes? And is the discussion around development plan for type 2 part of the partnering discussions? And secondly, are there additional indications such as obstructive sleep apnea that you see as potential for label expansion beyond obesity, NASH or type 2?

Yes. Patrick, thanks for the question. We're going to have to have an end of Phase II meeting with the FDA to answer the question about whether diabetics would be studied in Phase III. I can't really give you a firm answer on that at the current time. I would say we're not shying away from treating diabetics because we had excellent control of glucose and excellent safety in diabetics. So if that's something that the agency wants us to do, it's a program that we'll do. And certainly, if the agency requests that, partners will support that. And yes, as the program matures, we're going to be looking at a number of indications. So as you know, a common theme now in obesity is not just looking at weight loss, but looking at the complications of obesity. That's really what's most meaningful and also what's going to get reimbursed. The primary complication of obesity, as we see it, is NASH. And obviously, we have a NASH program. But there are a lot of other avenues that we could go in, like obstructive sleep apnea, we could go into HFpEF, for example. And there are a number of other important indications. But those are Phase III type looks. And that's something that we'll plan out as we further map out our Phase III program.

And I'm wondering if there was any pattern in the baseline characteristics in those patients who responded that would suggest certain patients respond better than others. And so therefore, would there be an opportunity to maybe enrich the expected Phase III enrollment in the obesity program?

That's a great question, Patrick. Those get to be complicated analyses involving techniques that require a lot of development, techniques like the population PK, to really sort out multiple covariants at baseline, factors that determine response, all moving at the same time. I can't give you an answer that we've identified a specific population right now, but we've been conducting modeling techniques now for some time and will apply this data to that model to answer that question.

Understanding that the collaboration discussions are underway, can you talk further a little bit more about a potential Phase III program or trial design, how it could differ, if at all, from those that have been conducted in the past, such as would you have to compare to approved compounds? Or could you have a true placebo? And at which dose, would you expect to bring forward? Again, understanding still have to talk to the FDA. But is there any scenario in which you would expect that you may move forward to Phase III on your own?

I'll leave the question about moving to Phase III on our own to Vipin. Let me answer your -- the first part of your question, Patrick. It's been the FDA's position for years that sponsors should conduct placebo-controlled trials. And we firmly believe that, for the next few years, weight loss trials in Phase III will compare to placebo. We believe that we have 3 effective doses that will be moved into Phase III and would -- for approval, that would be very attractive for physicians and offer the greatest flexibility, as I've described before, for dosing patients. So our current plan is to move all 3 doses into Phase III. I'll leave the final part of the question to Vipin.

Did you want to address a bit about the competitive dose? Yes. So as far as -- as we've said all along, our plan is to get Phase III ready by the middle of next year and have a partner at the -- when we start Phase III. And that -- we feel very comfortable, given our ongoing discussions, that we will have a partner lined up. So really, this is not a drug that we're probably going to launch on our own in the primary care market. We're eventually going to need a partner anyway, so it makes perfect sense to bring the partner on board as early as possible and definitely by the time we start Phase III program.

Yes. That's helpful. And one last one for me, is just with the understanding that we're looking further in the future, based on this product profile, we've seen in MOMENTUM, and assuming these results are repeated in Phase III, how do you envision positioning pemvidutide in the market compared to these approved GLP-1 compounds in obesity specifically?

Ray, do you want to take that?

Yes. So I think if you look at the individual products, some of that are approved and some are in development, I think you have to look at the individual attributes, right? So not all of them have robust reductions in lipids, LDLs and total cholesterol. Not all of them have robust and rapid reductions in liver fat. Not all of them have the safety profile that I think we're exhibiting. And I think the dose that we -- that Scott just mentioned is another attribute. So we can talk about that on a case-by-case basis. But again, those are some of the unique attributes when you do compare ours to the various programs.

Thank you. I would now like to turn the conference back over to Vipin Garg for closing remarks.

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

This concludes today's conference call. Thank you for participating. You may now disconnect.