Good day, ladies and gentlemen, and welcome to the Altimmune, Inc. MOMENTUM pemvidutide phase 2 obesity trial, week 48 data analysis call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session, and instructions will follow at that time. To ask a question during the session, you will need to press star one one on your telephone. 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, Inc. 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 top line 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 George, 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, 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 2, 48-week trial of pemvidutide that enrolled 391 subjects with overweight or obesity. Subjects were randomized 1- 1, to 1- 1, to 1 of 4 treatment arms, either pemvidutide 1.2 mg, 1.8 mg, 2.4 mg, or placebo, stratified by gender in 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 mg 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 if subjects experienced intolerability. Next slide. As shown in this slide, the key eligibility criteria included men and women 18- 75 years of age, with body mass index, or BMI, equal to or greater than 30 kilograms per meter squared, or 27 kg 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 CONSORT 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 suggest 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 kg per meter squared, and mean body weight of approximately 104 kg. 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 four 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 mg. 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 3 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 mg 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 are showing waterfall plots of the % 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 mg. Furthermore, it is important to appreciate that there are many subjects receiving the 1.2 and 1.8 doses of pemvidutide that are achieving 15%, even 20% weight loss at these dose levels. It is clear from these waterfall plots that all three 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 mg 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 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 positively 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% reduction in triglycerides is also impressive. We have not released VLDL data previously, and given that it is metabolized to LDL, we are 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 mg 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 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 effect of 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 mm 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 one drug-related SAE, serious adverse event, at the 2.4 mg 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 2 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 mg dose at week 48. This translated to a mean absolute weight loss of over 32 lbs and a maximum weight loss of 87 lbs. Over one third of subjects lost 20% or more body weight on 2.4 mg at week 48, and nearly one half 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 mg 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 are now in a position to advance our ongoing partnering discussions. In addition, we are planning an end of phase two 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?
As a reminder, to ask a question, please press star one, one on your telephone and wait for your name to be announced. To withdraw your question, please press star one, one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Seamus Fernandez from Guggenheim Securities.
Great, thanks for the question. So, just a couple of follow-ups. Maybe, first question, as we think about the, you know, weight loss at, the 15.4% weight loss and placebo subtracted, 13% looks pretty competitive with Wegovy, and sort of approaching that of, of tirzepatide. Just trying to get a better sense of, how you're thinking about and perhaps how your partner, you know, 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, you know, dose higher with this asset is, you know, definitely very important.
I think separately, in the past, you've commented that, you know, 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 are seeing some separation of that view, in the market where, you know, 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, you know, including the ability to manage HbA1c in terms of its importance to physicians, but maybe separating that to its importance to patients.
I guess that's, you know, both questions are really kind of more for your CDO than anything. Thanks.
Yeah, 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 thought of increasing the dose. And then finally, I'll invite Ray George 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 mg dose. And in fact, all three doses, if you look at the waterfall curve, it is clear that many patients are losing 15%-20% weight loss, even at the lower doses. So we think all three of these doses are active.
Our plan is to proceed with all three doses in phase 3 and seek approval for all of them. Clearly, 25, 2.4 mg dose will produce a very robust weight loss. So we think we're getting sufficient weight loss at 2.4 mg 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.
... 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 three doses forward, get them approved, and in terms of life cycle management of the product, we can always go and increase the dosage, like others are doing. Everybody else is doing the same thing. Scott, do you want to talk about the management? Yeah.
Yeah, Seamus. So, regarding the higher doses, we clearly think there's a pathway to higher doses that we could consider in follow-up programs. The opportunity is clearly there, and that's something that'll have to be considered, you know, as we develop the compound further. Ray, did you want to take the differentiation question?
Yeah, sure. Thanks, Scott. So I think one of the encouraging things with our discussions with partners to date is, you know, the aligned vision that we have. So I think what everybody's 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, you know, 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 if 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. You know, dyslipidemia is one of the largest market segments within this patient segment. You know, further, it's interesting, even before the SELECT data, and obviously even after, when they looked at the lipid profile, the blood pressure, the weight loss, all that in combination, you know, they were quickly having, you know, 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.
You know, and when we looked at 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, you know, we're really excited about just, you know, continuing those discussions with partners.
Great. And then as a follow-up, you know, 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 studies, that there will be, you know, let's call it six months of additional follow-up, with patients off treatment, you know, even if it's in a subset, so that we get maybe a little bit more information on that?
Just because I think there has been some speculation that impacting glucagon and the way that a glucagon agonism impacts visceral fat could perhaps play a role in that, you know, sort of, I guess, metabolic reset that has been discussed to some degree as one of the, you know, limitations of the current incretin treatment options. Then, you know, just a final question. We did get some questions on changes in HDL. Just wondering if you could maybe put some context around that as we, you know, look at the overall data set. And again, congrats, congrats on the data. I'll jump back in the queue. Thanks.
Yeah, thanks for the treatment, Seamus. The current protocol that we have does not call for follow-up beyond, you know, 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 4 design, in order to answer that question. I want to ask Scot Roberts to address your question about the HDL. Scot?
Sure. So, you know, we've seen the decreases in HDL, and we've been saying for some time that that's really a response to just the metabolic shock, if you will, of losing that much weight so quickly. And we expected that to normalize and return towards baseline, and that's what we're seeing. If we look at our, you know, 12-week data, 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 are looking at that currently. We hope to be able to report on those results shortly.
Thank you. One moment for our next question. Our next question comes from the line of Yasmin Rahimi from Piper Sandler.
Good morning, team, and congratulations to your outstanding data set. Really excited and 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 had a chance to do those type of modeling analyses to kind of predict, you know, what the weight loss curves would look like at a maybe 72-week or even a two-year mark? That would be fantastic. Secondly, could you maybe comment on, I know investors have been hypersensitized around ALT elevations, whether, you know, 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, you know, is there an opportunity to look already at, you know, MRI-PDFF reductions at a subset of patients that had those analyses? And I'm mindful this is top-line data. But really appreciate providing color and have one last follow-up beyond these three, but I'll save that at the end.
Thanks. Thanks, Yasmin. Yeah, 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 advise.
Yeah. 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 conclusion from that, that the weight loss should continue. We feel very comfortable saying that, rather than putting a number at it. You know, we already have a very robust weight loss, and it should, 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 top line 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 from that analysis that the rates of liver fat normalization in patients with elevated liver fat above 5% at baseline is approaching 80%. And again, I want to stress that-
Wow!
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 an end-of-phase 2 and a discussion could occur or even ahead of that regulatory filing. And I'll jump back into the queue. Thank you again.
You mean phase III sign-off from the FDA?
Yes. Yes.
So-
Like, 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 the 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?
Do you want to take that?
The partner wish list.
Oh, the partner wish list from our perspective. Yeah, thank you. Well, obviously, this is a very large indication, primary care market. We're looking for a, you know, multinational player, that's interested in both obesity and NASH. And the good news is that most of the players we are 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. I'll jump back in the queue.
Thank you. One moment for our next question. Our next question comes from the line of Corinne Jenkins from Goldman Sachs.
Hey, good morning. So I think you saw pretty notable improvement in the tolerability and discontinuation rate, particularly at the high dose from the interim readout to this one. So I was curious if there was any what you would attribute that improvement to, or if there's any kind of management that you had stated that helped there? And then in terms of, like, a phase 3 study with three separate doses, I guess I would just be curious how you think about kind of designing the size of that potential study and how you think about, like, stats plan for such a trial?
... Scott?
Yeah, thanks, Corinne. Well, when we read out previously on the adverse event discontinuations, it was only Corinne in 40% of the subjects. You now have 2.5 times 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 had 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 trial was conducted exactly the same way in the first and second half of the study.
What this represents is the fact that by having the full data set, you get the right number, and the right number is 19.6%. Regarding the phase three study design with three 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 three program. About 3,500 in your active drug arms and 1,500 in your placebo arms. Sponsors have elected to distribute those 5,000 patients in different ways, some sponsors conducting four trials and some conducting three. But there's plenty of power in the 5,000 patients to analyze three doses.
In fact, this is what was done in the tirzepatide program, and they ran a program of about 5,000 patients.
All right. That's super helpful. Thank you.
Sure.
Thank you. One moment for our next question. Our next question comes from the line of Roger Song from Jefferies.
Great. Add my congratulations to this impressive data on, you know, overall, it's very robust. So a couple questions, mostly related to the tolerability. So number 1 is, I believe in the past you have said the, you will incorporate the dose down titration in the phase 3. The goal probably is to even further lower the discontinuation due to AE down to single digit like other phase 3 incretin trial. My question is that maybe you can help us understand, you know, understand this will lower the discontinuation, but how this will impact the potential weight loss, efficacy or any other efficacy parameters. So that's number one question. Number 2 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 look like and, heart rate increase in those compound versus yours. And also, what's your hypothesis semaglutide is differentiated from other GLP-1 glucagon, co-agonists? Thank you.
You know, 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, be, let's say, would be dose reducing, and the difference between, say, the 2.4 and the 1.8 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.
Keep in mind that that dose, dose reduction is typically only temporary. So you reduce the dose, the patient acclimatizes to new dose, and then you come back up. So usually, this is just for a few weeks, and you come back up again.
Right. Regarding the cardiac AEs and arrhythmias, Roger, you know, we presented, let's say at the 2.4 milligram dose, three cardiac adverse events. I believe there was one 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%-14% in the retatrutide program. So clearly, there's really a differentiation there with regards to that. And, you know, we're not seeing meaningful increases in heart rate. We do believe that the increases in 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 are 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. You know, these peptides have to be modified so that they can, you know, allow for weekly dosing. And the way that we accomplish that is with a
... a modification called 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 of the pemvidutide into the bloodstream. And so, you know, that's measured by a thing called Tmax. It's the time that it takes to get the maximum blood concentration following the, you know, the subcutaneous injection. And what we know is that our Tmax is very much longer than the other glucagon-containing compounds that the data is available. For example, some of them are as fast as 14 hours, whereas ours is 72 hours.
What that means is that the drug enters the bloodstream more slowly, more gently, and you don't get this rush of the drug. 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. Thank you for the comments. Congrats again.
Thank you. One moment for our next question. Our next question comes from the line of Lisa Bayko from Evercore.
Hi, congratulations on the data, and thanks for taking the question. Can you talk about the use of concomitant background meds like statins, you know, maybe blood pressure medicines, other things?
Sure, Lisa. 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 here 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?
Yeah, absolutely. You know, as you get to smaller subsets, they get, you know, 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.
Did you use any antiemetics to help with some of the GI tolerability, or is that something-
Yeah, that's true. That was allowed in the trial, but I would point out that the nausea rates that we're seeing 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, you know, 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 from me. As we look at the data and, and I know sometimes you're expressing it as patients who kind of, you know, completed the study on medicine, patients who completed the study are sort of like ITT. So you looked at it in different ways. How did you handle discontinuations, just to kind of tally up the results that you... 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 the, how did you estimate the weight loss for those patients or even patients who, you know, kind of discontinued altogether? How did you calculate that?
Right, Lisa. 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 top-line 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 stop 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 nine. And on that curve, if you look at any time point and ask yourself the question, if the patient continued therapy, what would the weight loss be on average, and it would fall right on that line.
... Thank you. One moment for our next question. Our next question comes from the line of Mayank Mamtani from B. Riley Securities.
Good morning, team. Congrats on the results, and thanks for taking our question. 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 3 program, you know, which would have dose 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 two metrics, you know, it could be ranges that come up repeatedly in pharma discussions, and if those ranges tend to be different for injectables versus orals, you know, 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.
Yeah. Thanks. Thanks, Mayank. Let's take your second question first, and then we'll talk about your first question. Ray, do you wanna talk about the bar?
Yeah. Thank you, Mayank. You know, I think 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, I think, is most compelling to partners, at least the discussions we've had to date. And, you know, what people were looking for, I think, is what, you know, we've been communicating, which is, you know, that mid, mid-teen weight loss, you know, 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 the profile that we offer.
Yeah, 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 know, you can get all the weight loss you're talking about, but that's not gonna 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. Scott, any thoughts on the discontinuation rate? Yeah, go ahead, Scott.
Yeah. Well, a common theme in development in this space is that in phase 2, 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 2 to get better dosing regimens as they go to phase 3, and this is exactly what happened with the semaglutide program that had toward 30% adverse discontinuation rates in phase 2, and the Lilly program, which had about 25% in phase 2 and got them down to single digits in phase 3. What they used is by extending their 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 3 tirzepatide and semaglutide programs, 30% of patients had to either dose reduce 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 3 program, and we have great confidence that making that modification, which is a very simple modification, will be in the single digits also in phase 3.
Got it. And then, a quick follow-up on your liver fat substudy analysis data. Seems like something similar you are doing that you did for a subgroup of elevated LDL patients, where cholesterol reduction looks very interesting. But there's a general sense of, you know, capping out at 1.8 mg dose. The dose dependence 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 substudy analysis for 1.8 and 2.4 mg on liver normalization, liver fat normalization?
Yeah, 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 MRI-based technique, and it was a substudy. 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 3 and real-world, Scott. Any perspective on that would be helpful. And thanks again for taking our questions.
Right. Well, in the pemvidutide doses, the drug-related adverse events, leading to discontinuation were about 15%, and they were predominantly GI. You know, what we have here are three solid doses of drug. And recognize that unlike other approved agents, where you have to go through titration phases, the 1.2 mg dose, which is our lowest dose, does not. It's effective being prescribed right from the get-go. Same with the 1.8.... 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 mg 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 to higher weight loss, a physician could then go to 1.8 mg or even 2.4 mg. 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. Thanks for taking the question, and congrats on the data again.
Great. Thanks, Mark.
Thank you. One moment for our next question. Our next question comes from the line of John Wolleben from JMP.
Hey, good morning. Congrats on the data. Two from me. The first, just wondering, is there any difference between drug exposure between the three doses or patient populations? You know, given the doses are all evenly distributed, you see the 1.2 and 1.8, at least on the curves, behave pretty similarly, but then a big jump to the 2.4. You know, any rationale for the jump between the two, you know, low, mid, and then the high dose?
Yeah. You know, Jonathan, the phase 3 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 3, it'll be 400-600 patients per arm. We think as we get to larger trials, that 1.8 mg dose will converge on the 2.4 mg dose. You can look... 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 gonna see the 1.8 mg dose have greater weight loss than seen in the current trial.
That's helpful. Then thinking about the parallel path between NASH and obesity and how important this is for strategic, with, you know, several, you know, AASLD and other medical associations already recommending GLPs for obese and diabetic patients with NAFL and NASH, you know, how much greater opportunity do you think there is with running a dedicated phase 3 NASH program versus, you know, 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 3 and how important that is from a strategic perspective?
Well, as you mentioned, you know, 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 a direct effect on the liver. So it's really the best of both worlds. We're 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 two, you know, we think we're gonna hit it really both for obesity as well as for NASH, so we really like that scenario, as it develops.
How do you think pemvidutide would fare in the cirrhotic population with the recent failure of the FGF 21? 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, and cirrhotic patient population becomes kind of the next frontier in terms of what you do, you know, how do you expand the utility of these NASH drugs? So I think as far as the, the larger market is concerned, people are still focused on, on NASH and obesity, and, and that's where most of our conversations are. Clearly, as the program matures, we will look at the, in the next phase, at the cirrhotic population as well, but that's, that's not a requirement for us to get approval in NASH.
Makes sense. All right. Thanks for taking the questions, and congrats again, guys.
Thank you. One moment for our next question. Our next question comes from the line of Patrick Trucchio from H.C. Wainwright & Company.
Thanks. Good morning, and 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 3 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?
Yeah. Hi, Patrick. Thanks for the question. We're gonna have to have an end-of-phase two meeting with the FDA to answer the question about whether diabetics would be studied in phase three. 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, you know, if, if the agency requests that, partners will support that. And yes, as the program matures, we're gonna 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 gonna 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, you know, those, those are phase 3 type looks, and that's something that we'll plan out as we further map out our phase 3 program.
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. So therefore, would there be an opportunity to maybe enrich the expected phase 3 enrollment in the obesity program?
That's a great question, Patrick. You know, those get to be complicated analyses involving techniques that require a lot of development, techniques like a population PK, to really sort out multiple covariates 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 we'll apply this data to that model to answer that question.
Understanding that, you know, the collaboration discussions are underway, can you talk further a little bit more about a potential phase 3 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 or dose would you expect to bring forward, again, understanding, you know, still have to talk to the FDA. But if there is there any scenario in which you expect that you may move forward to phase 3 on your own?
I'll leave the question about moving to phase 3 on our own to Vipin. Let me answer the first part of your question, Patrick. It's been the FDA's position for years that sponsors should conduct placebo-controlled trials. We firmly believe that for the next few years, weight loss trials in phase 3 will compare to a placebo. We believe that we have three effective doses that will be moved into phase 3 and would, for approval, that would be very attractive for physicians and offer the greatest flexibility, as I've described before, for dosing patients. Our current plan is to move all three doses into phase 3. I'll leave the final part of the question to Vipin.
Did you want to address the bit about comparative dose? Yeah. So as far as, as we've said all along, our plan is to get Phase 3 ready by the middle of next year and have a partner at the, when we start Phase 3, and that, you know, we feel very comfortable, given our ongoing discussions, that we'll have a partner lined up. So really, this is not a drug that we are probably ever going to launch on our own in the primary care market. We are 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 3 program.
Yeah, that's helpful. One last one for me is just with the understanding that we're looking, you know, further in the future. Based on this product profile momentum, and assuming these results are repeated in phase 3, how do you envision positioning pemvidutide in the market compared to these approved GLP-1 compounds in obesity specifically?
Ray, you want to take that?
Yeah. So I think if you look at the, you know, individual products, some 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, LDL, 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 Scott just mentioned is another attribute. So, you know, we could 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.