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

Greetings, and welcome to this morning's conference call hosted by Altimmune. [Operator Instructions] As a reminder, this conference 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, Michelle, and good morning, everyone. Thank you for joining us. Members of the Altimmune team joining me on the call today are Vipin Garg, Chief Executive Officer; Scott Harris, Chief Medical Officer; Scott Roberts, Chief Scientific Officer; and Dr. Stephen Harrison, Medical Director of Pinnacle Research and principal investigator on our trial. Please note that we issued a press release and posted an accompanying slide deck this morning, which is the subject of our discussion today. You may find copies of these items on the IR section of our website, www.altimmune.com. 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, including those related to the ongoing conflict in Ukraine, COVID-19 and the impact on our business operations, clinical trials and results of operations. For a discussion of some of the risks and factors that could affect the company's future results, please see the risk factors and other cautionary statements contained in the company's filings with the SEC. I would also direct you to read the forward-looking statements disclaimed in our press release issued this morning and now available on our website. Any statements made on this conference call speak only as of today's date, Wednesday, September 14, 2022, 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. Good morning, everyone, and thank you for joining us today as we review the positive data from our Phase Ib 12-week NAFLD clinical trial for pemvidutide. Pemvidutide is our investigational GLP-1 glucagon dual receptor agonist under development for obesity and NASH. The results of this trial were announced in a press release this morning as well as accompanying slide deck posted this morning on our website. As you will see, we believe the Phase Ib clinical data we have collected is compelling, including significant reduction in liver fat, serum ALT and body weight. Pemvitutide was well tolerated, and there were no clinically significant ALT elevations defined as threefold or greater, the upper limit of normal. In fact, serum ALT was observed to decline significantly in all but the lowest dose cohort. These results strengthen our enthusiasm for the potential impact pemvitutide could have on the multibillion-dollar NASH and obesity market. I will now turn the call over to Dr. Scott Harris, our Chief Medical Officer. Scott?

Thank you, Vipin, and good morning, everyone. I'd like to start off setting the stage for today's discussion. The clinical trial results we are reporting are from a clinical trial in obese and overweight participants with significant liver fat content. For inclusion in the study, the participant was required to have at least 10% liver fat fraction, and in the end, the mean liver fat fraction across the study participants was 22%. So these subjects represent a unique subset of the general obese and overweight population. I would like to add that we are fortunate to have Dr. Stephen Harrison, Medical Director of Pinnacle Research service of clinical investigator on this trial. Dr. Harrison is a renowned hepatologist who has conducted numerous NAFLD and NASH studies. With that, it is a pleasure to introduce Dr. Harrison, so he can walk you through the top line trial data, and he'll follow the sequence on the slides that have been loaded on the website. Following his presentation, the entire management team and Dr. Harrison will be available for Q&A. So I'm going to turn the presentation over to Dr. Harrison starting with Slide 4 of the slide deck. Stephen?

Yes. Thank you, Scott. It's an honor and a pleasure to be here today to discuss the results of this exciting Phase Ib NAFL trial. And I just want to take a few minutes to walk you through what we have. So here on Slide 4 is the trial design. It's a 12-week randomized, placebo-controlled study of pemvidutide in subjects that are overweight or obese, and that have nonalcoholic fatty liver disease. 94 subjects were randomized to 1:1 to 1:1 and dosed across 13 sites. -- to 1 of the 4 treatment arms you see listed here and treatment was for 12 weeks, and they were stratified by the presence or absence of type 2 diabetes. If you look at the high dose arm, there was a 4-week titration period and then a stable 2.4-milligram weekly dosing for 8 weeks. The remainder of the dosing arms were not titrated. And I think it's important to also note, unlike a standard obesity trial, there were no calorie restrictions, no lifestyle intervention recommended here. All right. Let's go to the next slide, Slide 5. So it's important to recognize the key eligibility criteria. Again, this is a couple of points I want to make that maybe are a little different from a classic fatty liver study. The age is typical 18 to 65. The BMI greater than or equal to 28 kilograms per meter squared. Here you also had to have liver fat content as defined by MRI of at least 10% liver fat fraction. Now when you do that, that drives up the mean value of liver fat, as Scott mentioned, of around 22%, which is quite high. In addition, we wanted to have some metric where we could exclude significant fibrosis in this early Phase Ib study, and we set that as a noninvasive Fibroscan, liver stiffness measurement of less than 10 kilo Pascal. In addition, when we looked at eligibility criteria for our nondiabetic or diabetic population, they had to be on a stable dose of metformin or SGLT2 therapy. That could not use insulin Sofanarias DPP4 or score beyond current GLP-1 treatment. They had to be reasonably controlled in their diabetes. This is, again, a standard of value through all NAFLD/NASH trials that at least the ones I've been involved with a hemoglobin A1c needed to be less than 9.5%. And maybe a critical component here is the note that ALT and AST, the 2 liver chemistry tests we follow routinely in liver disease, had to be 75 international units per ml or less. Typically, we're looking for a minimum threshold of ALT and AST to enroll patients, and typically, we exclude them if they're greater than 3 to 5x the upper limit of normal, usually around 200. In this particular trial, we had 2 criteria that were quite different. We had to have less than a liver stiffness measurement, less than 10 and ALT less than or equal to 75, and we'll talk about that more as we go through the deck. So I'm going to move to Slide 6, which is study endpoints. So the overall primary endpoint was reduction in liver fat content by MRI-PDFF and we looked at both absolute and relative fat reductions. Key secondary endpoint was percent body weight loss. Of course, in this early phase trial, we're very keen to look at safety and tolerability, particularly serious and severe adverse events and, in particular, those adverse events that could lead to discontinuation. And as consistent with this mechanism of action, we wanted to assess, in particular, the GI tolerability. In addition, we know that ALT is a safety lab. We wanted to look to see if there were any elevations in ALT. We wanted to look at vital science and glycemic control as well. Now I'll move to Slide 7, which is the baseline characteristics of the study participants. And it is a relatively busy slide, but I think it speaks to the population, and I wanted to pull out a couple of salient features of our patient population. As you can see, the overall treatment numbers were roughly 23 to 24 in each group. They were relatively evenly split between male and female, and age was roughly close to 50. Importantly, and disparate from other trials in NAFLD and NASH, there is a predominance of Hispanics. In fact, you can see in the treatment arms, 75% to 87% of our population were white Hispanic, and that, I think, is important to note. When we look at BMI, they're in the obesity range here, 35 to 37, depending on which group you're in, and about 1/3 of the patients are diabetic. We've already alluded to the liver fat content being quite high, around 22%, looking at the ranges here from 20% to 23.8%. And again, that is a function of the requirement to have at least 10% liver fat content on MRI. Some studies are looking at 8% liver fat content for inclusion. When you do that, you tend to have mean values in the high teens, something like 17%, 18%. But when you push it to a requirement of 10%, you actually push those mean numbers over to the 20 points, and that's what we're seeing here. It is important to note that ALT is relatively low here across the group. 32.4% to 39.5%. And that, again, is a function of the requirement to have a low ALT or less than 75 at baseline when we included these patients. So that will come up as we move through the deck. The remainder of the data is representative of a NAFLD / NASH population, you see the cholesterol here generally being in the normal range, high normal range, the triglycerides do tend to be a little bit elevated as you see. But at the end of the day, I think it's very representative of an APL population. So let's move on to Slide 8, that's the study disposition slide. And as I alluded to in the study trial design slide, 94 patients were randomized and dosed. You see the breakdown here between the 4 different treatment arms. And in this consort diagram, you can see those lost to follow-up in the PIMB1.2-milligram, there were, one withdrew consent, one lost to follow-up and ultimately, 21 patients completed treatment in the 1.8 PIMB arm. There was one adverse event, 3 withdrew consent, one lost to follow-up at 18 completers and in the PEMB2.4, there was one adverse event to protocol deviations, one noncompliance, which led to 20 completers. If you look at the adverse event dropouts the one in the 1.8 and the one in the 2.4, those were due to GI intolerability. So let's move on to the next slide, and this is Slide 9. And it's the primary endpoint, which is exciting to show a reduction in liver fat content, both absolute and relative, were highly significant retiree to the change in placebo. And you see it peaked at the 1.8-milligram dose on both absolute and relative at 14.7 and 68.5. So in general, very, very good reductions. I think it's important to note also that this was at an early time point at week 12. Next slide. So this is Slide 10. And here, we wanted to break down the liver fat content reduction at week 12 in what we call responder analysis, and the field of NAFLD is very used to this. We're looking at 30% liver fat content reduction. You might say, why did we pick that number? Well, that is the magnitude of effect threshold at which we begin to see histopathologic improvement, both in the NAFL activity score as well as in NASH resolution. And here, you can see a 94.4% was the peak at the 1.8-milligram dose and achieved this 30% liver fat content reduction versus 4.2 per placebo, low dose, 1.2 milligram, 65%, which was also very good and at the high dose, 2.4, it was 85%. When we look at a more stringent or a higher degree of liver fat content reduction, still very, very good. None of the placebo hit this 40% low dose, 72% for the mid-dose and 2.4 hit 70%, achieving this 50% liver fat content reduction. And then probably the most stringent, the hardest criteria to hit is complete normalization of liver fat content that is defined as a liver fat content less than or equal to 5%. And remember, we're starting at a very high level of around 22% mean value on the liver fat content. So these patients have to fall a long way to get to less than 5%. And you're doing that in about half of the patients in the mid- and high-dose group again compared to none for placebo. So again, these are highly significant findings relative to placebo. And if you look at the ends at the bottom, 83 patients in this cohort completed 12 weeks of dosing and had MRIs at both baseline and week 12 and were included in this analysis. This is, again, a responder analysis. So moving to Slide 11. We're going to shift a little bit and look at the other noninvasive tests that also helps us with safety, but it also is an important predictor of response as hepatologists, we always want to try to improve ALT and even normalize ALT. So when we look at all subjects, again, you can see the different dosing arms. The -- just to orient you to the graph, the vertical axis is mean change from baseline and the horizontal axis is the different doses. So placebo would be the first bar on the left at minus 6.2, the 1.2 milligram, minus 11.2 and in the green bar, minus 13.8, which is significantly different from baseline placebo or from placebo. And then the high-dose 2.4-milligram minus 13.6, again significant relative to placebo. And that's all subjects. And remember, we're starting at a mean baseline in the 30s range. So seeing reductions on an absolute scale of this magnitude are very -- I think, are very, very encouraging. And then when we look at those that actually had what we considered arbitrarily elevated ALT and we picked 30 as that number for elevation, we can see even more striking changes because the patients actually have room to fall on their ALT and here a very nice dose response relationship relative to placebo. You see significance here for the high dose group, where the mean change was 27 units per liter. Now I think it's also important to note, because I mentioned this for the PDFF response, I said 30% relative drop in liver fat correlated with improvement in underlying histopathology, and we see that ALT can do that as well. And the data that we have from the FLINT trial with the beta cholic acid, it has been shown that 17 unit per liter drop in ALT has been correlated with improvement in underlying histopathology, particularly the NAFLD activity score, and we see that being achieved at all dosing groups, 1.2, 1.8 and 2.4. So let's go to the next slide, Slide 12, and look at weight loss. Now here, we broke this down into nondiabetics, diabetics and then all subjects. On the vertical axis is weight loss and then on the horizontal axis, as we've shown in other slides, we have the different dosing arms. And you see for placebo, very little weight loss, in fact, 0.2 in nondiabetic, 0.5 in diabetics and overall, all subjects 0.2. For low dose, you're seeing about a 3.4% to 3.3% body weight loss in the low dose, 4.9% in nondiabetics with the mid-dose and 3.5% in nondiabetics for the 2.4 milligram dose. When we look at diabetics, it's more of a dose response relationship. Although the numbers are smaller here, we're talking 6 to 7 patients in each arm. It is also important to note that whether it's nondiabetics or diabetics, there is significant differences in weight loss, particularly in the mid- and high dose groups. We look at all subjects comparing everybody together, there's significant differences in all the groups, and you see the change between 3.4 and 4.3. I think it's important to note here that the weight loss is what we would typically see, I think, for a NAFLD population that at least is exposed -- where there's a significant amount of liver fat content. So in addition, it's also important to note that this population was largely Hispanic relative to other trials, and there was no lifestyle intervention brought to bear in this particular study. So it is a new ground with respect to populations being studied and 12 weeks of treatment to see this weight loss, I think, is very, very encouraging. Let's go to the next slide. This is the changes in serum lipids at week 12. And we see total cholesterol changes of 9% to 12% in the treated groups compared to roughly 6% in placebo. No real change in LDL-cholesterol. HDL dropped slightly. You see about 5% in placebo and 1% to 9.7% in the treated groups consistent with acute weight loss. When we look at triglycerides, there was a bigger reduction here relative to placebo, but none of these reached statistical significance. So let's move to safety on Slide 14. I think it's important when we look at this graph to note that there are no serious adverse events. There were no SAEs. And AEs leading to treatment discontinuation were small. In fact, 2 patients or 4.2% and 4.3% in the 2 highest doses of pemvidutide. And when we break down the GI tolerability, the GI side effects that you see listed here, nausea, vomiting, diarrhea and constipation. There was more nausea, but it was generally mild in nature, and again, only led to treatment discontinuation in 2 cases. For vomiting, again, generally mild, and you see that it was 3 cases in the low dose, 2 in the mid dose and 2 in the high dose. And when we look at diarrhea, not a lot of differences between placebo and treated on a percent-wise, 16.7% for placebo and between 4% and 21.7% for the dosing arms. And when we look at constipation, a few more cases of constipation here, again, mild in nature. It's also important to note that there was no clinically significant increases in ALT in the study. So let's move to the next slide, and this is blood pressure and heart rate. And for blood pressure, if you look on the left-hand slide, and we're looking at -- on the vertical axis, again, blood pressure millimeters of mercury, we have systolic on the top diastolic on bottom. Each line represents a different cohort. Gray is in placebo and the color scheme stays the same here, whether it's a bar graph or a line draft. It's important to note that the mean systolic blood pressure decreases were around 6 to 10 millimeters of mercury for the dosing arms compared to placebo and a little less than that in the diastolic of 3 to 7 millimeters of mercury. When we look at heart rate, the mean heart rate increases, you see that on the right, were 1 to 3 beats per minute compared to placebo. In Slide 16, we look at glycemic variables, and we break this table into nondiabetics and diabetics. On the top are nondiabetics. Across the top, you see the treatment cohorts, placebo, low dose, mid-dose and high dose. And the take-home point here is there really are no changes in HbA1c or fasting glucose compared to placebo in this relatively short time period of 12 weeks of dosing. So if we move to Slide 17, just to summarize, I think it's important to note that the primary endpoint of this trial was met, which was a liver fat content reduction at 12 weeks that was robust at 68%, better than or equal to the effects of other leading NASH candidates there was a concomitant significant reduction in serum ALT despite a mean value that was relatively low compared to other trials. And I believe this also points to a potential potent histopathologic benefit if and when we go to a liver biopsy trial. Overall, with weight loss, the placebo-adjusted weight loss in nondiabetics was 4.7% at week 12, and for diabetics, it was 3.9%. When we look at safety and tolerability, no serious or severe adverse events and a low rate of adverse events leading to only a couple treatment discontinuations. So overall, well tolerated without a need for dose titration and consistent with our prior experience. Importantly, there were no threefold or greater ALT elevations and glycemic control was maintained. So at this point, I'd like to thank you for your attention, and I'll turn this back over to the CEO, Vipin Garg.

Thank you, Dr. Harrison. Dr. Harrison will join us for the Q&A session today. Operator, can you open the line for question and answers, please.

[Operator Instructions] The first question comes from Seamus Fernandez with Guggenheim.

So maybe just a few questions for Dr. Harrison. Dr. Harrison, I think what we're all trying to get a better understanding of is how you see pemvidutide lining up to other potential products as it relates to NAFLD, but also I think you've seen a number of obviously, NAFLDs patients. Just wondering how you're thinking about these data from an obesity patient population. And the second question there is, as you look at the safety and tolerability of this product, how is it lining up to some other products when we look at the data that was presented by Akero yesterday? Actually, it does look like this product is better tolerated, but obviously, different patient populations. And then maybe if you can just weigh in a little bit on the pace of the liver fat reductions that we're seeing here. That would be helpful. And then I just have a couple of follow-up questions for the team.

Yes, sure. I mean I think -- look, we're -- in the field of NASH, we have come a long way in the past decade. For sure, in the past couple of years, it's been exponential in the way we've been able to understand the disease and develop targets to hit the disease. In addition to that, we've also learned that some of our non-invasive tests can be insightful as to what we're potentially likely to see on underlying histopathology. Despite any of that, I think it's important to note that in the setting of fatty liver, just like it is with any liver disease, what we want to do is get rid of the inciting insult. Whatever is causing the liver to be irritated, that's what usually drives the activation of stellate cells, which begin to lay down the collagen that can get the patient in trouble over time as it progresses through to cirrhosis. So just parenthetically and maybe pragmatically, what we want to do in liver disease is get rid of whatever the insult is that's causing it, treat the C, suppress the B, treat the autoimmune hepatitis, quit drinking alcohol, if that's what's causing your problem. And the setting of non-alcoholic fatty liver, it's intuitive to me that what we want to do is get rid of the fat in the liver or reduce it as much as we possibly can. And one of the ways we can measure that is the gold standard PDFF. And we've seen through work done with Madrigal and resmetirom, worked on with aldafermin and NGM and proxafermin, with Akero, and a few others, that if you're able to reduce liver fat content that does link or is correlated to improvement in histopathology. And the more you're able to lose the better that effect can be. In fact, we started with 30% relative, and this was work generated from Rohit Loomba and myself of the REGAL trial. And then we've accentuated that with other mechanisms showing that 50% gives you a better shot on goal, 70% complete resolution of liver fat content. It just makes sense. The more fat you lose, the better, the healthier the liver is going to tend to be. And that's despite knowing that liver fat content is really a nitro-triglyceride, which by itself should not injure the liver, but it just so happens that at least in my mind, what -- when you're improving the liver fat content by measuring PDFF, you're probably also reducing toxic lipid species, whether that's ceramidase, glycerol or whatnot, even though we don't measure that directly. So I think at the end of the day, what we've been able to show in the literature is when you do see a PDFF response that tends to correlate with histology when histology is available. However, it doesn't mean that you can't have a histologic response if you do not move liver fat content. So it's not agnostic to mechanism. But when you do see it move, we do -- we can feel good that we're likely to have histopathology change. Now having said that as a backdrop, when we look at this particular trial, this is what I'm excited about because the liver fat content reductions are significant, but maybe more so in a short period of time. At 12 weeks, we're seeing the changes of -- that I mentioned, and even 50% normalization of liver fat content. And we can't throw aside the fact that we're starting with a very high level of liver fat content. So I think you asked me how do I put this in comparison to the Akero data? Well, I think the Akero data was very exciting. When you look at the liver fat content reduction and what we saw histopathologically, but that was at 24 weeks. And remember the mean value of liver fat content was lower than it was in this particular data set. So we're starting with a higher liver fat content and we're treating for a shorter period of time, but seeing very similar changes in liver fat content reduction. Now what does that mean on a read-through to histology? Not sure, but it is encouraging based on the data we saw yesterday from Akero. Now, if you also look at PDF, if you look at ALT reduction, and I alluded to this earlier, work done again by Rohit Loomba from the FLINT trial showing 17-unit liter reduction correlating with histopathologic improvement, we are seeing that even if we started at a lower baseline value of ALT, we see in those people that had abnormal ALTs, as defined by greater than 30, a very nice dose response relationship in ALT response, all of them hitting that 17 unit per liter threshold as a collective group. There was a more recent paper that just came out. It's impressed now looking at the combination of PDFF and ALT reduction, enhancing the probability of histopathologic response. Now we haven't done those post-hoc analyses in this trial yet, but it would be interesting to see if our patients hit both PDFF response and that ALT threshold response, what percentage hit that? And would that actually continue to increase our enthusiasm for what might happen on histopathologic response. So I think the tolerability question is also important because when we think about therapeutic index of drugs, it's not just the efficacy, but it's also can the patients take it? Will they take it? Is it going to be well tolerated? Is it going to be safe? It's important to know that with all these injectables that involve FGF21 or FGF19 or GLP in any form, there tends to be some GI tolerability issues. And so again, it's small numbers of patients treated for a relatively small time, but I do think that we stand -- I stand behind the fact that this is well tolerated and to have only 2 discontinuations for adverse events, I think is very, very encouraging. So a long-winded answer, but you asked me a lot of questions. I was trying to wrap it up as quickly as I could. Thank you.

Great. And just for the team, and for Dr. Harrison, as you guys look at the prospects for the 24-week OLE, I just wanted to get a sense of -- we have 2 different opportunities to see longer-term weight loss data. Just wondering how heavily should we rely on the OLE and the prospect for incremental weight loss in this patient population versus really focusing in on momentum? That's the first question. Then just a second question, Dr. Harrison, we didn't -- you sort of alluded to this with the Hispanic patient population, but in data sets, have you seen other limitations to, whether it be weight loss or other characteristics, when evaluating the results of drugs in this category in a Hispanic patient population? It would just be helpful to understand that a little bit better if you think that that's a point of influence.

Let me just answer that directly. This is Dr. Harrison again. So generally speaking, when we look at trials in general, not just NASH trials, the FDA and the regulators, in general, have made a point that we're not really enrolling patients across the broad spectrum of ethnic diversity that we see. And that's true. We tend to enroll Caucasian patients in the majority of our trials. In this particular trial, it's flipped the other way. The vast majority of these patients are white, Hispanic. And just to give you an example of that, if you look at the semaglutide NAFL trial that I was part of and we published at New England Journal, only around 11% of those patients were Hispanic. And so if you look at the weight loss, for instance, in that NASH population, at the 12-week time point, you're hitting around 4.5% to 5% body weight loss, very similar to what we're hitting here. But the point being, we don't know a lot about if you have ethnic diversity that's divergent from other trials are there genetic influences that could be playing a role such as PNPLA3 or other single nucleotide polymorphisms that may impact the rate of weight loss or may impact the rate of liver fat content reduction, it's just -- it's hard to know that. The point in bringing that up is that when we look at baseline demographics, this study is different from others and that it is enriched for that Hispanic population. I didn't mention this before, but I do think it's important to note here that the weight loss that was seen in our trial was linear. So I think that's an important point to make. And the other one is what we're seeing weight loss wise in this NAFLD obese population is consistent with the other trial that looked at a weight loss medication in an NAFLD population at the 12-week time point.

Seamus, thanks for your question. Let me follow up on the other parts of your question. You were talking about the 2 24-week readouts. The extension of the current study is not open label. It's being conducted in a blinded fashion. So to be clear, it's an extension, but it's not an open-label extension that's blinded. I think the important thing to point out is to distinguish critically between the study populations. And the fact that the read-through of this trial at 12 or 24 weeks is distinctly different from the read-through on the MOMENTUM trial. The patients are entirely different. There's a substantially lower proportion of Hispanics in this population, and, in addition, if you look at the obesity population in general, studies have shown that the average MRI-PDFF in the comparable population, as in this trial, is probably in the range of 7% or less, very, very different than the 22% mean that we saw in this trial. But methodologically, it's important to understand that this was conducted as an NAFLD trial, meaning there was no diet or exercise intervention, and I think it's important to realize that to understand the impact of that on the overall results is not simply a question of arithmetically subtracting the placebo response. There are synergistic effects of diet and exercise in an obesity trial that cannot be predicted by a simple arithmetic correction. And the whole nature of the way the trial is conducted makes a very, very different response. So we're very, very bullish about the prospects we're seeing much better weight loss when we go to a committed obesity trial, such as the minimum trial, and read that out at 24 weeks in the first quarter of next year.

The next question comes from Yasmeen Rahimi with Piper.

Dr. Harris, a couple of questions for you. Maybe I'll go one by one. The first question to you is what is different between a NAFLD population to a NASH population to an obese population and wave loss? As you can imagine, despite really compelling data, investors are a little confused why in the obese population study that Altimmune team conducted an 8.7% placebo-adjusted weight loss and here, we have 4.9%. Can you just really clearly outline to us. We talked about the Hispanic population and contribution to weight loss, but what else is mechanistically different in these patients that could have led to a different weight loss? And then I have a couple more follow-ups.

Yes. That's a great question. I think we don't have a lot of data on weight loss in an NAFLD population, at least in well-defined clinical trials. Again, I alluded to the semaglutide trial because that really is the comparison that I think makes the most sense. And again, it's early days, so 12 weeks of treatment and you're seeing the changes in body weight that we showed, which is in line with what Simo was showing in the same time period. Now what could be the reason for that, it could be the power of the study, relatively small numbers, 24 patients or so in each group. It could be the ethnic diversity, although there, I can't give you a solid reason as to why ethnic diversity would play a role in weight loss percentage. But I think it's -- all we can do is point out the differences and it continued to explore what's going on here. I do think it's also important to note, as I pointed out, that the weight loss is linear at this point. So very similar again to what was shown in the semaglutide paper. So I don't want to speculate. I don't know the answer to your question completely. I just want to point out that there are differences here that I think are potentially important.

Thank you Dr. Harrison. Just to clarify, when you say the shape of the curve is linear, are you referring to the changes when you compare week 6 to week 12? And given that there was not a scatter plot of weight loss, could this data be maybe impacted by some outliers, if you could comment on both of these questions for us.

Yes. Yasmeen, perhaps I should have Scott chime in on that particular question.

Yes, Yasmeen. So I wanted to point out first regarding the comparison to the earlier trial, yes, it was a small study, but there are no Hispanics, and the average liver fat content was well below 5%. In other words, as a mean these patients did not have high livery content, so a very distinct difference from the current trial. And in terms of the outliers, yes, there were outliers in the -- in at least the 2.4 milligram group that created some scatter in the data and we're still looking at that.

Okay. And then one last question for you. I know publicly, you guys have said that you have accessibility to blinded data and this is across the MOMENTUM study as well as the NAFLD study. Looking at the placebo ranges, which end up being very, very small, are you still very confident based on what we saw this morning that you're going to achieve greater than 20% weight loss at week 48? What does the shape of the curve look like when we go beyond 12 weeks? I appreciate any commentary you could provide us on that question.

Stephen, let me address this question. That when we have done blinded looks at the data across the studies, and I want to emphasize the limitations of blinded data, and we looked at the MOMENTUM trial that the overall weight loss that we're seeing in a blinded fashion is much more similar to the original study than in this study. And again, it's blinded data, but just as directive to our investors, we think that what we're achieving, based on that blinded look and MOMENTUM is similar to the first study, and that's the study that we're discussing today. So given that, we think that the prospect of achieving 20% weight loss at the end of the year in the minimum trial is very, very good.

Our next question comes from Roger Song with Jefferies.

Great. A lot of questions already being answered. Maybe just to clarify a few things here. First, just curious about the weight loss kinetics here. So maybe just to clarify how this counts up before the 12 weeks, the weight loss starting looking at? And also, I think, Scott, you mentioned earlier, maybe just to clarify, how this data changed your expectation for the weight loss at the latest time point, 24 and the 48-week, granted you have slightly different populations.

Yes. Thanks, Roger. So as Stephen mentioned, the kinetics were linear in the dose groups, and this is the pattern of the trajectory that we saw in the data in the first study, and we suspect that it will remain linear for some time. It could remain linear all the way up for many, many weeks. But it's -- without having that data at this point, I can't comment on where we're going to land. In terms of the expectation for 24 and 48 weeks for the MOMENTUM trial, we remain very bullish. As I mentioned before, this population -- this was conducted as an NAFLD trial in an apathy population that not only had high liver fat content, but had a close to 80% mean Hispanic population. We don't know what the impact of that is. And very, very important, the absence of diet and exercise may also have had a very, very important effect. Again, as we look at the blinded data across the 3 studies, the MOMENTUM study, which is the 48-week obesity study, looking at the blinded data looks much more similar to the data from the first study than this study, and it suggests that this study is an outlier because of the differences in populations that have been described. So consequently, we remain bullish about hitting those targets in the MOMENTUM trial.

And Scott, this is Dr. Harrison again. Let me just add, at the end of the day, and I'm speaking from a NASH perspective. I don't want to lose -- this is an NAFL study, right? It's not an obesity study. It's a study looking at obese NAFL patients. And I don't think we should lose sight of the fact that what we were measuring here, the result was very, very positive. I mean the liver fat content reduction that we're seeing is highly significant and relative and is associated with significant changes in serum liver chemistry tests like ALT. And for a short trial duration of 12 weeks to be able to achieve this degree of liver fat content, this degree of drop in ALT, when our mean values are relatively low to begin with is very, very positive. And the weight loss that was seen here is also important, but I think it's important to note that this population of patients, as you alluded to, is different from a standard obese population. And really, what we were trying to look at in this trial was change in liver fat content, which was significantly improved. And I just -- I don't want to lose sight of that because to me, that's the intent of the study, and that's what we showed.

Got it. Yes. No, that's clear now. Thanks for all the comments. Another point I want to ask is the serum lipid reduction. As we remember for the Phase Ia in overweight study, you see 30%, 40% kind of serum lipid reduction across different LDL and target in the total cholesterol. So this trial seems kind of a lesser degree. So maybe just contextualize this, that also due to the baseline kind of the math of the patient population?

Sure, Roger. This is Scott Roberts. So I think there's a couple of aspects that we're thinking about when we look at the lipid response here. I mean, overall, I would say it's very good, right? We have significant reductions in triglycerides. It's now 40% approximately. Total cholesterol is also down 10% to 12%. And the LDLs seem to be a bit less than what we saw in the 101 study. When we think about what might be behind that, I think there's 2 things. One is this idea that this patient population is really very differentiated from the 101 for the reasons we've already talked about, and primarily, high liver fat content, possibly also a demographic effect there. So that certainly has to be contemplated. I think the other issue is that there's a kinetic thing here that we've reduced the fat in the liver significantly over this period of time, and maybe some of these lipids are lagging a bit. So I think that the 24-week data will be very interesting to take a look at the lipids and see what they're doing at that point.

Got it. Okay. That's great. Maybe just a last one for the team. So on the company. It seems that we are getting this very significant liver fat reduction, understanding you're focusing on obesity for the Phase II. So what is the plan for the NASH moving forward?

Yes, Roger, this is Vipin. Just look, we continue to look at both of these indications. We're very bullish on the obesity indication. Based on this data, we have to look at the 24-week interim analysis at the -- in the first quarter. And that would really guide us which way to take this program. We've always said that the purpose of this NAFLD study was to create the foundation for NASH discussion and I think we have that now. I think it's going to help us in our strategic evaluation of the program overall as to where we take it from here. But this combined with the 24-week interim results would really guide us whether to pursue both indications or continue pursuing obesity over NASH, we'll figure that out once we have all of that information.

The next question comes from Liisa Bayko with Evercore.

Dr. Harrison, could you maybe comment on the magnitude of impact of diet and exercise that you would expect in a study of this duration? I mean, if diet and exercise had been kind of overlaid here, I guess, what kind of additional benefit do you think we would see just based on your historical understanding?

Yes, that's a good question. I think probably around 2% or so additional. If you look at historical studies that have kind of overlaid lifestyle modification on top of therapy, so that'd be -- that roughly something around that range.

In the first 12 weeks, is that 2%? Or is that more over a year or?

No. I mean when we look at, at least in my experience, when we look at weight loss, there's what I call a smile curve in clinic, and that is you tell people to modify their lifestyle, cut the carbs, exercise more, decrease their total calorie intake, cut out the sweetened beverages. And people are highly motivated at first, and generally, maximum weight losses achieved by around 12 weeks, and then they tend to gain it back over the next 12 weeks. So when we see weight loss changes in clinic, it tends to be relatively early. And so my guess is that would be in the first 12 weeks or so.

Liisa, this is Scott. I'd like to add to Stephen's response. We think the diet and exercise is particularly important in the first 12-week period. If you look at the placebo curves in studies with diet and exercise, the effects always occurs in the first 12 weeks. And also, let's get back to the concept of the speed of the weight loss and the momentum, not a pun on words, maybe because our trial is named MOMENTUM, but the momentum that's gained by having that rapid weight loss early is a positive feedback to the patient to get more exercise, to put down that second serving on the like. So we think that if all things that diet and exercise intervention is extremely important. It accelerates the weight loss, it gives better effects, better patient participation, buy-in and encouragement. And as I said before, it's difficult to say that you can just simply subtract the placebo and get a number called placebo adjusted. We think it has a big impact. We think that methodologically to really understand the effect in an obesity population and a trial conducted the way obesity trials are conducted you need to have that diet and exercise intervention to actually understand what's happening over the course of time and the population and the response of the drug.

Okay. And then for -- I noticed in the study, and I don't know if this is a function of small numbers, but the diabetic patient population didn't really have the typical, like we kind of described it as about a 30% discount in weight loss, and it seems a little bit less than that. And in fact, on the higher dose it's actually higher. I don't know if this is just a function of small numbers, or do you think there's something mechanistically that would make sense to explain that differential?

Yes, Liisa, let me take that on as one. I think it's really a question of the small numbers. And you look at the data in different ways. You could say it's comparable. You could say it's less. You have to look at different dose groups. You have to subtract the placebo. Is it the right placebo to attract from each dose group. So what we can say, in general, that it's probably less, we don't know how much. It may be comparable. It's tough with small numbers. So I think if you just take a general average across the groups and placebo adjusted, it's about 30% less, but again, there's a lot of wobble on those numbers.

Okay. And then Dr. Harrison, can you maybe comment on the tolerability? How does the tolerability here look relative to some of the other drugs either in development or already approved?

Sure. I mean, I think from a tolerability perspective it is, if you look at it relative to other injectables for this disease indication, I'm just focused on fatty liver and NASH, it's well tolerated. I mean it -- you see a majority of these adverse events are mild and very few discontinuations as a result of that. So comparatively speaking, I think it's well tolerated.

And relative to obesity drugs?

There, I'm not as certain because I don't -- that's not an area that I focus on routinely. But for NASH, yes, for sure.

Yes. Liisa, let me fill in on the obesity. You're generally seeing with obesity drugs adverse event discontinuation rates approaching about 10%. And it's -- this is lower than that. So we -- and by the way, they're achieving that with dose titration. We're not using dose titration, and if anything, we think that these results are strong confirmation that dose titration is not needed with pemvidutide. And that's a big improvement over other drugs that are titrating out to 4 to 5 months. So we think the adverse event profile, even if comparable, that we actually think it could even be better is strong confirmation the dose the absence of dose titration is a real possibility with these drugs, especially as we move to obesity.

Even with the 2.4 mg? I know you dose titrated in that study.

Yes. That's a little harder to say for that reason, absolutely. But you kind of try to find the sweet spot here, and the 1.8 milligram dose appears to be the best in this trial, also like the 101 study. So if you kind of focus on -- we're not seeing a better response to 2.4. It's not convincing, it may be not. But if you focus on the 1.8-milligram dose, you look at the tolerability there, it's very acceptable based on the adverse event discontinuations. So we stand behind the second confirmation, the second trial confirming that GLP-1-based agents with the proper agent, with the proper kinetics, with the proper medicinal chemistry, does not -- do not have to be dose titrated, and that's in stark contrast to other drugs in the class.

Okay. And then just final question, and then I'll let you move on. I guess I'm just wondering about like the effect of higher BMI and higher baseline weight. It seems like that's a major factor. We've seen in other studies that this can be a variable that leads to a lower weight loss. Do you think that was an impact here? We are seeing lower weight loss obviously, than in the first study, and there is a considerable difference in baseline BMI and baseline weight, which is probably more comparable to the other -- now to the other weight loss drugs in the mid for BMI in the mid-30s. Do you think that's another big factor here?

Yes. Thanks, Liisa. Great question. The short answer is no. We don't think it's a factor, and for several reasons. Number one, if weight were a factor when you got to the higher dose, we should have seen a better effect. The reduction in weight loss with drugs when you get to the super obese and the heavier people is that their serum concentrations drop, and that leads to less body weight, and that's been in the public domain for semaglutide and the FDA comments and the review of the drug. We're seeing levels of exposure here that are comparable to our initial trial and very, very importantly, if you take the exposures and you line them up in this study versus the first study at the same exposures we're seeing less weight loss. So it's not a question of exposure here. We want to make that clear. There's something different about the populations such that given the same exposures between this study and the first study, we're seeing different weight loss, and that's probably related to the study population. I mean that's the only explanation that we can come up really at this point in time. And we want to point out to follow that, Liisa, that Q1 -- excuse me, the MOMENTUM study population will be different from this population. It will look like the population in the first-in-human study. Therefore, we expect the exposures that we will achieve, which we're hitting both in this study and in the first study, but also in the MOMENTUM study will lead to the weight loss that we saw in the first study because of the similarity in the study population, which is causing a disconnect in the exposure response.

Our next question comes from Mayank Mamtani with B. Riley.

So maybe first hearing Dr. Harrison's perspective on the drug's mechanistic contribution on diet intake versus energy expenditure given the dual mechanism here. I'm just curious, Dr. Harrison, are there markets that delineate sort of the nonclinical measures, just relative impact of those 2 phenomena, on kinetics, et cetera? Because to your point, semaglutide weight loss in Phase III across NAFLD obesity can't really be compared because of the dose differences and treatment duration, but it does look kind of comparable. And then kind of a second part question, do we know of other glucagon-mediated programs glucon-targeting drugs where we kind of know of that kinetics for glucagon beyond 12 to 24 weeks?

Hey, Mayank, this is Scott, Roberts. I think we're looking at this continually, and obviously, thoughts include the ones that you're alluding to. I think that the rapid defatting of the liver, which I think everybody associates with glucagon because you just don't see that with the indirect effects of like, for example, semaglutide. We're seeing that, right? And we're seeing that in spades. So with 70% -- nearly 70% reduction in just 12 weeks. So that's not where we're at right now. We think that there's a metabolic insensitivity that characterizes this patient population. It's related, we believe, to the high amount of liver fat and possibly also demographics. And so we're looking at a little bit more holistically when we look at markers. I think that the liver fat, the rapid liver fat reduction is the sort of biomarker that you're talking about, for example, and that looks like it's working extremely well. So we're going to continue to think about this and to try to understand how this population differs from 101 from our first in-human and the MOMENTUM study that's coming up. We're convinced for the reasons we've talked about already that it is quite distinct, and that gives us confidence in moving forward with the obesity. But mechanistically, and I'm going to understand that's where you're trying to go with this, I go to the liver fat reduction and say things are looking good there.

Okay. And maybe just staying on that point of liver fat reduction and also ALT and putting also in context what we saw with Akero data yesterday. Like just can you comment on like if there is a hypothetical Phase IIb NASH study, what size and duration would look like this year updated, thoughts there? And then maybe also if you're able to just process question, when will we be able to see the patient level disclosure from this NAFL study, like kind of how you guys did for the earlier Phase I study in a very transparent way? And then on the hyperglycaemia kinetics, could you just comment on specifically that cohort diabetic cohort where you did have some passing in HBA1C data. Just -- do you have those sort of kinetics between 0 to 12 weeks data and kind of when can we see that?

Scott, do you want to take the hypoglycaemia -- or sorry, the diabetic question?

Yes, Mayank. We have that data. It just kind of looks flat. And we just thought that the summary date week 12 was a lot easier to understand. But no, we're not seeing excursions of glucose and haemoglobin A1c is only measured at week 12. I think the important thing to recognize is our base case was that we would not see a change in haemoglobin A1c or any glucose homeostasis at week 12, similar to the 101 study. That's pretty much what we saw in this study. We want to emphasize that as further weight loss will occur, we think we're going to see the 24 weeks. We'll probably end up seeing that we could see it in both studies, but certainly in the MOMENTUM study. Although the MOMENTUM study doesn't have the diabetics, but we think we're going to see general improvement of haemoglobin A1c over time.

Yes, and with regards to your other question, I mean, look, we will continue to focus on our strategy as we have laid out so far. We are proceeding with our MOMENTUM study. We want to see that data. We're not speculating right now what we're going to do on a NASH study. We'll have plenty of time to evaluate that. We'll look at all of the data and wait for the 24-week interim data from the obesity study. So we're -- stay tuned. We'll talk more about it as time progresses. But right now, our focus is -- our strategy is the same as it's always been. Drive the obesity program. We don't -- we see that -- the significant value in that, and then we'll evaluate our strategic options with regards to NASH for the NAFLD / NASH studies.

And on the patient level data disclosure, will we get that sort of after your 24-week data, I guess? And will that be within this year, mentioned?

That's right. I mean the 24-week data, as we have said, we'll have it in the fourth quarter, and that's when we'll have the full study readout. And obviously, there'll be a number of conferences coming up that we'll be participating at.

And I would I would also note, Mayank, that we're planning to submit a late-breaking abstract to the AASLD meeting. So it will be a better opportunity to see all of this data in that meeting in November in Washington, D.C.

Our next question comes from Patrick Trucchio with HCW.

Just a few follow-up questions for me. It's the understanding of the NAFLD study and MOMENTUM study are in different population and have different endpoints. I'm wondering if there is any predictors of either response or GI and tolerability that have emerged from the NAFLD study that would perhaps impact involvement of patients in the MOMENTUM study or if the baseline characteristics of those patients that have already been enrolled would be consistent going forward in the MOMENTUM study?

Right. So Patrick, the MOMENTUM study population looks to our -- the cross section that we've seen, and we haven't finished the randomization. We will very shortly. It will occur this month as we promised before. We anticipate that, that population will look like the classic obesity population in terms of BMI, body weight and also low liver fat. As I said, if you do MRI-PDFFs in the general obesity population, you see average MRI-PDFFs are 7% or less. And we think that the tolerability profile between the first study and the NAFLD study are remarkably similar. And I would anticipate that, that would also continue in the MOMENTUM obesity trial with good evidence of tolerability sufficient not to have to rely on dose titration.

Got it. And then maybe just a follow-up, and this was addressed earlier, I think, but just if you could elaborate a bit more on why some measures like ALP reduction and weight loss in diabetic patients there did appear to be more of a dose response on some of these other measures, there wasn't. So I'm just wondering, and I know you alluded to this earlier, but if you could just kind of maybe talk to those specific measures specifically.

Yes. Patrick, with low numbers, it's a bit difficult to make strong statements about dose titration. We think there's variability between the groups. Remember that there are only about 7 subjects in each of the diabetes groups. So consequently, one outlier changes the means very greatly. So I would encourage you not to look at the dose response in the diabetic population. All in all, it looked like 1.8 was doing at least as well as 2.4. Remember that 2.4, however, was titrated for the first 4 weeks. Although 2 of those weeks were at 1.8 milligrams. So the question is, did we lose some effect from the first 2 weeks at lower doses, and we'll see that better in the 24-week data. We really don't know. At this point in time, the way we interpret the data is that the 1.8-milligram dose appears to be the best at this point in time that remarkably similar to the first study, but we'll continue to explore 2.4 to see if there's any additional benefit, especially in patients who are heavier who might need higher exposures.

The next question comes from Yasmeen Rahimi with Piper.

Dr. Harrison, did you measure any type of fibrotic NITs in the study? And do you feel now based on the data we saw yesterday from Akero that really the greater the fat reductions and defatting of the liver occurs, the greater is the propensity to show both national solution benefit but also fibrosis benefits? If you could just clarify both of these for me, that would be great.

Yes, sure. Yes. In reference to your second question first, I do think the totality of the data that we're generating on the specific non-invasive tests do point to the fact that the higher the liver fat content reduction, the greater the probability that you will impact underlying liver disease, not just the components of NASH or NASH resolution, but ultimately on fibrosis as well. And you and I have talked a lot about this before, it's important to realize that in my -- again, this is just my opinion, the components of histology that we focus on in NASH, steatosis, inflammation, ballooning and fibrosis, in my opinion, are all very dynamic and can move relatively quickly, whether you look at the aldafermin data, the efruxifermin data or any other data set where we've done early liver biopsies, we've been able to show changes in fibrosis, not just changes in steatosis inflammation or ballooning. And interestingly, if you look at some of the post-hoc work done off of the Madrigal trial data, when you achieve significant liver fat content reduction that's in the super responder range, we are beginning to see -- you're beginning to see changes in fibrosis. So we haven't done post-op correlations with liver fat content in the efruxifermin data to my knowledge. But it would make sense that given the robust changes in fibrosis there that that's likely correlated to repeating that fat reduction. So I think at the end of the day, the more fat you lose, the better off your liver is going to be, and I think those changes can occur relatively quickly. And in response to your first question, we do not have that data relative to things like Pro-C3 or e.l.f. in this small data set to my knowledge.

Stephen, let me comment on that. We do have markers of fibrosis. We haven't presented them in this presentation, simply to concentrate on the metrics that we have, but we are planning to present that data at the ASLD when we submit the late-breaking abstract.

Our next question comes from Jonathan Wolleben with JMP.

Just hoping you could comment on your overall thoughts on the profile for the 2.4 milligram dose and the effects of the titration. Do you think that's necessary? Or do you think the 1.8 is giving you everything you need so far?

Yes. Thanks for the question. Yes, that's a tough one at this point. I think based on just the data from this study, the 1.8%, again, looks like the sweet spot. I'm not sure we're seeing any additional benefit of 2.4, though we take a little bit of -- we lose a couple of weeks early on because doses that are probably less effective. We don't know. Let's take a look at later time points. I think certainly, the 24-week readout in the momentum interim analysis is going to be really important. I think the preliminary answer is that we've hit it with 1.8 getting back to the idea of higher body weight and BMI affecting this. We're not seeing this because if we are we have a better response to 2.4 milligrams, we think. And we think we're hitting the exposures that we saw in the 101 study and that the difference is not the exposures, it's not the body weight. It's actually the biological response to the drug for some reason, probably for the factors that we've talked about before. So the short answer is that we don't think the 2.4 is necessary, but let's just see the rest of the data.

Yes. And I would just add that even if 2.4, even if we take it forward, there is a real chance that we don't need to do titration on 2.4 either. So we just did a short titration going forward, if we continue to include 2.4 we'll definitely include an arm that does not have titration. So we think 2.4 also has a real chance of being a successful dose without the need for titration.

Got it. And maybe one for Dr. Harrison. We hear a lot about the associations between liver fat and histologic response, but how well do we understand the kinetics or the lag time between reducing liver fat and when something could show up on a bias in terms of menus resolution or fibrosis improvement? Just wondering given how quickly we're seeing the liver fat improve here versus standard time points for the longer NASH trials.

Yes. We don't really know the answer to that yet. One of the things that we're focusing on now in the NASH field is the kinetics of response. In other words, if you have week 4 PDFF or week 6 and week 12 and week 24, does -- if you hit a magnitude of effect, let's say you hit the 30% relative change at week 4, does that give you a better shot on goal of histology improvement compared to somebody that say, hits that at week 24. What we do know from at least the aldafermin data, where I did liver biopsies at week 12 and I have PDFF as well is that there is significant liver fat content reduction. There was significant improvement in an NAFL activity score and there was fibrosis improvement that was seen at that early time point. So that kind of gets me back to my original comment that said I don't think that's sampling variability because the NITs all moved in a very positive direction. And so I do think that all the components of NASH to include fibrosis can -- are dynamic and can change relatively quickly whether or not we could use PDFF to predict the time of that change, I think, is still unknown.

At this time, there are no more questions in the queue. I would now like to turn the conference back to Vipin Garg for closing remarks.

Thank you, everyone, for participating today. Have a nice day.

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