Greetings, welcome to this morning's conference call hosted by Altimmune. All participants are in a listen-only mode. A brief question-and-answer session will follow the prepared remarks. To ask a question during the session, you will need to press star one one on your telephone. 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, Latonya. 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, Scot Roberts, Chief Scientific Officer, and Dr. Stephen Harrison, Chairman and Co-Founder of Pinnacle Clinical Research and Summit Clinical Research and Principal Investigator on our trial. Please note that we issued a press release we posted on 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 statement disclaimer in our press release issued this morning and now available on our website. Any statements made on this conference call speak only as of today's date, Tuesday, December 20th, 2022. 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, thank you for joining us today as we review the positive 24-week data from our phase I-B NAF LD clinical trial of pemvidutide. Pemvidutide is our investigational GLP-1 glucagon dual receptor agonist under development for Obesity and NASH. The 12-week results of the trial were announced in September of this year. We are now sharing 24-week results for subjects that elected to roll over into a 12-week extension trial. Those participants received a total of 24 weeks of treatment. The results of this extension study were announced in a press release this morning, as well as accompanying slide deck posted this morning on our website. We believe the clinical data we have collected in these NAF LD subjects are compelling, including significant reductions in liver fat, markers of liver inflammation, and body weight. Pemvidutide was well-tolerated as we continued to have low rates of discontinuation associated with adverse events. These results strengthen our enthusiasm for the potential impact pemvidutide could have on the multi-billion dollar NASH and Obesity markets. We look forward to the weight loss data from the interim analysis of our MOMENTUM Obesity trial in Q1 2023, as well as commencing our phase II-B NASH trial in 2023. I'll now turn the call over to Dr. Scott Harris, our Chief Medical Officer. Scott. Thank you, Vipin. Good morning, everyone. The clinical trial results we are reporting are from a randomized double-blind phase I-B clinical trial of pemvidutide in obese and overweight participants with significant liver fat content. In light of these results, we are extremely enthusiastic about our prospects for success in both NASH and Obesity. We are fortunate to have Stephen Harrison, Chairman and Co-Founder of Pinnacle Clinical Research and Summit Clinical Research, serve as the principal investigator on this trial. Dr. Harrison is a renowned hepatologist who has conducted numerous NAFLD and NASH studies. With that, it's a pleasure to introduce Dr. Harrison so he can walk you through the top-line trial data. Following his presentation, the entire management team and Dr. Harrison will be available for Q&A. Stephen. Thanks, Scott, and also thanks Vipin for that introduction. You know, look, it's good to be here with you guys this morning and to walk you through some of this exciting data. I'm just gonna go slide by slide. I'll call out the slide number and you guys can turn to that slide. Just starting with slide one, the title slide. This is a 24-week, but mainly 12-week extension trial of pemvidutide, I'll call it pemvidutide from here on out, in subjects with non-alcoholic fatty liver disease. The focus of this is on that 12-week extension. If you go forward to slide three This is just a reminder of the extension trial design. Just reminding you where we were. This is a phase I-B NAFLD trial. As Scott mentioned, it's randomized into three different doses, 1.2 mg, 1.8 mg, and a 4-week titration dosing up to 2.4 mg weekly with a placebo arm. In total, there are four different arms of the trial. The original trial was 12 weeks. We've reported that data in September. What you see here are the hashed line indicating at the week 12 point that there's an additional 12 weeks of treatment in some of these patients. Of the 94 patients enrolled in the trial, 83 of the subjects who completed the 12-week phase I-B NAFLD trial were invited to participate to receive an additional 12 weeks or a total of 24 weeks of treatment. Of the 83 who completed the parent trial, 66 or around 70% consented to roll over to this extension. Two were screen failed due to missing more than one dose in the parent trial, and 17 declined to participate. I'll now go to slide four. And this is the key eligibility criteria. I just wanna highlight that the eligibility criteria were exactly the same as in the parent trial. These were men and women aged 18- 65. They had to be overweight, not necessarily obese, BMIs at least 28 kg per meter squared. What was important is that they all had to have baseline liver fat content by MRI-PDFF of at least 10%. Importantly, and distinctively from other trials, we were really focused on how this drug worked in an earlier stage population of patients. We wanted to exclude those with significant fibrosis as defined by a FibroScan liver stiffness measurement less than 10 kPa. In addition, the ALT and AST lab values needed to be less than or equal to 75 IU/L. We looked at nondiabetics or diabetics, but they had to be on a stable dose of at least three months of metformin or an SGLT2 therapy and no use of insulin, sulfonylureas, DPP-4s, or GLP-1 treatment. In addition, the hemoglobin A1c was less than 9.5%. Slide five looks at the study endpoints. Just to remind you, the primary endpoint of the trial is reduction in liver fat content as measured by the gold standard MRI-PDFF at week 24 now compared to week zero. Key secondary endpoints included measurements of liver inflammatory activity as noted by serum ALT and multiparametric MRI or corrected T1, otherwise known as cT1. This was imaging done at week 24, again compared to week zero. Weight loss was looked at as a secondary endpoint, but it was not a weight loss trial, and that's an important concept to note. The study was conducted at liver centers, not weight loss centers. The expectation of weight loss was not messaged in the informed consent, and diet and exercise were not employed as they would be in the same manner for an obesity trial. Importantly, safety data was accumulated looking at adverse events, both serious and severe adverse events, and adverse events leading to discontinuation, as well as a focus on GI tolerability. Vital signs and glycemic control were also looked at. Moving to slide six, this is the CONSORT diagram or study disposition slide. While it's relatively busy, I think you'll see that it's important to do it this way because I wanna highlight what happened to the patients. You've seen the top two or three rows already. That's the initial 12-week trial, where we enrolled 94 patients into placebo or three different dosing arms. That's listed across the top. The next row is the completed treaters. This is 83 completed the initial 12 weeks of treatment. When we begin to look at the rollover study, we see on row three, declined or screen failed were 19, and you see the breakdown there. Placebo, four declined. The 1.2 mg dose, five declined. The 1.8 mg, two declined. In the 2.4 mg weekly dose, six declined. There were two screen failure patients. Now there's a dotted line looking at row four. Here this is the extension study, 64 patients. You see 19 in placebo, 16, 15, and 14 respectively in the three different dosing arms. Below that were three that withdrew consent. They were for work or family reasons and people who could not commit to the intensity of the study procedure over the full 24 weeks. The adverse events leading to withdrawals will be summarized in the safety summary. You see a prohibited med that led to withdrawal in a diabetic at the 1.8 mg dose. This patient was started on a gliptin by his family medical doctor, which is an exclusionary med. Finally, looking at the hyperglycemia case, this study had a stringent glucose control criteria, and one subject failed to meet this. One in 24 patients is consistent with the rate seen in other trials such as the semaglutide and the tirzepatide trials. Let's move forward to slide seven and look at the baseline characteristics of the extension study subjects. The demographics of the subjects who chose to roll over were virtually identical to the parent study. I think it's important to highlight a couple salient features of this group. When we look at body weight, you see, this is kilogram per meters or kilograms. You see roughly around 100 kg- 107 kg. Around, varying between 20% and 40% were diabetic. Highlighting again the liver fat content of this population, somewhere around 22% as a mean. It's also important to note the ALTs were not that high at baseline, ranging from 32- 41. The response rates at the end of the 12-week parent trial were also virtually identical in those that did not roll over. I think that's an important concept to note. Let's go to slide eight. Now here we see first the robust reduction in liver fat content by MRI-PDFF at week 24, and you see both absolute reduction on the left and relative reduction on the right. The asterisks connote significance. There were additional increases in absolute and relative changes in liver fat content over the second 12 weeks of treatment. While much of this improvement occurred in the 1.2 mg dose, we think likely given more time for that dose to catch up, each of these doses continued to improve. We look at just to highlight where we were at week 12, roughly in the mid to upper 60s% for relative reduction, growing to around 75%, particularly with the top two doses. This amount of liver fat content reduction is very, very good for a trial of this nature. Next slide is slide nine. This is what we call the responder analysis, and in this slide we break liver fat content reduction down into those that achieved at least a 30% reduction, a 50% reduction, and normalization of liver fat content defined as less than or equal to 5% liver fat content. There were additional increases, again, in absolute and relative changes in liver fat content over the second 12 weeks of treatment. I would like to highlight that in the top two doses, the 1.8 mg and the 2.4 mg dose, almost everybody to everyone actually met this 30% relative reduction 92%-100%. In addition, the rates of 50% liver fat content reduction, including the lowest dose at 1.2 mg, were at least 60%, climbing to 84.6% for the 1.8 mg dose. Finally, normalization of liver fat content is a relatively new concept in the field, but as we're seeing molecules that are robust in improving liver fat content, we're seeing more and more data come out on normalization of liver fat content. For pemvi, this is a very, very good reduction, achieving 53.8% in the mid-dose 1.8 mg group. All of these were very significant relative to placebo. All right, let's go to the next slide. Here in slide 10, I wanna illustrate a particular example. This is one patient that at baseline had a liver fat content of 32.3%, so very, very high. At week 24, dropped to by anybody's assessment into the normal range at 1.7%. This is with the 1.8 mg dose of pemvi. Importantly, and I would say, more novel, is this reduction was accompanied by a 38.1% decrease in liver volume. This is a relatively new concept that's being introduced, really this year, at EASL and at AASLD. As livers begin to heal and liver fat content begins to dissipate, we see reductions in liver volume. It's important to note that liver volume decreases that have been seen with different mechanisms of action are not all related and cannot be all accounted for by the liver fat content reduction itself, suggesting that there are other processes being mediated to reduce liver volume. This is still under investigation, but this could be due to inflammatory improvement where there's less water concentration in the liver, which also contributes to the decrease in liver volume. This is an evolving story. More to come. Stay tuned as the field begins to dive into this concept a bit more. Let's go to slide 11 and really look at overall. I showed you one example. This slide on slide 11 illustrates absolute reduction in liver volume on the left and relative liver volume reduction on the right. You can see on the left liver volume reductions ranging from 0.29 to 0.44 with the mid-dose 1.8 mg. These are significant relative to placebo. The relative reductions ranging from 12.6% for the 1.2 mg dose up to 18% and 19.1% for the two highest doses. Significant relative to placebo. These liver relative liver fat content reductions are in line with what we've seen from other mechanisms of action. On slide 12, we look at serum ALT, we see a dose-response relationship between low dose and high dose for all subjects, as well as subjects with baseline ALTs of at least 30 IU/L. It's really important to remember where the baseline ALT values were, which were between 32 IU/L and 41 IU/L. As you can see here, with low dose to high dose dropping between 13 U/L and 15 U/L, you're really taking these patients into the normal range for ALT, well into the normal range. That, along with the liver fat content reduction, is very, very encouraging. Okay. Next slide is slide 13. I wanted to show here an additional marker of inflammation. This is an imaging marker, multiparametric MRI. You guys know this as cT1. I wanted to show really kind of a responder analysis here. This response is defined as at least an 80 ms reduction in cT1 from baseline. Why is that? Well, the literature would suggest, and albeit it's early days, but it does suggest that 80 ms reduction in cT1 has been linked to at least a two-point reduction in the NAFLD Activity Score. Furthermore, elevated cT1 levels have been associated with increased risk of MACE as well as MALO, or Major Adverse Liver Outcomes. You can see relative to placebo that all doses had a very robust response. It is important to note that the overall numbers of patients here illustrated are very small, but this is an emerging concept, and it's one that's worth noting, particularly in light of the liver fat content reduction and ALT reduction that's being seen. Let's go to slide 14 and look at weight loss. This is efficacy estimand, I think it's important to highlight that there was continued weight loss observed from the 12-week time point, where we had 4.9% weight loss increasing to 7.2% for the mid dose in nondiabetics and from 4.3%- 6.2% in all subjects, particularly in the mid dose. We feel like that additional weight loss is expected to occur as treatment continues. I do think this weight loss distinguishes pemvidutide from other compounds with this degree of liver fat content reduction as well as ALT reduction. Now in the center part is the diabetics, and this data is highly variable and really, probably unreliable due to the small numbers of subjects you see there between three and six subjects. Next slide. This looks at, this is slide 15, looking at changes in serum lipids at week 24. What we have listed across the top are a placebo 1.2 mg, 1.8 mg, and 2.4 mg with the ends below that. On the left we see, total cholesterol, LDL, HDL triglycerides, and then baseline in week 24. The group mean differences in lipids from baseline to week 24 at the best pemvidutide doses were a total cholesterol of 13.4 mg/dL, LDL cholesterol 10.8 mg/dL, and triglycerides 45.1 mg/dL. While there continues to be reduction in HDL cholesterol, these are known to occur during periods of acute weight loss and are expected to reverse as weight loss stabilizes. Slide 16 is next. This is looking at improvements in blood pressure without clinically meaningful increases in heart rate at week 24. You can see the reductions in systolic blood pressure in the solid colored lines and diastolic blood pressure in the hatched colored lines. Relative to placebo, at the 1.2 mg dose and the 2.4 mg dose, statistically significant changes in systolic blood pressure. Overall, these reductions in systolic and diastolic blood pressure are expected to be linked to a cardiac benefit or cardioprotective. Looking on the right at heart rate, you see that really there is no dose linkage to heart rate. Really no change in heart rate with the top two doses. Unlike some other GLP-1 glucagon dual and triple agonist, we're not seeing meaningful changes in heart rate here. Next slide is slide 17, and this is the safety overview focusing on adverse events during the 12-week extension study. I think it's clear to see here the tolerability of the compound was excellent in the second 12 weeks of treatment, as the rates of GI adverse events were low. The three serious and severe adverse events were the same events, and they were unrelated to pemvi. One of these adverse events, Salmonella, led to treatment discontinuation, and there were two mild GI adverse events that also led to discontinuation. Next slide. This is slide 18, looking at glycemic control at week 24. Again, we, very similar to the lipids, we have the three different doses versus placebo. Starting out with non-diabetics, we look at fasting glucose baseline to week 24 and hemoglobin A1C baseline to week 24. Not a lot of difference here. The numbers are decent from nine to 14 patients, but again, not a lot of differences seen. When we focus on the diabetics, while the number of diabetics were small, the trends here are very encouraging and consistent with our expectation that HbA1c and fasting glucose would decrease at 24 weeks as subjects lost weight. You see those numbers here listed, particularly with the HbA1c going from 7.8%- 7.4% in the 1.2 mg dose and 6.8%- 6.3% in the 2.4 mg dose. Again, these numbers are small, but the trends are encouraging. Let's go to the summary slide on slide 19 and focus first on liver fat content reduction. Greater than 75% relative liver fat reduction at 24 weeks, better than or equal to the effects of other leading NASH candidates, particularly when we begin to look at those patients that normalize liver fat content. Significant reductions and normalization in ALT and improvement in multiparametric MRI point to potent effects in NASH clinical trials that are anticipated as we move forward to phase II-B. Looking at weight loss in non-diabetics, continued weight loss is seen growing to 7.2% at the 1.8 mg dose of pemvi at week 24. With amongst the diabetics, 5.3% weight loss at the 1.8 mg dose at week 24 was seen. Importantly, safety and tolerability, there were low rates of adverse events leading to treatment discontinuation with no serious or severe adverse events related to pemvi. The cardioprotective reductions in blood pressure, without increases in heart rate are very encouraging. Glycemic control was maintained with trends toward improvement in fasting glucose in HbA1c in subjects with diabetes, and there were no clinically significant ALT reductions observed in this trial. Moving to slide 20, I'll turn this over, back to Rich for questions pertaining to this presentation. Thank you. Thank you, everybody, for joining the call today. Operator, we can now move to Q&A. Certainly. Ladies and gentlemen, if you would like to ask a question, please press star one and one on your telephone. Please stand by while we compile the Q&A roster. Our first question will come from Seamus Fernandez of Guggenheim. Your line is open. Hi, guys. Thanks for the question. This is Evan Wang on for Seamus. Just first off, encouraging liver fat measures. Can you comment on the effect of the dose and duration of treatment? Asking in terms of the slope of the different doses and, you know, duration on factors like liver fat, weight loss, lipid profile. Do you expect further improvement with the longer duration treatment? I have a follow-up. Scott, do you want to take that, then Dr. Harrison, if you want to comment. Hey, Seamus, good morning. Regarding the liver fat, it appears that most of the changes occur in the first 12 weeks. That's what we saw. We saw very remarkable changes of about 68% at the 1.2 mg dose at that point in time. The effects continued. I think that's important because it is important to show that the effect is maintained, and it continues to increase, which is what you would expect. We would expect that very close to about 24 weeks probably, the liver fat has maxed out. That is the effect. I think the most important thing to realize regarding that is how rapid the effects occurs and how robust they are. To get this magnitude of liver fat reduction early means that in a 52-week or longer trial, that the liver is going to enjoy the majority of that, or let's say 46+ weeks to heal and return to normal. That includes fibrosis improvement. The magnitude and the speed, especially early on, are extremely important. Regarding the weight loss, we would expect the weight loss to continue. It's continuing here, and we would expect it to continue, you know, indefinitely. I can't give you a number of what we would hit, but obviously we went from 4.9%- 7.2% at the 1.8 mg dose between week 12 and week 24. One would estimate that over a year this would continue. As we mentioned, this is not a weight loss trial. This was a trial, as Stephen pointed out, was a trial in patients with NAFLD. It was not run as a weight loss trial. Consequently, the weight loss was basically a secondary determination. As Stephen mentioned, this kind of liver fat reduction, combined with weight loss has not really been seen with other drugs. There are some drugs that are potent with regards to liver fat, but not weight loss and vice versa. We can go through examples of that. The combination is very unique. Despite not running this as a weight loss trial, we got very, very good weight loss that's continuing. I think the prospects we're seeing even better weight loss in the MOMENTUM trial when we do our interim analysis in the first quarter of next year are excellent. Great. Then a follow-up on, you know, the safety profile, just in terms of the discontinuations, the abdominal pain. Can you comment in terms of, you know, how safety looks in the second 12 weeks versus the first 12 weeks? Any kind of additional color there would be helpful. Yeah. Well, Seamus, as you can see, the tolerability of the drug, specifically adverse events, GI adverse events in the second 12 weeks was excellent. Any events that you saw here when you count patients were pretty much patients who had the same events in the first 12 weeks. Consequently, if one were to look at a 24-week snapshot, it wouldn't have changed from the 12 weeks because basically any GI intolerability was expressed early on. The adverse events that led to discontinuation are things that are gonna accrue to a trial if you go long enough in a susceptible population. It's pretty clear from the way we describe them that they didn't have any relationship to pemvi. Consequently, we think this is a superb safety profile. It's clear that any adverse events are occurring early. The abdominal pains that led to discontinuation were mild. It's somewhat curious that they would lead to discontinuation. I think the thing to stress is that the rates continue to be low in the single digits, which compares very, very well across the compounds and development for NASH and Obesity. Great. Just one question for Dr. Harrison. You know, I know there's some recent NASH/NAFLD data recently. Can you help, you know, put this stat in context of, you know, some recent developments there? I know, you know, slightly different study populations, but that would just be helpful. Seamus, I didn't understand what you asked. My apologies. Can you repeat the question? Just... Yeah. Can you help, you know, put this data in context of, you know, how you're seeing kind of recent developments in the NAFLD/NASH space? I know there's some recent data, different, you know, patient populations or study populations, but any kind of comments there would be helpful. Yeah. I mean, I think, if you look at where we've been and even where we've come in 2022, it's been a remarkable year. That's built off of the bones of prior drug development where we weren't successful. You know, one of my slides I talk about when we talk about emerging therapies in NASH is my slide on drug failures. I hate using the word failure because we learn from all of these trials. Not only about trial design, but we also learn about mechanism, and we learn about what's important in pathophysiology of NASH. I feel like what we've learned is that we really need to target upstream in this disease because the liver has such an amazing ability to regenerate and it, you know, in multiple redundant pathways. For instance, if all we did was target a stellate cell and tried to block fibrosis, let's say through TGF-β, there are multiple redundant ways to activate a stellate cell. You know, you might block one, but what we've learned is that it gets activated by other mechanisms. Really what we wanna do is target way upstream. We wanna block free fatty acid flux. We wanna get after lipotoxicity that ultimately drives inflammation, injury, and stellate cell activation. Where we've seen drugs that do that's where we're beginning to see more and more success. Importantly, we've turned toward, again, modulating what's causing the injury. If we can improve liver fat content, that is where we've seen significant strides in histopathologic improvement. There's work still to do with completely understanding how these non-invasive tests, such as MRI-PDFF, equate to or correlate to histopathologic benefit. What we do have in the literature is work looking at 30% relative content reduction, 50%, and now we're seeing more and more data come out with 70% and complete liver fat content normalization. That data has yet to be fully mined for all of its richness relative to histopathologic correlation. I suspect in the coming months, you'll see more and more of that come out, whether that's from an FGF21, whether it's from a THR-β or additional data with other mechanisms that modulate liver fat content. Having said that, putting this in perspective, looking at a recent letter that Rohit Loomba wrote, one of my good friends in the field, looking at combining liver fat content reduction with ALT reduction, you see there's an additive effect on histopathology. One of the things I talked about at EASL this year was looking at time to effect in these non-invasive test improvements. In other words, looking at the kinetics of the change, how quickly do we see changes in ALT or PDFF or other non-invasive tests. The other concept was stacked NITs. The more of these that reach certain magnitude of effect changes, you know, do we see additive impact? The first tranche of data that we have suggests that combining PDFF with ALT, we get additive benefit. You know, just to summarize, Seamus, putting this in perspective, seeing the weight loss that we're seeing at 24 weeks, the liver fat content reduction, the ALT reduction. I really wanna highlight, I think the ALT reduction is a bit abrogated here because our baseline values will only allow us to go down so far. I think as we move into more active populations of NASH with higher baseline ALTs, that will likely be accentuated. Again, liver fat content reductions being very, very positive here, really give me hope and promise and conviction that this is going to be a very good drug for MASH as we move forward. I haven't even mentioned the cT1 data, which while some of that change is related to liver fat content change, not all of it is. The liver volume piece we haven't even spoken of yet. That's also probably playing a significant role. Really lots to be excited about here as we move into a paired liver biopsy study in 2023. Great. Thanks, guys. One moment. Our next question will come from Yasmeen Rahimi. Your line is open. PSC. Hi, this is Emma on for Yas. Thanks for taking our questions. First, could you comment on whether the one case of hyperglycemia was a diabetic or a non-diabetic patient? Like when did it occur and go away? Any color would be helpful. As well as you noted no significant ALT elevations. Does that mean no grade one or two or three or four? Any additional color on that would also be helpful. I got a few follow-ups. Thank you. Scott? Yeah. Hi. Thanks for the question. The hyperglycemia occurred in the subject who was a diabetic with baseline hyperglycemia, and the elevation occurred about five weeks into the treatment in that phase, which would have been combined with the 12 earlier weeks, about week 17. Consequently, we just think it was a normal fluctuation that occurred in a diabetic. As Stephen mentioned, these hyperglycemia events occur all the time, even in trials that have direct incretin drugs that have direct incretin effects, such as semaglutide and tirzepatide are rated about 3%. Statistically, this would have been expected. Regarding the ALT elevation, we define a significant ALT elevation as threefold or greater. As in the 12-week study, we're not seeing these elevations. We don't really think that there's any kind of direct link between this drug and any hepatotoxic events. The other thing to remember is that combined, looking at the aggregate ALTs decreased in this study, then we decrease very significantly. Combined with that, we don't think that there's any indication of pemvi's effect adversely on the liver. If anything, it's very positive. Thank you. Based on, or despite strong MRI-PDFF reductions, we didn't see much further changes in the lipid profile. How could you explain that? As you prepare for phase II-B in NASH, what can you comment about design? Thank you. Right. Vipin, I'll take that one as well. Yeah. We are seeing changes in lipids, as Stephen mentioned. They're actually very good. They're not as large as they were in the phase I trial. It could be the population and the amount of weight loss that was actually achieved that would have been combined to affect the lipids. You know, we expect that this will grow with time, and we expect that in our committed obesity trial that we'll see the robust lipid effect we saw in our first study. The final thing about the phase II-B design for NASH, any color there? Yeah. I can take that. We are still working on that. We, you know, we will discuss and disclose that in due course. I think what I can say is that we're preparing that within the background. We've been preparing for a phase II-B NASH study. We expect to have more information in the first quarter. Thank you. One moment. Our next question will come from Corinne Johnson of Goldman Sachs. Your line's open, Corinne. Good morning, everyone. Maybe one for Dr. Harrison. Just in your experience with NAFLD and NASH patients, how do these patients kind of generally fare on different weight loss programs or other therapeutics as compared to the more general obese population? Yeah, I mean, I think in general, they do well. You know, one of the interesting concepts that are beginning to unfold for us is how these trials are designed and how they're run. You know, I, I think there are likely a couple things at play here, and Scott mentioned this a little bit at the initial start of this meeting. You know, if you're enrolling your trial at weight loss centers, that's probably different than if you're enrolling your trial at a predominantly NAFLD center or liver research center. The focus is a little bit different, right? You know, focus from a hepatology perspective is all about looking at the liver fat content, ALT, AST, adverse events, that sort of thing. We generally, we foundationally speak about diet and exercise, but we don't enforce that. You know, we're not leading CrossFit exercises every morning with our team because we really wanna know what the drug effect is relative to placebo. Again, I don't do predominantly obesity trials, but my understanding is the focus is a little bit different. Then there's the second piece about the physiology of these patients, I think that's something we're still learning about. Are there in the setting of fatty liver, are there additional influences that could impact weight loss, such as genetic influences? You know, in this trial we were enriched for Hispanics. Is there something unique about that population that's different from Caucasians or Asians or African Americans or other ethnicities that could predispose to differences in weight reduction? This idea of liver fat content. You know, this study was super enriched with liver fat, probably more so than we see in, well, certainly more so than we see in a typical obesity trial. Is there some influence there that maybe we heretofore have not known about? Those are questions that I think I don't have the answers to, but they're thoughtful questions that need to be addressed. Having said that, as you see from this particular trial, the weight loss is incremental. It doesn't stop at 12 weeks. It's continuing. I think that's what we've seen in NASH trials. NASH patients can lose weight. We see it happen, and I think drugs that modulate weight loss will be impactful in this disease. I can't really compare it necessarily to a separate obesity trial. My focus has been on liver. What I can say is this degree of weight loss with this degree of liver fat content reduction is very impressive. I can't wait to see what the paired liver biopsy phase II results look like. Okay. Maybe just one more from me. Based on the data today and the 24-week readout, how are we thinking about dose selection in the phase II-B study? Scott, do you wanna take that? Right now, we anticipate taking the same three doses going forward into a NASH phase II-B trial. Prior to initiating that trial, we'll likely have the readout from the interim analysis of the MOMENTUM trial. It's possible that what we see in that trial could influence our dose selection. Okay. Thank you. One moment. Our next question will come from Roger Song. Your line is open. Hey. Thank you for taking the question and congrats for the data. A couple from us, maybe the first one for Dr. Harrison as well. Given your experience in this population, pemvidutide is a little bit unique in targeting the weight loss and the liver fat. How would you kinda comment on this correlation between the liver fat reduction or liver benefit versus the weight loss benefit you are seeing here? In other words, will this kind of liver fat benefit coming from the mostly coming from the weight loss or actually pemvidutide doing something directly to the liver? Thank you. I think that's an incredibly important question and one that deserves a thoughtful answer. I'll give you my shot at it. It's important to know the GLP-1 receptor agonist work outside the liver. There are no GLP-1 receptors in the liver. The weight loss that we see with a GLP-1 is solely unrelated to anything happening in the liver. Working on decreasing gut transit time, working on satiety receptors, that's how we're modulating weight loss with a GLP-1. Any effects we're seeing in the liver are tangential effects. They're good effects, right? We see that with semaglutide, for instance, in the New England Journal phase II-B study, where it's a pure GLP-1 receptor agonist. We see weight loss. We see impacts on NASH resolution, particularly at the high dose relative to placebo. No impact yet on reduction of fibrosis. Now you add in glucagon. That is a direct effect on the liver. We're increasing energy burn where we're driving liver fat content at a much higher rate than what you would get with just a GLP-1 alone. I think that's the difference. Now we're seeing direct liver impact plus peripheral or extrahepatic impact from GLP-1. While we're getting weight loss and we're getting liver health improvement from that weight loss, it's the additive impact of the glucagon that I think is the difference between a pure GLP-1 versus something like a GLP-1 glucagon dual agonist. How that translates in histopathology is yet to be seen, but that's what we're talking about today. We're talking about looking at these noninvasive tests and the encouraging data that we're seeing. In fact, in some regard, really unprecedented changes in some of these liver fat content as well as ALT reductions that we're seeing with this particular mechanism. The only other one that's come close to this liver fat content normalization is an FGF21 with 24 weeks of treatment. There we see very encouraging histopathologic changes. Just not having a crystal ball, but thinking about the data that we have in front of us, I would anticipate that this dual agonist, where you have extrahepatic benefit as well as direct liver benefit, will be very effective when we go into paired liver biopsy trials. That's great. I really appreciate this, Dr. Harrison, for this very thorough answer. Another question also may be related to the clinical practice as well. In terms of the glycemic control, in this diabetic patient population, when do you expect to see the glycemic reduction in terms of the fasting and HbA1c, and will be acceptable for diabetic population because those patients are supposed to reduce the HbA1c and the fasting glucose? Yeah, I mean, I think, again, it's important to note that this is a small study. When we look at the diabetics at week 24, you know, you're talking three to six patients in each arm. It makes sense to me that if you're losing weight and you're improving metabolic profiles, that glycemic control, whether it be, you know, fasting glucose or HbA1c would improve because this is what goes along with improvement of insulin sensitivity. It's, you know, you can begin to see better results at week 24 than you can at week 12, and I think that's just part of the process. You know, the trend is happening, and I suspect that'll continue to improve as we add more numbers, as we treat patients that have less controlled diabetes. I mean, if you look at the mean HbA1c, they range from 6.1% in placebo to 7.8% in the 1.2 mg dose, but really 6.4% in the 1.8 mg and 6.8%. These are generally well-controlled diabetics that we're looking at. As we move forward into patients that maybe have less control and treat them for perhaps longer time, we should see incremental additive benefit. That would be what I would expect to see. Excellent. Thank you. That's all from us. Really appreciate the answer. One moment. Our next question will come from Liisa Bayko of Evercore. Your line is open. Hi there. Just a follow-up, maybe along the lines of what you were talking about earlier. Just to be curious as you know, kind of think about how the field is evolving between, you know, these Obesity drugs now, several MASH drugs that look like they hold quite a bit of promise and sort of all the overlap there. You know, how do you see, like, treating patients, you know, treating from the obesity side, from the NAFL study, your side, MASH side? How you know, maybe you can just walk us through, you know, how you see the treatment paradigm evolving there. Thanks. Thanks, Liisa. I assume that's for me. This is Stephen. Yeah. Okay. Yeah. Well, look, as we mentioned, this is rapidly evolving. Lots of encouraging data coming out. You know, it seems like we've gone from, you know, NASH being a bad word and everybody running for the hills when we talk about drug development in NASH and the focus shifting to Obesity. Now with all of the positive data coming out in 2022 to include data with Altimmune and pemvidutide, the shift I feel like is happening in the reverse. Now we're starting to see positive momentum in the fatty liver space. I think it was just a matter of time, right? We had to go through this period of learning about the disease, understanding how drugs work, understanding how to accurately assess efficacy in these patients. I'll parenthetically say, we have a ways to go there. There's a lot we still need to learn about accurately assessing liver disease, particularly for an endpoint assessment. Given in light of some of the recent data that's coming out with different mechanisms, whether it be an FGF21, a THR-β, you know, encouraging results with my gosh, with other compounds, whether it be a deuterated pioglitazone, or with this, where we're beginning to see positive impacts with modulation of both GLP-1 with glucagon or GLP-1 with GIP or even a triple combination. It's just opened up a whole new aperture on how to target metabolic disease. You know, we recently had a conference in Washington called the Mosaic Conference, which really it's a conference pulling all of the subspecialty stakeholders together, whether it be cardiovascular, renal, liver, pulling them all together, because now we're getting to the point where we have drugs that can target multi-organ disease, and that's what metabolic syndrome is. From a liver perspective, you know, I can be very myopic, where I'm focused just on liver histology, but I would be doing a disservice to my patient if I did that. As a physician, I need to step back and say, "What's best for my patient?" If I have an obese diabetic NASH patient, what are these people gonna die from? They're gonna die from cardiovascular disease, they're gonna die from extrahepatic malignancy, and finally, they're gonna die of liver-related death. Now that we're broadening our aperture of drugs that can hit things like obesity and liver fat content and ALP reduction, I think it allows us to begin to be more precise with our medical practice in who gets what drug. For instance, we know in a NASH patient, if there's evidence of advanced liver disease, that patient is much more likely to die a liver-related death than a cardiovascular death or extrahepatic malignancy death. On the other hand, if the patient has mild to moderate fibrosis, the other metabolic features of that patient might tend to weigh more heavily on the outcome of that patient. Once I understand that natural history, now I can begin to look at the armamentarium of what I have in my tool chest to target those patients. If I have a more advanced patient from a liver perspective, I might target that patient with a drug that has robust efficacy on fibrosis and the drivers of NASH for a period of time, and then pivot that patient to a drug that perhaps is more tolerated for the long run. What we know with injectables is that there's a tendency to be quite potent, at least with some of the data that we've seen heretofore. The data from Altimmune suggests, at least noninvasively, very, very good potency here. We'll just have to see if that translates into histopathology. My guess is, based on all the data that we have with non-invasive to date, that that's likely the case. Using this injectable, or other injectables, to me, gives us the opportunity to do it a couple ways. If I have a patient with more advanced disease and I need to hit them hard and get them under control, then an injectable like this one, if it pans out to have effects on fibrosis, which I suspect it will, or an FGF21 would be a great opportunity because we're also getting at the drivers of this disease from a weight loss perspective. On the other hand, if I have a patient that maybe isn't significantly obese, they're overweight, they have elevated lipids, they have cardiovascular risk factors, and they have NASH, I might go with something slightly different that has been shown to be efficacious. Ultimately, you know, there's just management for the long haul. These patients, we don't just treat for six months. These patients are really going to require lifelong therapy. This is an evolving area, and I don't pretend to have all the answers, and I'm still learning myself. To me, I see, and I put this in my slides before, that the ideal NASH drug gets at histopathology, both NASH and fibrosis. It gets at weight reduction, liver fat content reduction, glycemic control, and atherogenic lipids. That's the ideal drug. The next thing is it oral or is it injectable, and what's the side effect profile? Looking at that allows us to frame what drugs we're gonna use in monotherapy and what drugs we're gonna use in combination therapy. When I just focus this back on pemvidutide, what I see is a drug that's moving weight, it's moving liver fat content, and it's moving these non-invasive tests in such a way that I suspect we're going to have very good data on histopathology. We're beginning to see trends and changes in glycemic control and even early changes in lipids. If that can hold up as we move through phase II-B and then into phase III, you've got a drug that essentially does all of those things. Then the focus will be on, do we still have the same tolerability profile that we have and what we're showing today? If so, that really creates a very good drug to treat a broad swath of these fatty liver patients, both with multiple different phenotypes, those that have advanced disease and those that have milder disease, but maybe they have more extrahepatic complications. I think that's a long-winded answer, Lisa, but it's my best shot at where we are today. All right. Thanks a lot, Dr. Harrison. One moment. Our next question will come from Mayank Mamtani of B. Riley. Your line's open. Good morning, team. Thanks for taking our question. I have three quick follow-ups, very targeted questions. Any chance you've had a chance to do Hispanic versus non-Hispanic subgroup analysis? I know we are talking small patient numbers, but I'd be curious about not just weight loss differences but also lipometabolic parameters and even GI AEs, if, you know, if there's any correlation with ethnicity you could comment on. Scott, do you wanna take that? Yeah, Mayank, I'll take that one. Well, you know, there aren't a lot of non-Hispanics in the trial so that you're dealing there with small numbers. We have to start with that by saying that any analyses that we do are not the most potent analyses. We've looked at our data, and we looked at the data across other studies, and it's clear the Hispanics in other studies, subjects that are surpassed to trial. Also in our own data, we're seeing Hispanics lose less weight than non-Hispanics. It's a little difficult to continue to do analyses as the population gets smaller between the parent 12-week trial and then the additional 12 weeks where there are some subjects who decided not to continue. Across the board, it looks like non-Hispanics have better responses than Hispanics. On GI profile, AE, anything around tolerability on Hispanic versus non-Hispanic bits? Yeah. You know, when you're having a small number of AEs like we've had in the second 12 weeks in this trial, and even not very many AEs in the first, it's just very difficult to tease that out. We would expect that the Hispanics and non-Hispanics have about the same rates of adverse events. Got it. Just on the weight loss, you know, patient-level kinetics data that you know, I think you commented at 12 weeks, it was linear. Could you just clarify, how is it looking at 24 weeks? Scott, you can take it or Dr. Harrison can take it. No, I'll take that one, Mayank. I'll let Steve add any other color that he would like. You know, we're seeing continued weight loss. I think that's important. I think that if you look at what we have at, let's say, the 1.8 mg dose, we had 4.9%. That increased to 7.2% at 24 weeks. It's continuing to go up. You know, this is conducted as a liver trial, a NAFLD/NASH trial, not a weight loss trial. We think the kinetics here are totally separate from the kinetics in that we're gonna see in MOMENTUM. I would point out that the transition between the 12 and the 24 weeks did have a bit of an impact on the weight loss in that the weight loss in the subjects who decided not to roll over was actually about 0.5% greater at 12 weeks than it was in those that did decide to roll over. In actuality, that 7.2% that we saw at 1.8 mg, if we didn't have the changes that we saw at the rollover could have been as high as, say, 7.7%. I think when you look at all of this, Mayank, you're seeing progressive weight loss, and we think it's gonna continue beyond the 24 weeks. It's tough to tell you what would happen at the end of a year, you know, you could, roughly put yourself in that double digit range. I don't wanna, you know, commit to that because we don't have that data. I think the most important thing is that we are seeing continued weight loss and the continued effects of the drug and weight. Understood. Thank you. Just quickly, on the liver volume and cT1 data that was presented today, just specifically, Dr. Stephen Harrison, if you could, you know, help compare, you know, what you may have seen with other drug classes. I think you mentioned FGF21 and THR-β. Also as you learn, you know, on cirrhosis, inflammation and ballooning kind of profile here, how are you know, thinking about defining some of the endpoints for the next biopsy study? I know the FDA guidance is open to being more flexible based on the drug's mechanism of action. If you're able to comment on the design of the phase II study, that would be very helpful. Yeah, I think I'll let the sponsors comment on the phase II trial design, and I'll just speak more holistically. I would say stay tuned to the liver and spleen volume reduction story because we have this ability with AI pathology to really look at correlations with our MRI data that we're collecting and what we're seeing histopathologically. I don't know if you were present at AASLD when I gave an analysis of liver fat content reduction and volume reduction relative to what we're seeing histopathologically. There is a link between both of them. What we showed was that when you correct for liver fat content reduction, you see additive histopathologic benefit. When you additionally correct for volume reduction, we see more additive benefit on histopathology. I believe that's real because we showed it not just with a THR-β, but we showed it with an FGF19 also, at least the liver fat content reduction. We didn't have volume data for FGF19, and we only had that with a THR-β. I think we've got more work to do in this space, but I think it's critically important. If you begin to compress liver architecture, then I suspect there is real change that if you don't correct for that, you won't appreciate on histopathology. More to come there. Then the liver volume size, the change that we've seen, this is around 20% or so. I'm only aware of the THR-β with resmetirom being around 20% as well. Off the top of my head, I can't recall if efruxifermin has generated that data. If they have, I've forgotten it. I don't recall that number. Speaking more broadly, change is afoot, if I could use that. Again, we're gonna talk about this at NASH-TAG in greater detail, but drug development is evolving, particularly in our field, very rapidly. If you recall, the FDA draft guidance is still in draft guidance since 2018 when it came out. It's there, it's in draft for a reason, because these endpoints are rapidly evolving. I think we're on the precipice of something big relative to looking at alternative surrogate endpoints. I think it's important to remember that the FDA says that the surrogate endpoint just has to have a reasonable likelihood of providing clinical benefit, not definitive likelihood. So we're on the precipice of having that. Just turning this back to Altimmune, with these non-invasive test reductions that we're seeing, particularly in liver fat content, and perhaps others that we could roll into a phase II-B liver biopsy trial, and I'm anxious to talk to Altimmune about what those others might be. I think we have the ability in phase II-B to get after data that would allow us to have a frank conversation with the FDA about what surrogate endpoint we could use in phase III. This is, you know, I'm trying to be more general in my comments because I do think that there is a body of data growing in the non-invasive space that will allow us to take Herculean moves forward and advance this field much more rapidly. It's having drugs like what we're talking about today, drugs that we talked about earlier this week, all having an impact. As these drugs begin to have a bigger and bigger impact, it's easier for us to find a non-invasive test to link to that. Stay tuned. Yeah. Mayank, I'm not sure what was your question about the phase II design. Was there a question that didn't get answered? Yeah. I mean, if you could comment from a sponsor standpoint how you intend to design the, you know, definition of NASH resolution and fibrosis improvement and... There are some differences across, you know... Yeah. Even phase III trials. Yeah. Look, as you can see, we're just hot off the press. We're getting the 24-week data here. We've got a very accomplished team sort of working in the background, our advisors, and we're gonna consult them and put together the trial design. Stay tuned. We'll certainly talk more about it, but we're gonna take all of this advice into consideration, and we'll come up with a very thoughtful design, including looking at these non-invasive markers and trying to connect or correlate them with fibrosis benefits. Stay tuned. Thank you for taking our questions. Dr. Harrison look forward to NASH-TAG. One moment. Our next question will come from Jon Wolleben of JMP. Your line's open. Hi. Thanks. Just two for me. Just clarification, was there any break in dosing between the initial 12 weeks and the start of the extension trial? Then also with regards to the heart rate increase, I know you guys didn't see any here, but just wondering what would be a worrisome increase for the class? Thanks. Scott. Hey, Jon. Good morning. There was no break in dosing. Dosing was continuous so that for the subject that walled over, that subject would have gotten a continuous 24 weeks of dosing. Regarding the heart rate increase, it's a bit difficult to say. You know, we haven't really taken drugs with significant heart rate increases into late phase development in the past. With semaglutide and tirzepatide, the heart rate increases were in the range of 1 BPM-3 BPM, maybe 4 BPM, and that was considered acceptable by the agency. Well, why is that? Well, what you're really worried about is the cardiac workload. The cardiac workload as it pumps is related to not only the heart rate but the systolic blood pressure. In other words, what is the resistance that it's seeing as it pumps and how often is it doing the work? We have a parameter which is known as the rate pressure product, and there are a lot of papers about what an appropriate rate pressure product would be. It turns out that at the normal values for systolic times heart rate would be about 10,000 or less. We're clearly, with the amount of systolic blood pressure drops we're getting, we're reducing the rate pressure product, and that's going to have a cardioprotective benefit, especially in the absence of the heart rate increases. Look at other compounds in development. We're seeing heart rate increases with some dual and triple agonists involving glucagon as high as 30 BPM in single-dose studies and 10 BPM-15 BPM in multiple of those studies. I don't have a crystal ball of how a cardiac reviewer at the FDA would view that in terms of the cardiac risk. It may mitigate over time, but the risk could be very great in the first four to eight weeks of dosing until the heart rate starts coming down. What I can say is that we don't have it. We're having blood pressure and heart rate changes very much within the range of other drugs that have been acceptable that will have cardioprotective benefit like semaglutide and tirzepatide. You know, we don't have to face that problem that other drugs are facing. Very helpful context. Thanks. One moment. Our next question will come from Patrick Trucchio. Your line is open. Patrick, your line is open. Hi. Good morning. Thank you. Just a few follow-up questions. Just the first one is on slide 14. Can you discuss what the weight loss could have been had diet and exercise been part of the protocol in the program? Would you anticipate that diet and exercise would be expected to be part of the clinical development program going forward? You take that. Why don't I take that? Good morning, Patrick. You know, again, we're comparing across trials that are being done differently, right? This was run as a NASH trial or a NAFLD trial, where specifically you would not have diet and exercise. If we had put that into this trial, we then wouldn't have been able to compare all of these multiple parameters across trials. In Obesity trials, speaking about those, typically the diet and exercise that's used results in about a 2% additional weight loss. That has to be factored in here. What we don't know is if simply adding 2% to the numbers because it's not just simple arithmetic. There are synergistic effects of diet and exercise that affect patient behavior, right? When a patient is losing weight, they get very encouraged, and they become participants in the program. If a subject loses you know, a lot of weight, whether it's due to the diet and exercise or not, they go out, they get an additional walk each day, they push aside the serving. It could be that there are synergistic effects of diet and exercise that go beyond simply adding 2%. I can estimate what might happen here with the 2%, but we're comparing across trials of different design, and I'm not really sure that's really valid here. Yeah. That makes sense. Then I'm just wondering if you could provide a little bit more perspective on the baseline characteristics and trial design in the NAFLD study as compared to the MOMENTUM study, and why it would be expected that the weight loss in MOMENTUM interim analysis would be expected to be more robust relative to the NAFLD study. As well, I'm wondering as you have the 24-week data, you know, has there been any additional learnings that can maybe provide a read-through to this MOMENTUM interim analysis? Well, Patrick, there are two questions there. The first is regards to the demographics between the NAFLD trial. Remember, the demographics of the 12 weeks were the same as the 24 weeks, so I'm going to consider them together versus MOMENTUM. For one thing, as we pointed out before, this trial had approximately 80% Hispanics, at least to start. The MOMENTUM trial has about 20%. It's because when we conducted the trial, we went to centers like Dr. Harrison's and other centers in Texas and in the Southwest, where lo and behold, you're going to have Mexican patients of Hispanic origin, right? Very, probably very high in certain polymorphisms like PNPLA3 and the like. The Hispanic content is going to be very different and, as importantly, the baseline liver fat. If you look at an obesity population with a BMI of about 36, which is what we expect in MOMENTUM and was based on our initial demographics, the liver fat content in baseline is about, you know, in the range of 5%-6%, and that's what we saw in MOMENTUM. It reflects the level of metabolic illness. If you're having 22% liver fat at baseline, whether or not you're diabetic, you're metabolically ill, and you wouldn't expect as much liver fat, you wouldn't expect as much weight loss. We think that those are two major features as well, going beyond the demographics, the basic design of the study that we've talked about many times in this call, that the study's being conducted differently and, you know, based on a snapshot that we did at the data that we've talked about before, the MOMENTUM data, at comparable time points, we're just seeing across the board with all the doses pulled together very, very different effects. Regarding the knock on or the rethrough effects of this data, again, the trials are not comparable based on the factors that we talked about before. Nonetheless, we're seeing continued weight loss. I think that's very important despite the obstacles in the study population in the way this study is designed. We're seeing trends to improvement of hemoglobin A1c, which we think are encouraging. Of course, the MOMENTUM trial is in non-diabetics, nonetheless, you know, it's important in the pre-diabetic population to have an impact there. All in all, we find the data very encouraging. Yep. That's great. Thank you so much. I'm showing no further questions from the phone lines. I would now like to hand the call to Vipin Garg for closing remarks. Well, again, thank you everyone for participating today. We appreciate your interest, and have a nice day. We'll look forward to talking to you soon. Ladies and gentlemen, this concludes today's conference. Thank you for your participation. You may now disconnect.