Greetings, and welcome to the Altimmune, Inc. Key Opinion Leader call on pemvidutide under development for obesity and NASH. At this time, all participants are in listen-only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Mr. Will Brown, Chief Financial Officer. Thank you. You may begin. Thank you, operator, and thank you everyone for participating in today's key opinion leader call on the previously announced results of our 12-week phase I clinical trial of pemvidutide in overweight and obese subjects. Leading the call today will be Dr. Scott Harris, Chief Medical Officer of Altimmune, along with Dr. Stephen Harrison, key opinion leader. After the prepared remarks, we will open up the call for a Q&A session. As a reminder, this conference call is being recorded and will be available for audio rebroadcast on Altimmune's website at www.altimmune.com. Please click the webcast link on our Events and Presentations page to view the slide presentations. 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 COVID-19 and its 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. Any statements made on this conference call speak only as of today's date, Thursday, 30th September, 2021, 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. With that, I will now turn the call over to Scott Harris, Chief Medical Officer of Altimmune. Scott, please go ahead. Thank you, Will. Good morning, everyone. It is my pleasure to welcome you to this key opinion leader call, in which I'll be providing a safety update on the results of our 12-week phase I clinical trial of pemvidutide, formerly ALT-801, in overweight and obese subjects. In particular, I will provide further details about the single subject who experienced ALT elevation in the study, as described in our prior press release and during our investor call on Tuesday, 28th September. We are very fortunate to have with us today Dr. Stephen Harrison of Pinnacle Research. Dr. Harrison is a world-renowned authority on NASH and liver disease, author of 150 peer-reviewed journal articles, and lead investigator in a number of clinical trials. He served as Professor of Medicine at the Uniformed Services University of the Health Sciences and is currently a Visiting Professor of Hepatology at Radcliffe Department of Medicine, University of Oxford. During his Army tenure, he served as the Director of Graduate Medical Education at Brooke Army Medical Center, Associate Dean for the San Antonio Uniformed Services Health Education Consortium and Gastroenterology Consortium, and Gastroenterology Consultant to the Army Surgeon General. As you are aware, this was a 12-week, phase I, placebo-controlled single and multiple ascending dose study of pemvidutide. The study was conducted in Australia under a clinical trial application and enrolled otherwise healthy overweight and obese volunteers. The SAD portion of the study enrolled 36 subjects, and the MAD portion enrolled three cohorts at doses of 1.2, 1.8, and 2.4 milligrams randomized four to one to drug or placebo weekly for 12 weeks. The study did not employ dose titration. Subjects receiving the 1.8 mg weekly dose achieved an absolute mean weight loss of 10.3% at 12 weeks of treatment with pemvidutide and a similar degree of weight loss of 9% at the 2.4 mg dose. Pemvidutide was well-tolerated, even in the absence of dose titration, with no adverse events leading to study discontinuations and predominantly mild adverse events that did not require treatment at the 1.2 and 1.8 mg doses. A single subject experienced approximately five-fold elevation of ALT during the trial, and I would like to present further information on this subject. The subject was a 25-year-old male with no other clinically important past medical history or concomitant medications. The subject received pemvidutide doses of 1.8 mg weekly. At baseline, his weight was 83.1 kg, and BMI was only marginally overweight at 26.8. Baseline liver fat content by MRI-PDFF was within normal limits at 3.8%, with the definition of fatty liver being 5% or greater. At screening, his ALT was elevated at 61, with an upper limit of normal for the Australian laboratory of 50. AST was elevated at 55, with an upper limit of normal of 40, and GGT was normal at 37, with an upper limit of normal of 50, as were all other liver function tests. He had no history to suggest alcohol or drug abuse, and the etiology of the liver function abnormalities was not determined. On study day 8, 1 week after the first dose of study medication, the subject was noted to have an asymptomatic rise in ALT to 147. Treatment, however, was continued, and a repeat ALT value the following week spontaneously improved to 92, declining to 68 at week 4. By week six, the subject had lost 3.1 kilograms or 3.7% of his body weight, and his BMI declined to 25.8. At that time, he reported transient mild nausea and abdominal pain that resolved rapidly and spontaneously. A repeat MRI-PDFF demonstrated no detectable liver fat, signifying rapid and perhaps complete defatting of the liver. Also around that time, the ALT was observed to increase slowly, peaking at 323, approximately 5-fold his baseline value at the start of week 11. AST rose approximately 2-fold to 95, and GGT rose to 90. Bilirubin, alkaline phosphatase, INR, albumin, and globulin all remain within normal limits. By this time, the subject's weight had declined 5.3% to 78.7 kilograms, and his BMI had declined to 25.4 and subsequently to 25.2 by week 12. Dosing was paused, and the ALT rapidly improved to 80 at week 12 and 56 by week 16, the end of the safety follow-up period. All other liver function tests followed a similar pattern of resolution. A thorough workup for non-drug related causes of ALT elevation or underlying liver disease was performed. Markers for viral hepatitis, autoimmune disease, metabolic liver disease, and allergic reactions were negative, and an ultrasound was unremarkable. The subject also indicated that he had not received vaccination in the recent past. This morning, we posted the mean ALT values for subjects who participated in the 3 MAD cohorts to the pemvidutide phase I 12-week slide deck on our corporate website. They demonstrate no aggregate changes in ALT across these cohorts, with repeat dosing showing no pattern in ALT elevations. Similar results were observed for AST and GGT, showing no pattern in these liver function tests as well. ALT abnormalities were not dose related and did not occur in patients who received the higher 2.4 mg dose. We wish to point out that an isolated 5-fold ALT elevation does not meet FDA's criterion or definition of drug-induced liver injury, commonly referred to Hy's Law, per its 2009 DILI guidance, which states that isolated episodes of 5-fold elevations have limited predictive value for future events and also recommends the discrete continuation of the drug be considered when 5-fold elevations persist for more than two weeks, a criterion this patient also did not meet as the 5-fold elevation was limited to just four days. I would like to also highlight that a subject who received placebo in the trial demonstrated a 3-fold elevation of ALT during the same treatment period. This demonstrates that ALT elevations of similar or greater magnitude are common events in clinical trials and often appear without explanation even when there is no exposure to active agent. We believe the type of leaner individual described above, who may be subject to near complete and rapid defatting of the liver or BMI dropping to a 25, which would be the normal range, is unlikely to participate in our upcoming obesity and NASH trials since these trials will enroll obese individuals with an average BMI approximating 34-35 and considerably higher liver fat content. This will make significant liver function abnormalities unlikely to occur as the development of pemvidutide unfolds. In summary, we do not believe that a singular rise in ALT, which also occurred in the placebo group, has predictive value for drug-induced liver injury in future development. Finally, note that we have updated the slide on ketone body productions, which were incorrectly converted from the central laboratory in Australia. The relative rise in ketone bodies from baseline with pemvidutide treatment, a measure of the effects of glucagon on liver fat metabolism, the ratio did not change, but the absolute values are now considerably lower and below the thresholds associated with diabetic ketoacidosis. I would now like to hand the call over to Dr. Stephen Harrison to provide his thoughts on the one subject with ALT elevation. Following his discussion, the operator will open the lines for questions from both myself and Dr. Harrison. Stephen? Yeah. Thanks, Scott, for going through that. It's also great to be a part of the call today and try to lend some perspective to this particular situation. I spend my life in drug development for NASH, and it's interesting, this intrinsic association between rapid and complete defatting of the liver by MRI-PDFF, and there we're measuring liver triglycerides specifically, and a rise in an ALT is an interesting association. The link between these findings, in addition to being interesting, certainly warrant further investigation and understanding. We're seeing this in other drugs that move liver fat quickly and efficiently. It's not the first time. Elevated ALT, it's important to understand, may indicate liver cell injury or hepatocellular injury. However, this increase in liver chemistry test does not by itself represent a DILI event, a drug-induced liver injury event. You need hepatocellular injury plus loss of function. Hepatocellular injury, as measured by ALT, is not an assessment of functionality of the liver. That would be things like total bilirubin. If you have elevated liver chemistry test and elevated total bilirubin, that's when we get into what we call Hy's Law, where you have elevations in both of those, putting you in the upper right quadrant, if you will. That's consistent with drug-induced liver injury. Looking closely at this particular subject, there is no Hy's Law. There is what we call Temple's Corollary, which has been seen by other drugs, parenthetically, in development for NASH. Those have been disclosed. You can see these transient elevations in liver chemistry test. The thing that's interesting about this case is there's no other findings. There's no association with higher dosing. If you look at the cohort of patients at 2.4, we do not see this. We don't see it in any others at 1.8, and there's no PK data that reflected an increase in drug exposure that could explain this. When you look at DILI, more specifically, most people exposed to a new drug show no injury. We call those tolerators. Some people show transient injury but adapt, and we call those adapters, and a few patients fail to adapt and show serious toxicity. We call those susceptibles. The difference between adapters and susceptibles is just that. You have a bump in serum in liver chemistry tests with adapters, but no rise in cholestatic profiles, no rise in loss of function test, again, pointing to total bilirubin, which is the example we illustrated for Hy's Law. You see these transient climbs and falls that are linked to drug exposure, that are linked to dosing, and that's exactly what we saw in this case. The liver chemistry test rose and then fell as outlined by Scott. Finally, I would just say, going from 55- 320, that's something we live with quite often. I mean, patients with NASH can present with liver chemistry test de novo at 320. This rise, while 5-fold, is not something that is unusual for what we see in drug development. Quite frankly, values of 300, we see at baseline in NASH patients, not very often, but we do see it. Scott, that's my initial thoughts on this case. Maybe we'll turn it back to you or open it up to questions. Thank you, Stephen. Operator, please open up the line for the Q&A. Thank you. To ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Again, if you would like to ask a question, press the star, then the one key on your touch-tone telephone. Our first question comes from Seamus Fernandez with Guggenheim. Your line is open. Oh, great. Thanks, guys, for all of the incremental detail. I think this provides quite a bit of clarity relative to the liver safety that we're seeing in the broader population. Really appreciate that. two questions for Dr. Harrison. Dr. Harrison, there was a sort of circulating thesis that the ketone elevation could be associated and drive liver injury. I'm sure you've seen scenarios that perhaps could look like that, but what do you see in the literature as it relates to ketone elevation? Obviously the data look quite different today in the wake of the corrected information. What do you see in this data in particular as it relates to the ketones and perhaps any association to diabetic ketoacidosis? The second question is, in phase I trials, I'm sure you've done a number. When you look at the tolerability profile of this particular product as it relates to nausea and other programs and reporting, including those that have reported out for semaglutide or perhaps even other products like tirzepatide, other incretins in category, how does the profile of the tolerability of this product strike you given your overall experience? Thanks so much. Yeah, I think those are great questions. I think we can put the first one to bed pretty quickly. There was a corrected analysis on the ketone elevations seen in the trial. I don't think there is a link at all here between what we see with ketones and liver chemistry test elevation in this one particular patient. Speaking more broadly on ketoacidosis, particularly diabetic ketoacidosis, that would be a concern and something that we would want to follow if that were the case. In all the drugs I've been involved with developing, that's not something that has been an issue. I would not expect that to be an issue with this compound either. Speaking of the tolerability profile, most patients that had an adverse event had mild symptomatology, mainly mild nausea. You would ask about how that relates to other drugs in this class, other similar drugs. Quite frankly, you can broaden that out to any injectable or any medication that works through similar type pathways. Nausea is going to be present. The good news story here is we don't see that leading towards a lot of emesis or vomiting or belly pain or diarrhea or things that would elevate my concern and would make me want to think, Okay, if we're going to have that type of symptomatology, we've really got to knock it out of the ballpark on efficacy, right? The old analogy of, is the juice worth the squeeze? Is the view worth the climb? I think here, the nice thing that we've seen, albeit in a small population of obese healthies, is that this is a well-tolerated therapy so far, specifically relative to other drugs in development. Just highlighting again, what tends to drive patients away from trials, from staying in a study, from taking therapies is not necessarily mild nausea. It's the emesis, it's the diarrhea, it's the belly pain. I think so far, early days, but it appears that this is much better tolerated than that. Great. Thank you. Thank you. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Hey, thanks. This is Swapnil on for Yas. Thanks for taking our questions, a couple of them. First is, you said the NASH patients typically develop these de novo ALT elevations. Can you provide some context of how often do you see this, how high these levels go, and what is the persistence of the ALT elevations in these patients? The second part is, you also said in your prepared remarks that placebo patients showed ALT elevations as well. Was that elevation only in ALT, or did you look at any other liver enzymes that were also elevated in the placebo patients? Yeah. Hey, thanks for that. Please tell Yas I said hello. I'll take the first one, and maybe Scott, you can elucidate a little bit more on the placebo patient, if you're okay with that. With NASH patients, as you know, this is a disease that generally presents with hepatocellular elevation. Elevations in liver chemistry test, ALT and AST. Generally in NASH, it's more of an ALT-predominant disease. Prototypically, if you look at large studies that enroll NASH patients, looking at phase III trials, whether it's REGENERATE, RESOLVE-IT, MAESTRO-NAFLD-1, MAESTRO-NASH, any of these others, what you see is a mean ALT in the 60-ish range. Mean AST is in the 45-ish range, maybe pushing a little bit closer to 50. It's generally ALT predominant. Having said that's mean, right? We can see patients present with ALTs in the hundreds range, in the 100, 200, even 300 range. I don't think I've ever seen a NASH patient that had pure NASH have an ALT of 400 or higher coming in through the door. I think I might have had a couple cases of elevations that high and higher, but generally, that's been linked to concomitant disease, something else going on, maybe NASH and autoimmune hepatitis or something. Classically, when we look at NASH, ALTs will be in kind of the double-digit numbers. There is that bell-shaped curve where we will see people shift to the right and have elevations in the hundreds range, even up to 300 or so. It doesn't happen very often, but it can. Scott, do you want to maybe comment on the placebo? Sure. Thanks for the question. In the placebo patient, as I mentioned, that placebo patient had a threefold elevation of ALT without explanation. His GGT actually rose to 70, about the same magnitude of this patient, and his AST was elevated as well. The same pattern. We have two subjects here. One exposed to drug, one didn't, who had similar patterns of liver enzyme abnormalities occurring. One clearly spontaneously and the other for reasons that we don't know. spontaneously as well. We just don't know. Got it. Thank you. Then one follow-up question, I guess, for Dr. Harrison is how well is the correlation between the weight loss and liver fat reductions understood, and what are your expectations for the upcoming NASH RELIEF study? Is there any control data available out there that tells us the chances of obese patients losing weight is higher as compared to less obese patients who have a lower BMI? Yeah. I don't think we have all those answers. Your questions are certainly couched in the knowledge of what's out there already. I can just speak to that broadly. We know that at 3% body weight loss, we begin to improve liver fat. I presented a pyramid that gets used often that speaks to a foundationally 3% body weight, we begin to lose steatosis, and then you bump that to 5%, 7%. That's where we begin to see improvement in inflammatory cells, inflammation, ballooning degeneration, NASH resolution. Then at 10% body weight is where we begin to see fibrosis improvement. Holistically, everything tends to get better at that point. We can point to bariatric surgery data that's been published even recently, alluding to the fact that patients followed over a two, three, four, five-year period of time with weight loss, incrementally having drops in BMI show increasing resolution of NASH. I'll just take it one step further. Looking back on our elafibranor data, this data hasn't been published, but it's been presented. As you see improvements in the NAFLD activity score, there is an association with improvement in fibrosis. Again, there's additional data that's been published by the NASH CRN and David Kleiner and Elizabeth Brunt showing exactly that. That as you go from NASH to NAFLD, you see incremental increases in the percentage of patients who have none to mild fibrosis relative to those with advanced disease. In summary, it appears that the more weight loss you have, the better impact that will have on liver disease relative to inflammation and ballooning, and ultimately what that does in a positive way to fibrosis. Got it. Thanks for taking the questions. Thank you. Our next question comes from Kelechi Chikere with Jefferies. Your line is open. Good morning, thank you for the additional details here. I guess, Dr. Harrison, can you opine on whether you would be concerned or hesitant with using this particular drug in later-stage NASH patients or in patients with liver injury or function signals or signals of detriment there? Yeah. Generally speaking, we don't jump right into cirrhotic patients in drug development for NASH. We want to kind of incrementally work our way through the severity of disease. Certainly before we go study this in advanced patients, we want to have hepatic impairment data. We want to look closely at exposure of drug as you advance from a Child-Pugh A to a B to a C patient. I'm not adverse to studying this drug in that population, but I think we need to do it very scientifically and very rationally. We start first, as is the plan with Altimmune, to study this in a patient population that has NAFLD with or without NASH, show what we've got there, show what the impact is, and then we step that forward to a paired liver biopsy study like is traditional in. probably an F2-3 population, and then look at what opportunities might exist. I do think more broadly that if you look at holistically drug development, foundationally, yes, we are beholden to a histopathologic endpoint of NASH resolution without worsening of fibrosis or fibrosis improvement without worsening of NASH. I feel like we need to step back and look at the broader picture. These patients that we see in clinic are obese, diabetic, metabolic syndrome. In fact, I recently published data in Journal of Hepatology on a very large prevalent study that I conducted while I was in the Army at Brooke Army Medical Center, really highlighting the fact that if you take metabolic syndrome and you look at diabetics, obese, and hypertensive, around 75% of those guys and gals have fatty liver, but up to about 40%-46% have NASH when we do liver biopsies. It's not just treating the NASH is what I'm trying to say. We need to be holistic in our management and approach to treating these patients. Where we're able to impact extrahepatically, if I could use that phrase, that is going to be important in drug development for this disease and for this field. Getting at weight loss, getting at glycemic control, getting at atherogenic lipids. The more we're able to do that, in addition to what we're getting on liver biopsy or non-invasive assessment of liver injury, the better off we're going to be at the end of the day. I think that's what's setting us up nicely here, is we're hitting at some of the foundational principles of NASH, not just modulating a mechanism that could lead to downregulation of inflammatory cascades or turning off of stellate cells. We're actually speaking at a broader level at hitting some of these fundamental principles that derive the pathogenesis of this disease. Hopefully that answered your question. It does. That's very helpful. I guess just one follow-up question. I know many investors were hoping, at least going into the event, that, for the most part, AEs typically occur in the first few weeks of treatment. In the latter six weeks of treatment, you shouldn't see a real increase there. Can you speculate as to why, at least in this small study, in the latter six weeks, we're seeing almost a 2 to 3-fold increase in some GI issues? Any color there would be really helpful. Well, I would read that with caution in the sense that it's a small study. Okay. It's a small sample size, and it's in a relatively healthy population. It's hard to speculate what that might be. I think there's a lot of noise looking at trying to parse out the timing of those adverse events. It's just early days. I would say we need to get more data relative to the timing of those. Got it. Thank you. Thank you. Our next question comes from Liisa Bayko with Evercore ISI. Your line is open. Hi, this is Liisa. Dr. Harrison, thanks for taking the question and the Altimmune team as well for putting this together. I just wanted to first ask about sort of efficacy and then turn to some of the tolerability kind of differentiating factors. Here we have about a little over 10% weight loss in 12 weeks. If we placebo adjust, it's 8.7% in 12 weeks. This is in a non-diabetic, young, kind of slightly obese population, I would say. In the context of the population we're studying, how do you think of that degree of weight loss, and how do you think it will evolve as we get into a population that's older, with potentially higher BMI and also including diabetics? How should we think of this degree of weight loss at this point in time, vis-a-vis what the kind of status will look like as we evolve into a more normal population for phase II? Liisa, is that a question directly for me, Stephen, or more for the company and Scott? I guess I'd start with you and then if they want to elaborate at all, but I'd love your insights, given you do a lot of studies in this area. Yeah. I think that's a great question because when we study obese healthies or healthy volunteers in these early phase trials, we're really getting after how well is the drug tolerated, what's our PK profiles looking like. Efficacy is not a main goal of these early phase studies. We get into that in phase II-A, where we're taking some different doses, and maybe in NASH, we're looking at non-invasive tests like PDFF or PRO-C3 or ELF or ALT or FibroScan or MRE, other modalities. It's interesting here that in this MAD study, that there is some evidence that we're hitting weight loss that puts us into a category that should have a histopathologic benefit at minimum, and potentially much more impactful if we look holistically. How does that translate if we move from an obese healthy population into a diseased population? Clinically, I can tell you that patients that present for studies are generally highly motivated. If you think of an iceberg and you think that iceberg is like a NAFLD population, that part above the waterline would be the NASH patients. We're only enrolling the tip of that iceberg. These are NASH patients that have been identified as being interested in studies, being willing to go through the whole protocol, the regimen of coming into clinic visits. I'll say, despite COVID and the two waves of COVID that we've had, we've been able to generate these clinical trial data sets, albeit maybe slightly delayed, but it's still happening. What's happening is these people are even more motivated. I think when we take a population that is enriched for a metabolic milieu that drives NASH, this should translate very readily into that population. The results we're seeing here, if you look at the 1.8 mg dose and what happened, if you just follow the trend lines out of all those patients that received the dose, you see by day 85, we're actually still having positive impacts on weight loss. I think that's going to translate very nicely into the next phase trial where we really get into NAFLD patients and NASH patients. I'm positive about what we're seeing. Maybe I'll ask Scott or the Altimmune team if they have additional thoughts. Hey, Stephen. Thank you, and thanks for the question, Liisa. It's been observed by a number of people that the weight loss that you see in phase I studies in this group of drugs or in this indication typically predicts what you're going to see in phase II or III, and we can follow up on that with actual reference and context if you wish. In terms of the age of the subjects, since this was a younger population, more university-based. I'm sure you're aware of the information we posted on our website. Beyond that, if you look at other studies, such as the recent publication of the AWARD-11 study in dulaglutide, still relevant, still a GLP, or the Lingvay analysis of the STEP trials that was presented recently at the ADA meetings. There's really no effect of age on weight loss in subsequent development. In fact, if anything, there's more weight loss with increasing age. It's been said also, although we didn't see in our trial, that higher BMI actually predicts more weight loss proportionate, not less. Consequently, either this would convey exactly to the older, more obese subjects in phase II or III, or actually be amplified. Okay, great. Thank you. Then just turning to the tolerability profile, as we look at the rates of nausea, for kind of the early time for 12 weeks, it does look relatively high as we can compare across semaglutide, tirzepatide, and others. Can you comment on what's the right way to think about kind of nausea? A lot of it is mild. Is this kind of also what's seen across semaglutide, tirzepatide, and again, we're just at 12 weeks, and then how to consider that in the context of some of the other GI side effects. I'm just wondering if the kind of mild GI and good tolerability on GI positioning is really accurate. Do we need to, with what you're seeing, do you think the company does need to consider doing some dose titration or how to think about these early studies in the context of what we're seeing for some of the more advanced studies in the field? Thanks. Scott, you want to take that one first, and I can add on. Sure. Thanks again for the question, Liisa. You have pointed out that we're seeing adverse events in a lean, younger population. The likelihood is that the adverse events are going to drop as we go to heavier people merely based on the pharmacokinetics. I think that those adverse events are going to go down, and it's also been stated that diabetics that will comprise half of the NASH population and certainly a reasonable portion of the obesity population seem to report lower adverse events than non-diabetics. You have to be a little bit careful comparing a study in non-diabetics to diabetics, but all in all, based on the information I just provided to you, I believe that we will see lower rates of adverse events going forward. Before I hand this over to Stephen Harrison for his comments, I would also say that as a gastroenterologist hepatologist being involved in drug development for years, I've really come to appreciate the impact of patient-reported outcomes and how different the interpretation of nausea is across trials, especially when you have intensive monitoring, like weekly visits or even inpatient admission, when the subject is being asked a question often and repeatedly. It just pulls out more adverse events. For that reason, Liisa Bayko, typically adverse events are higher in phase I studies in any phase of development. We, as drug developers, know it, and consequently, we don't think that it means anything, and what we focused on repeatedly were the adverse events leading to discontinuation. Those have been high in other trials. For example, in the cotadutide trials, exceeded 20%. Even in the PIONEER study of oral RYBELSUS, PIONEER 5, 14% dropout rates for adverse events. We saw nothing. We're trying to pull out the meaningful data upon which to make decisions and portray the safety profile of our compound, and we think that's the most important attribute. I'll stop there, and I'll turn it over to Stephen for his comments. Yeah. Those are helpful, Scott. I think from my perspective, the things that I look at are, is the side effect profile leading to discontinuation of the drug. We haven't seen that yet, albeit 12-week study, but we didn't see discontinuations. When you look at the AE profile, five patients in the 1.8 milligram dose had mild nausea. You saw one in the low dose. There was one case of mild and one case of moderate vomiting, relative to the high dose, but that was in line with what we saw with pooled placebo as well. Again, mild nausea is relatively subjective. The real question is, are patients willing to continue the drug? Can that be managed? We see that when you look at this type of therapy across the board. This is kind of in line with what we would see with FGF21s, with FGF19, and with the GLP-1 receptor agonist as well. The additional comment here is maybe some of the positive, what we don't see. We're not seeing diarrhea in this population. We're not seeing a lot of abdominal pain here as well. I think those are two things that maybe are overlooked in this AE profile that probably deserve a little bit of attention. Again, I would say it's small numbers, early days, but that's positive for me as I look at the AE profile. Mild nausea, I got it. That's kind of what we see with many of these drugs to treat NASH. Does it lead to discontinuation? The answer is no. Are we seeing other GI issues, abdominal pain, diarrhea? The answer there is no. I think that bodes well for further development of this drug in this field. Just a couple quick follow-up questions, and then I'll step aside. Do these tolerability issues change as you go from a kind of younger, non-diabetic, kind of, I would say on the low side of obese, low BMI-ish, group to kind of that more obese diabetic, high BMI population? Would we expect any changes, or are those kind of consistent across? Also the timing of the discontinuations for some of these other studies. Are those early events, like in the first 12 weeks, would we expect to see that, or are discontinuations later events? Maybe you can just talk about the timing. Thank you. Well, it's hard to talk about timing for this particular compound. When you look more broadly, Liisa, it's really a mixed bag. In my patients that I see, I don't know from visit to visit if they're going to have a complaint of nausea. It's not like we sit back and say, "Okay, this pool of patients are coming in for their week 24 visit. We anticipate that a third of them are going to have events this visit because that's just the way that this is kind of happening." It's really hit or miss. Patients may present right off the bat with it. It may not happen until week six or week 12, or it may not happen until the very end. It's kind of all over the map, just to be frank. Okay. What about just, do these tolerability events, do you think, change as you get into a different population, or would you expect that? No. I haven't seen that. Okay. Whether it's severity of liver disease, so a NAFLD patient versus a NASH 2, 3, versus a Child-Pugh A, I haven't seen differences in tolerability. If it's a female versus a male, I haven't seen differences. If it's a low BMI versus a high BMI, a diabetic versus a non-diabetic. At least to my knowledge, I haven't seen any data that's broken out tolerability profiles relative to specific subsets of populations. I think that's a good question, something that deserves a look at, but I haven't seen that to my knowledge. Thanks. Thank you. Our next question comes from Mayank Mamtani with B. Riley Securities. Your line is open. Good morning. Thanks for taking our questions, and also appreciate the level of detail here on this one subject and very valuable perspective here from Dr. Harrison. It does seem like we are missing the big picture here on this being theoretically best in class. I have very quick three clarifying questions for Dr. Harrison and maybe just one follow-up for Scott. As you look at your data, geeks like you, Dr. Harrison, digging into the semaglutide publication. There were one-off cases there also, adverse as pancreatitis and gallbladder. I'm just curious, in your real-world experience, these one-offs, have you seen specifically the semaglutide, be it around ALT or even worse liver function issues? I'm not sure I fully understand your question. In relation to semaglutide and elevations of liver chemistry tests relative to what? Just what have you seen with semaglutide in clinical trials? Again, not many patients in terms of, be it issues around gallbladder or even just other issues that are a function of how events could happen from not just LFT elevations. Yeah. Thank you for that. In general, those have been mainly gastrointestinal adverse events that we've seen. Nausea, vomiting, abdominal pain, diarrhea. To my knowledge, in my own personal experience, I haven't experienced issues relative to gallbladder issues, gallstones, cholecystitis, choledocholithiasis, choledochocystitis. I haven't seen pancreatitis. Quite frankly, I'm more concerned about that in an FXR population, at least the gallstone issue, than I am in this particular mechanism of action. Did that answer your question? Yeah. Maybe along the same lines, my follow-up was, how convinced are you that, we recognize that the agency is obviously, it's a revolving door with them a little bit in NASH, so how convinced are you that they would require dose titration, just from an FDA standpoint, in making sure that a lowest therapeutically effective dose has been already identified from your early work? Yeah. It's early days to say if dose titration is needed. I might have Scott speak more specifically on that. The results that we're seeing at the 1.8 milligram relative to tolerability would speak, in my opinion, that this could be used right off the bat without dose titration. Having said that, would we derive additional benefit if we looked at dose titration? Possibly. Perhaps. That's, again, something that could be vetted out in an early-phase trial, getting at what is the optimal dose. It's probably looking at this early multi-ascending dose data. It doesn't appear there's a lot of difference between 1.8 and 2.4 relative to weight loss. There obviously are more adverse events at the higher dose, which might speak to some dose titration, but it also presents the opportunity to not necessarily have to do dose titration. Maybe we'll have Scott chime in and opine more on that. Sure. Thanks, Stephen, and thanks for your question, Mayank. I agree with Stephen's comments. I think the tolerability profile at the 1.2 and 1.8 doses do not lead us to believe the dose titration would be needed. One of the questions we have, and we still haven't resolved it, is whether there is an opportunity based on the small numbers to see greater efficacy at the 2.4 milligram dose. Now, we know it's not as well tolerated, might it be possible to do a very rapid dose titration in order to get there and then at least observe whether the 2.4 dose is working to give greater weight loss. That's something we're considering right now. To answer your question directly, clearly, at our most efficacious dose, which we think was well tolerated with dose titration, we don't anticipate the dose titration, which will be needed, which will be a great benefit going forward because as these weight loss drugs move into primary care, into the office of primary care doctors who have 10 minutes in front of a patient, dose titration will not be as well accepted as it is in current use when endocrinologists and specialists are prescribing it. Great. Thank you both. Just my final clarifying question. In the ongoing phase I NAFL study population, it looks like you're going, from an age standpoint, as low as 18 years, and you're going on BMI as low as 28. Just maybe comment on, based on all this discussion, is there anything you're thinking about at baseline, age, BMI, PDFF, ALT, ethnicity, how you may want to enroll your phase I NAFL population. Also this concept of liver versus visceral fat. At what point, do you think six weeks could be a time point when you can also look at a PDFF readout? I'm just curious about any learnings from what you know today that could be applied to the phase I NAFL study. Stephen, would you like me to answer that question for Mayank? Okay. Sure. Maybe I'll chime in. Yeah. Right. We are allowing down to a BMI of 28, which we think is safe. Recognize that the other requirement for this study is the patients come in with an MRI of at least 10%. Very often, these patients come in with MRIs, liver fat content exceeding 20%. We think if there is a mechanism, and we try to stay away from that because we just don't have the information with small numbers, if it is fatty liver, patients starting with a liver fat content, remembering this patient had a normal liver fat content of 3.8%, so it was quite easy to near completely defat the liver. We just don't think that's going to happen. I do want to be cautious about the mechanism here and emphasize the fact that outside of any potential mechanism, as Stephen well-described, this isolated ALT, which appeared in drug development, pretty much matched by a placebo, we just don't think is consequential. Getting to the second part of your question, yes, we are obtaining MRI-PDFFs at baseline, week 12, but also at week six What that will do, it'll allow us to continue to establish the slope of the line for all of these changes, which we think are very important. Stephen, did you have any other comments? No, I was just going to make the comment about the additional week 6 MRI. Again, to me, that is going to be a significant add-on. To allow us to generate the speed at which liver fat content is being reduced relative to this compound and to the ability where we're able to measure some potential other toxic lipid species. That may be helpful as well, because we know that MRI-PDFF really measures inert liver triglyceride content. When we look at drugs that impact liver fat content relative to histopathology, it's really not the liver triglyceride content reduction that's leading to the histopathologic change. It's a surrogate for other toxic lipid species that are also improving, but we just don't have a great mechanism to really get after assessing that. Having said that, you look at MRI-PDFF twofold. One, what is it doing relative to histopathology? Can we infer changes in MRI-PDFF on liver histopathology? The other one is speaking to what I mentioned at the very top end of my comments, and that is that the link between liver fat content reduction and these transient elevations in liver chemistry tests deserve further attention than what we're seeing. As we develop drugs that really get after improving toxic lipid species, reducing lipotoxicity, understanding that relationship of architectural remodeling and what's happening to hepatocytes is going to become very important. I look at this as a very positive initial result, and I'm anxious to see what happens in the next phase of drug development for this compound. Thank you so much for taking our questions. Our next question comes from Jonathan Wolleben with JMP Securities. Your line is open. Thanks for setting this up and taking the questions. One for Dr. Harrison, a follow-up. You mentioned in your remarks that this ALT elevation would fall into the range of Temple's Corollary. Can you discuss a little bit about what that is, its implications? You mentioned other NASH drugs have had these findings as well. Can you discuss which ones of those NASH drugs have hit this as well? Yeah, I'll just be brief on that. I don't want to speak to other compounds. I can just tell you that they're out there. When we look at this whole notion of drug development, there's been a tremendous amount of effort put in by people like Hy Zimmerman and Bob Temple and others. In fact, as Scott mentioned, this seminal publication in 2009 really speaking to what happens to these patients over time if you were to follow them. There is this graph that was developed by the FDA and Bob Temple really looking at, on the vertical axis, peaks in total bilirubin, and on the horizontal axis, peaks in ALT. Really, there are four different categories. There's normal range, meaning ALT and total bilirubin are both normal. That's bottom left. Bottom right is elevations in ALT, but normal bilirubin elevations. That's Temple's corollary. Hy's Law, which is upper right, would be elevations in bilirubin and ALT. Those are really the three we focus on. The upper left would be cholestatic, mainly Gilbert's or indirect bilirubin elevations that really don't mean a whole lot. We focus on where is that DILI group. That's people that are presenting with hepatocellular injury plus loss of function, which would be most classically a rise in bilirubin. Temple's Corollary, which is what we would see in this particular case, is normal or no rise in bilirubin, but some pops in ALT, for instance. Again, that is not a DILI event. Maybe that's where I'll stop. That's the way I break that down. That's helpful. Just maybe one for Scott. You mentioned that the placebo patient had an elevation 3x upper limit of normal. Did any ALT-801 patients have 3x upper limit of normal elevation? If so, did you dose through those patients here? Yeah, only the one patient that we noted, Jonathan. The only other elevation of that magnitude occurred in the placebo. There's 1.5 times upper limit of normal on treatment, and that was the only elevation you saw? Exactly. The only elevation any more than threefold or higher elevated was the patient we described today, and then a patient in the placebo group, and no other cases, including no other cases at higher doses of pemvidutide. Perfect. Thank you. Thank you. I believe we don't have any other questions in the queue. I'm going to close the call. I want to thank Dr. Stephen Harrison for his remarks. I want to thank everyone for listening in today, and we look forward to continuing the conversation on pemvidutide in future calls. Once again, thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.