Study Result

Sep 28, 2021

Greetings and 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. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host for today's call, Will Brown, Chief Financial Officer at Altimmune. Will, you may begin. Thank you, operator, and good morning, everyone. Thank you for joining us. Members of the Altimmune team joining me on the call today are Vipin Garg, Chief Executive Officer Scott Harris, Chief Medical Officer and Scott Roberts, Chief Scientific Officer. Please note that we issued a press release and 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. Before we begin, I would like to remind everyone that remarks and 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-nineteen and its impact on our business operations, clinical trials and results of operations. For a discussion of some of the risk 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, Tuesday, 09/28/2021, The and 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 Doctor. Vipengard to begin today's call. Thank you, Will. Good morning, everyone, and thank you for joining us today as we review the positive Phase one twelve week clinical data for our GLP-oneglucagon dual receptor agonist on the development for obesity and NASH. These study results were announced in a press release and an accompanying slide deck this morning. To begin, we are excited to share the proposed non proprietary name for ALT-eight zero one, pemblidutide. Going forward, we will be referring to the compound by this name and hope to receive the official approval for the name pembidutide sometime next year. As you will see, we believe the Phase one clinical data we have collected is compelling with our best performing cohort of subjects achieving weight loss of greater than 10% in just twelve weeks. That is an average weight loss of nearly 20 pounds in this study. Furthermore, patients experienced primarily mild GI effects and there were no study discontinuations due to adverse events. These results obtained without the use of dose titration fuel our enthusiasm for the potential impact PEMV could have on the multibillion dollar obesity and NASH marketplace. Progress in our obesity and NASH programs is moving swiftly with this report of the Phase one study results, the recent FDA clearance of our IND for NASH and the anticipated filing of an IND in obesity later this year. As Scott Harris will discuss, we have robust development plans in place that we expect will allow this program to expeditiously move forward. We look forward with great anticipation to our Phase two obesity trial, which will study the effect of PEMB when dosed for up to one year. We saw no decrease or leveling off in weight loss during this twelve week study. And recall that in our animal experiments, loss only ceased once animals returned to their lean normal body weight. So far our animal models have been good predictor of PEMB's effect in humans and we hope to see that relationship maintained in our longer term studies. In non invasive and well tolerated therapy that elicits weight loss approaching bariatric surgery would change the paradigm for doctors and healthcare providers in the midst of a worldwide epidemic of obesity. I will now turn the call over to Doctor. Scott Harris, our Chief Medical Officer, who will review the twelve week Phase one clinical data. Scott? Thank you, Vipin, and good morning, everyone. First, let me share how thrilled I am that we were able to achieve double digit weight loss with good tolerability in the one point eight milligram dose arm of the Phase one trial without the use of dose titration. Not only was the mean weight loss greater than 10%, but we also saw the majority of subjects at the 1.8 achieved greater than 10% loss of body weight. Regarding safety and tolerability, there were no adverse events related study discontinuations and only mild or moderate events noted. The results we shared this morning are from our twelve week Phase one placebo controlled single and multiple ascending dose study of pembidutide. The study was conducted in Australia under a clinical trial application and enrolled healthy but overweight and obese volunteers. The study did not employ caloric restriction or other behavioral weight loss programs and importantly did not employ dose titration, a stepwise dosing mechanism that gradually increases the dose over months before reaching the intended therapeutic dose. Dose titration is typically used with drugs in the GLP-one class to ameliorate the incidence of severity of GI side effects. But we were able to achieve acceptable tolerability with PEMV in the study without using dose titration. The purpose of the SAD phase of the study was to find the appropriate dosages to carry forward to the MAD portion of the study and consisted of 36 subjects receiving single doses from zero point four milligrams to four point eight milligrams. We carried forward the findings of this stage to enroll three cohorts in the MAPD portion at doses of one point two, one point eight and two point four milligrams randomized four:one to drug or placebo. Subjects received one weekly subcutaneous doses for twelve weeks with subjects staying in the unit for the first and last week of the trial. The primary objectives of this Phase I study were safety and tolerability, pharmacokinetics and weight loss. We have also included in this presentation the data on blood pressure, heart rate, glucose control, including hemoglobin A1c levels, HOMA IR, a measure of insulin resistance and lipids. Additionally, we have provided data on ketone bodies, a measure of glucagon engagement. We have provided the baseline demographics of the MAD cohorts for your information, noting the mean age, sex, race, body weight and BMI of the treatment groups. Importantly, we observed no correlation between the amount of weight loss and age or baseline BMI. Subjects receiving a one point eight milligram subcutaneous once weekly dose achieved an absolute mean weight loss of 10.3% in twelve weeks of treatment with pemvadutide. At a lower dose of one point two milligrams, subjects achieved an absolute mean weight loss of 4.9 at week twelve. And at the highest dose of two point four milligrams, we saw a weight loss of 9%. The amount of weight loss at the one point eight and two point four milligram doses are essentially the same given the sample size and overlapping confidence intervals. So higher doses than one point eight milligrams may not promote additional weight loss over twelve weeks. We have provided the individual weight loss curves on Slides eight and nine of the presentation, and we are excited to see a consistent rate of weight loss over the twelve weeks. At the one point eight milligram dose, an impressive fifty five percent of subjects achieved at least 10% weight loss at week twelve and one hundred percent of subjects achieved at least 5% weight loss. We also note the mean weight loss at twelve weeks is almost double the amount reported at six weeks, ten point three percent versus five point four percent. We are encouraged that this rate of weight loss could continue beyond twelve weeks. Importantly, pembidutide was well tolerated in the trial even in the absence of dose titration with no adverse events leading to discontinuations and predominantly mild adverse events that did not require treatment at the one point eight milligram dose. At the one point eight milligram dose, we saw very low instances of vomiting and constipation with no reports of diarrhea. These events resolved while dosing continued. The absence of diarrhea is important as diarrhea has been cited as one of the most frequent causes of study discontinuation. While the weight loss was similar at the two point four milligram dose, we saw an increase in the incidence and severity of GI adverse events. And therefore, we see one point eight milligrams as the foundation for further dose evaluations in our upcoming studies based on the balance of weight loss and tolerability. It is especially encouraging that we experienced no dropouts or withdrawals during the twelve week trial for any reason at the one point eight dose our best performing dose. Subjective patient reported outcomes and reported variability across studies in different phases of development are notoriously difficult to compare. And we believe that the most telling indicator acceptance of a medical intervention is the dropout rate. While patients are rapidly losing this weight, in the case of our phase one trial nearly 20 pounds in only twelve weeks, they become highly motivated to maintain treatment and could even assume lifestyle changes that promote further weight loss. Favorable trends were also observed in secondary measures, including a 28% decrease in total on LDL cholesterol and a 38 decrease in triglycerides. Coincident with these changes, we observed an increase in ketone bodies supportive of glucagon's effect on fat metabolism. It should be stressed that these changes occurred in only twelve weeks. Glucose homeostasis as assessed by fasting glucose and hemoglobin A1c was maintained. A trend towards a reduction in HOMA IR, an accepted measure of insulin resistance was also noted. Systolic and diastolic blood pressures also decreased despite the absence of significant increases in heart rate. Regarding our near term development plans for PEMVY, we are pleased to have received clearance of our U. S. IND for NASH and are in the process of initiating a twelve week Phase Ib study of subjects with nonalcoholic liver disease or NAFLD in The United States. This study will expand the enrollment criteria used in the Phase one study in Australia to include diabetic and older subjects and should commence in the near future. The primary readout from this study will be reduction in liver fat by MRI PDFF. We have also initiated a drug drug interaction trial to look for any interactions that could arise between PEMV and drugs that could be affected by changes in gastric emptying. Drug drug interaction studies have been performed routinely with GLP-one agonists and have not typically shown such interactions. Finally, we are planning to initiate a trial in type two diabetes in the fourth quarter of this year to study the effects of PEMB on glucose management in this population. We anticipate the top line data from the NAFLD drug interaction and diabetes trials will occur in the first half of next year. We anticipate that these trials will allow us to begin two Phase two studies, one in obesity and one in NASH. We plan to file the obesity IND shortly now that the pemvadutide IND for NASH has been accepted. The Phase II obesity trial will dose subjects for up to one year with a planned twenty four week interim analysis occurring late next year. The NASH trial will be a fifty two week biopsy driven Phase II trial, which we expect to initiate in the first half of twenty twenty two. We anticipate that trial to read out in 2023. We are also considering the possibility of an extension study to our soon to commence NAFLD study that would allow more extended administration and an earlier look at twenty four week weight loss. Will now turn it back over to Vipin for his closing remarks. Vipin? Thank you for that overview, Scott. Rapid double digit weight loss in twelve weeks, no adverse events related dropouts and the lack of dose titration are compelling potential advantages of pembidutide. And we have an exciting opportunity to carry forward a potentially highly differentiated therapeutic agent in the metabolic space. We're especially pleased to have the opportunity to share these data with you today and we look forward to additional data readouts and to advancing panbutanide in a comprehensive clinical development program in NASH and obesity. Operator, that concludes my formal remarks this morning. Could you please instruct the audience on the Q and A procedure? Our first question comes from Samus Fernandez with Guggenheim. Great. Thanks for the question. So maybe just to first off, congratulations on double digit weight loss. I think this is something that clearly we haven't seen with any of the other dual incretins so far and certainly not at twelve weeks. So congratulations on achieving those metrics. Maybe just to kind of get the one controversy that's out there is this single patient with ALT elevation. Can you guys talk about the characteristics of this patient? It says in the press release that the patient was paused on treatment and that's also included in your slide deck. So just wanted to get a little bit more color on the patient. Can you help us understand the magnitude of the ALT elevation? When the patient or was the patient reintroduced to treatment, consistent with the comment that it was paused? And it sounds like there were no other ALT elevations on any of the other doses based on the press release, just wanted to confirm that. So just wanted to get a better sense of the liver safety dynamics across the overall trial. And then as a follow-up to that, the NAFLD study, were there any restrictions or any comments from the agency as you move forward in the NAFLD study? Any elevated ALT monitoring or anything like that, that would suggest a higher level of monitoring for that. This seems to be a bit overdone from my perspective, but I just wanted to kind of get this one tackled. Thanks. Yes. Good morning, Seamus, and thank you for the question. Scott Harris, I know you're ready to answer that question, so I'll turn it over to you. Sorry, Vipin. Yes, thank you Seamus for that question. First of all, in NAFLD studies and NASH studies, there's a very rigorous drug induced liver injury program in all studies. That applies to any sponsors and we just simply have adopted that and there were no comments in the IND about ALT elevations. I will tell you that there were no trends in ALT elevations in an aggregate level in the study at any dose level. So that this was an isolated case of one hundred, subjects. And we simply will simply continue to observe it and monitor it going forward. But in aggregate, there was no dose trend. It occurred at the one point eight milligram dose. It did not occur despite going to the two point four milligram dose and there were no trends that would be observed in ALTs in any of the dose groups. And can you just confirm that the patient was reintroduced to treatment so that the pause is consistent with reintroducing the patient to treatment and that there were no ALT elevations after that? Or was the pause a pause in the patient and then the patient was simply followed to the end of the study? The event occurred at the end of dosing at twelve weeks. When the dose drug was stopped, the ALT returned immediately to normal? There were no other drug related information on that specifically. No excess use of NSAIDs, no binge drinking event that occurred in that context. And do we understand do we know what the magnitude of weight loss was for that individual patient? Was this one of the patients that had uniquely robust weight loss? There were no really identifying features that the patient that we would point out to. The subject lost a robust amount of weight. I don't have the number immediately in front of me, but it was probably average of what the other subjects lost. Okay, great. And then just as a final question. In terms of the next steps for the program, when do you guys anticipate initiating the various studies? And how are you thinking about the initiation of a biopsy driven NASH study? Are you anticipating sequencing that after the initiation of the NAFLD study and having that complete? And then but initiating the obesity study. Can you just give us a little bit of a sense of the timelines and how those might lay out for the individual catalysts? Thanks. Sure. As we've announced, we'll initiate the obesity study around the first quarter of next year. And, we are in the process of launching the twelve week NAFLD study. And, we do have the option of performing an interim analysis at week six in order to make the determination of any change in doses for the NASH study that would commence right after that. The anticipated sequence would be the obesity study starting in the first quarter, followed by the NASH study probably starting sometime in the first half, maybe the second quarter, but after the obesity trial. Perfect. Thanks guys. Our next question comes from Yasmeen Rahimi with Piper Sandler. Good morning team and thank you for taking my questions and congratulations on the outstanding data. Team, I'm sorry to rehash the one ALT observation made, but I really need your help to provide a little bit more detail to the extent you can. So let's go back. First question is can you comment on how high the ALT elevations were observed? Second question, did you see any other liver enzymes elevations of bilirubin to go up in this population? Third question, is there any underlying liver disease in this population in this patient? So just please take the time to provide a little bit more color on this question. It is absolutely critical to many of the people who are listening to this call. Right. So Yasmin, there were no other, associated changes of drug induced liver injury such as elevated bilirubin or INR. It was essentially an isolated ALT elevation with a very mild increase in AST that you would expect for any transaminase elevations. The magnitude of the elevation was fivefold at its peak and it rapidly came down afterwards and it resolved essentially within two weeks. There were also no real underlying causes of liver disease in the subject. And at what point during the course of the twelve weeks did this occur? Was this at early point of when they were introduced to ALT-eight zero one or towards the middle of the treatment? It occurred towards the end of dosing, Yasmin. And based on that, we would have reintroduced the drug, but we did you know, it was toward the end of the dosing period and we just decided to observe the patient and follow-up. Thank you so much for that really detailed details. And then I have a question on, the nausea that was reported. So in the 1.8 group, it was commented that that fifty five percent of the patients saw mild nausea. So if you could just comment on when did that occur? How transient was it? I know at week six, it was reported to be at about 22. So that would be really helpful. Right. Well, was transient in many patients and untreated. And as we reported, you know, at the twelve week readout, we saw the incidences that we reported compared to the six weeks. And I just wanted to go back to the questions that are coming in again to deliver and Zen. You noted that there was no increase in GGT. Is that correct? That is correct. It might be worthwhile providing more color on nausea and our sort of take on it, with regards to this particular setting that we are in with obesity and NASH. Yes. So, it has to be stressed, Yasmin, that these are mild events of really no consequence that could simply be reported because they were elicited in Phase one type setting. These are not events that would in any way, influence the satisfaction or the ability of the subject to stay in the trial. They just don't drive discontinuations. And we expect them to decrease over the course of development as we get into outpatient trials reminding you that this was an inpatient based trial. So the setting is very different. It's very difficult to compare patient reported outcomes like nausea across treatment across studies. There's really no standard for capturing them. And there's a lot of differences in reporting and the like. The one thing that's consistent that can be looked at for straight comparisons of the discontinuation rates, We have discontinuance rates in the PIONEER study of Rybelsus of fourteen percent and discontinuation rates as high as twenty three percent in other studies of GLP-one agonists. And even those that achieve or approach, they don't achieve this level of weight loss. The magnitude of the events is much higher. So consequently, to achieve this level of weight loss with this safety and tolerability profile with no discontinuations, especially the balance of the two is absolutely outstanding and remarkable. And we think this predicts a really excellent effect going forward. Team, those data is outstanding. Thank you. I'll jump back into the queue and let my fellow colleagues ask questions. The next question comes from Kaleishi Chikli with Jefferies. Yes. Thank you. And again, congratulations on the data here. Just two questions from me. First, I know you reported no correlation between weight loss and BMI. But wondering generally, do weight loss drugs see more or less weight loss with higher BMI or when the BMI is higher? And the reason why I'm asking you this is because the BMI you have here is notably lower than what is usually done in some of the other studies and Phase 2b studies for other drugs? And my second question is just related to the secondary measures, including LDL and triglyceride reduction. Is that more robust than what other drugs report at twelve weeks similar to the weight loss that you're seeing here? Thank you. Right. So you're right, Kilechi, and thanks for the question. The proportion the percent of weight loss actually increases with higher BMI. So consequently, we go into studies like obesity studies and NASH studies or NAFLD studies, when we were going to see a BMI of approaching thirty five, That trend, that observation would suggest the magnitude of the weight loss in these subjects would be even higher. I unfortunately don't have immediate data to share with you on the comparisons of the triglycerides and the LDL cholesterol and other studies at twelve weeks. I, believe that most of those studies report out over much longer periods of time. But these the magnitude of these changes are pretty impressive at twelve weeks. Got it. Thank you. Our next question comes from Lisa Bakel with Evercore ISI. Hi there. Thanks for taking the questions and congrats on the data. Can you just give us a little more background if we can just dig into the ALT a little bit more? Was this patient of higher BMI, different age, anything potentially baseline with their ALT? And also could you comment on oftentimes when you see improved liver health, you actually see a blip in ALT. Can you comment on that as well? Thanks. Regarding the second, seeing a blip of ALT with higher liver health, I'm not sure where to take that because I'm not sure I've seen that before. Clearly in studies of viral hepatitis, you might see a blip in ALT during treatment. But you know, I just really can't take that any further. Regarding this subject, I wouldn't say that there are any identifying features that would specifically highlight this patient per se. Okay. Yes, I was referring to the experience with hep C that's often referred to as the liver health improves actually. Sometimes you do see some temporal spikes in ALT. Yes. I think that's due to a different mechanism, which is in order to clear the virus, you need to basically do some liver enzyme elevation to show the virus is being cleared. I'm not really sure that will apply to the diseases that we're going to be treating. Understood. Okay. Thank you. Hey, Scott, it might be worth mentioning that this the BMI of this patient was on the low side. So perhaps that's a detail we should you can elaborate on. Yes. I didn't really want to get deeply into mechanisms here. But let me go there on this one. The patient, barely had an elevated BMI. And when, the patient was treated, the BMI dropped down to the 25 or less range. So it was a subject who, did not start very high, would not have been a candidate for obesity trials or for NASH trials. We actually think that this is a subject that would never really present himself or herself for treatment in the future either based on commercial use or in studies. Okay. Had speaking of that, you had a couple of patients who were kind of really on the borderline, like below 26, a couple of like, say, looks like 25 of BMI at screening. Like how did I mean, obviously, there's no correlation. And we know that we've done a bunch of work with KOLs and we looked at other studies. There isn't necessarily a correlation with BMI and degree of weight loss. But like why were those people allowed in this study actually? This seems like Yeah, they're not allowed it's a Phase I study. You generally include people of a somewhat different range than you would in a Phase II study. Remember that the higher BMI patients and the older people were difficult recruit in the COVID environment. And I should make a comment on that, that the study discontinuations were essentially due to the COVID environment, although we did not have any COVID cases in the study. Intense COVID restrictions in Victoria, Australia during the study, locked down the border and kind of kept a couple of people out or shifting jobs that went over the provincial border and the like. And just the whole environment of people leaving the houses, we didn't get we had the discontinuations were predominantly due to that. They weren't related to drug and it also changed the nature of the age of the patients coming and studied older people who may have been somewhat heavier did not come into the study. Okay. And then can you just talk about the importance of the speed of weight loss? Because it's pretty dramatic and I think that's really differentiating here. And then just to kind of follow-up to that, did you note any changes in lifestyle either diet or exercise even though it wasn't part of the regimen? Did you note any of that as the study progressed? Yes. We didn't have any measures, Lisa, for capturing changes in diet and exercise. I'm not aware of that being captured in any of the other studies. But we I want to agree with you and I want to state this very clearly, are beyond our enthusiasm for these results. These are spectacular weight loss results. And even with some adverse events that might be comparable to those in other studies, other studies have not achieved this profile of weight loss and really not very remarkable adverse events. I mean, you can count up adverse events, but they were mild and they did lead to study discontinuation. And those studies that approached this level of weight loss had much greater adverse events. And those that may have had lesser adverse events may have had much lower weight loss and they used dose titration. So the results, the combined results of this study of weight loss and the tolerability is unmatched by other drugs. The trends that you see that we provided are extremely strong. The rate of weight loss is very great. That's 20 pounds essentially in 12. And looking at the slopes of the curve, there was no evidence at all that this was going to stop in the near future. We plan to extend those observations as soon as possible. We'll have the obesity trial that will start next year. We're giving a lot of consideration to adding on an extension study to our NAFLD study to allow an observation out to say twenty four weeks and try to get earlier weight loss data. But I would stress that we haven't made that decision yet. We're looking at that. There would be a possibility of a readout that occurs much as six months earlier. But again, that decision has not yet been made. Okay. And then just final question for me and it kind of parlays with what you're saying. The patients on this study, are you continuing to follow them? Will they continue beyond twelve weeks? I know the study kind of wraps up at twelve weeks, but what are the next steps for this particular study? And will there be any follow-up? There's routinely a safety observation period, which in this case will be approximately a month. And we'll continue to observe people and we'll have weights on them then. And typically when the drug is stopped, the weights go up again, the weight loss diminishes as the drug is withdrawn. But typically there's a follow-up period of about a month after the drug is discontinued. Okay. Thanks. Our next question comes from Mike Mentummi with B. Riley Securities. Good morning. Congrats again on compelling weight loss data and thanks for taking our question. And we just did the lipid cross trial comparison. Don't see this level of decline that you show even with forty weeks of Lilly and Novo drug. I guess my question quickly on the study design feature that you had here on unblinding at six weeks with the one point two mg and one point eight mg and that not being there for the two point four mg dose. Obviously, a weight loss standpoint, that kind of put a higher bar on the two point four mg dose. But also from a safety standpoint, if subjects kind of know that they're receiving drug and they're benefiting from it, can you maybe comment on like the probability of them maybe also reporting these mild nausea events? And maybe this one individual younger on the younger side engaging in an activity like binge drinking or something that caused ALT elevation. Could you just comment on this phenomena that you had where you took an interim look at six weeks versus for the higher dose you didn't? We didn't have May I thanks for the question. And when we had promised the Street a readout at six weeks. And at the six week point, the third cohort was still ongoing. So we couldn't read out on that. So that's why that data was not included. As we announced to the street, we would provide an update on that additional cohort that was being dosed at the time of the six week interim analysis at twelve weeks. And that's what we've done. Regarding this subject, you know, it's impossible to note if there was drinking or anything else that was going on. And this is something that wasn't captured. But I want to stress that it was one subject out of 100. It resolved quickly upon stopping the drug, which is extremely important because it means we have a handle on it. There was no other evidence of liver injury such as bilirubin elevation. And, it was not dose related. So we saw no cases of the two point four milligram dose. I think we think it's an isolated case. We don't really have a handle on why it occurred. We think this patient is an outlier in terms of not only the liver abnormalities, but the likelihood of being included or profile of this type of patient be included in later trials with patients with higher BMI. Great. Thanks. And on the next Phase II study, could you just clarify the doses that you're thinking? You said 1.8 as a foundational dose. And we also noticed that, I think you had previously said twenty four week length for that study, but I think now you're saying that forty eight week. Can you just clarify sort of what you've learned from this update that has informed how you're thinking about your Phase II study obesity? And then I just have a quick liver fat question, the NAFLD side of things. Right. So thank you for the question, Mayank. And again, it will be a forty eight week study that will be with a twenty four week interim analysis. We thought about, doing only a twenty four week study. We think that would be acceptable to the agency to get ready for Phase three and to rationalize going into Phase three. We thought it would be more worthwhile to people if we extended it to forty eight weeks. But we will pose to the agency the question when we file the IND of whether we could take the twenty four week interim analysis and use that to file the IND, say six months earlier. And also to continue the trial as we get ready for the Phase three. So it's possible the two might be going on at the same time. But I want to stress that conversation hasn't taken place with the agency and their preference may be to see forty eight week data. Regarding the doses going forward, we're certainly going to take the one point two and the one point eight milligram dose going forward. We're trying to make a decision now about the two point four milligram dose and having made that, we'll make that shortly. Great. Thank you. And on the liver fat side, ketone body data looks very impressive. Could you maybe comment on, had some PDFF greater than ten percent, about twenty percent of this proportion of the patients in the study. Did you do a subset analysis on maybe how they did? Just trying to understand how the liver fat readout could look like from your NAFLD twelve week study early next year. Yes, we don't have the results. We did MR scanning, right, to look at body composition. We don't have those results yet. We could look at the liver fat. When we looked at those initially at the beginning of the trial, patients were not coming in with a sufficient amount of liver fat to do that analysis. So we'll have to go back and look to see if we can still do that MRI analysis of the liver fat. Great. Thanks again for taking my questions. Great. Our next question comes from John Walden with JMP Securities. Hey, thanks for taking the questions and my congratulations on the data as well. Just a couple short ones for me. How many centers were involved in the study? And then you mentioned the patient with the ALT elevation was had a lower BMI. Was the drug exposure level any higher in that patient? Yes. Thanks. It was only conducted at one center, John. And your second question had to do with I'm sorry, can you repeat that? The drug exposure in the patient with ALT elevation, if there was any higher than the average? No, it was about average. It was not unusual. Okay. And I was hoping you could comment a little bit on the characterization of mild to moderate nausea and the time course. I think there may be a difference of these are one patient reporting one instance early on versus a patient reporting it every week throughout the trial. So maybe any color on that front could be helpful. It was predominantly one off events, although it was a bit mixed, but there were many events that were simply one off. And in terms of the definition, mild cases or cases that resolve spontaneously that do not interfere with daily activities, that's the definition. You might have mild nausea right now, but continue with the rest of your day. And, these are these mild events were untreated by definition. The definition of moderate is that there's some imposition on daily activities as assessed by the investigator. And very often that's associated with treatment, but not necessarily. But clearly with the mild events, the unremarkable events to the subject, simply noted by the subject and not requiring treatment. That's helpful. Thanks again. Yeah. And I'll double up on that by saying that I'm not really sure what a mild event means to a subject like this that means to a subject that's losing a very substantial amount of weight loss. And in terms of the balance of their own intention, their own therapeutic effort to lose weight, which is otherwise very hard in the lives of these people to be getting a 20 pound weight loss and feeling a bit of mild nausea maybe once in twelve weeks is pretty remarkable, we think. Our next question comes from Patrick Trujillo with H. C. Wainwright. Hi, good morning and congrats on the data. I have a few follow-up questions. The first one is on Slide 16, glucose homeostasis was maintained. Can you tell us what the contribution is from glucagon versus GLP-one and over on to the overall mechanism of pembidutide and your level of confidence that pembidutide should not impact glucose homeostasis in diabetic patients based on the data that's been generated to date? Right. We don't think there's going to be an impact, Patrick. These are subjects that were predominantly pre diabetic and had abnormalities of glucose homeostasis. And that's evidenced by the HOMA IR that you saw a normal one being about 1.5 and certainly no higher than about 1.9. And you'd expect a 2.5 in a younger population, that was overweight and obese. So these are subjects who had high insulin levels to begin with. And we're maintaining glucose homeostasis with the pressure of increased beta cell activity in order to maintain that. So consequently, this is a very relevant population for assessing glucose control in the future. We did not see any mean changes in blood sugar. We didn't see any mean changes in hemoglobin A1c. We didn't see any hyperglycemic events. We think that's attributed to the perfect balance here between GLP-one and glucagon, which is the intent of the molecule to get one to one balance so that the GLP-one where it balances out the effects of the glucagon. And I think it's evident here with the really excellent, maintenance of the glucose levels in these patients. Now, going forward, we do think that that maintenance will be seen in diabetics. We even think there's a real potential for glucose lowering effects, especially over the longer duration of treatment as subjects lose weight and continue to improve their insulin sensitivity. And as noted in the STEP-two trials, the predominant factor accounting for the drop in the hemoglobin A1c at the sixty eight week mark, which was the duration of the STEP-two trial was not the incretin effect of the GLP-one on insulin secretion, but it was the reduction in body weight and improvement of insulin sensitivity. So we think it's we think there'll be no at worst, no differences in the diabetics in that study. It's a safety study to show that at a minimum, leukocytosis is maintained. But there's also the great potential to see improvement of hemoglobin A1c, maybe not necessarily in the twelve weeks, but certainly in a trial of longer duration. Yes, that's helpful. And then on Slide 17, which outlines the production of ketone bodies, can you further discuss these increases and how they are driven by the mechanism and help us frame these levels of ketones, including implications of increases of the magnitude outlined relative to placebo? Right. So these are very relevant increases and what they suggest is a shift to fat metabolism, which results in the production of ketone bodies. It shows fat burn. And it's consistent with the mechanism of glucagon shifting the utilization of carbohydrates in these obese people to utilization of fat, which is exactly where we want to be with them. Okay. And then just last on the Phase two obesity trial, the dose subjects up to one year with the planned 24 interim analysis late in 2022. Can you tell us what the baseline characteristics of the patients enrolled in this trial would be expected to be? What proportion would be diabetic patients? Secondly, can you give us an idea of how many patients would be included in the interim analysis and what it would be powered to generate in terms of weight loss or other endpoints? And finally, if the interim analysis demonstrates sufficient safety and efficacy, would you then take that data and move straight into the Phase three program prior to having a full dataset? Right. So, let me try to take all those questions and not necessarily in the order you ask them. The twenty four week interim analysis, it will be powered for efficacy. And the clear result will be to have sufficient changes at twenty four weeks, which should be possible because a great deal of the changes occur by twenty four weeks in order to justify efficacy and also, to move ahead into Phase III. That study will be a study in non diabetic, individuals. We are thinking about conducting a separate study in diabetics, but that's not on the books. And I believe there was one more aspect to your question, which I didn't address, and I'd be happy to take that, if you could repeat your question. How many patients would be included in the interim analysis? And what can you tell us what it would be powered to generate weight loss? I don't have that actual figure in front of me. The the full details of the protocol are on the drawing board right now. My assumption would be that because of the rapid enrollment of this trial, because these trials are much faster to enroll than NASH trials, we would probably include all the subjects in the interim analysis. Got it. That's really helpful. Thank you very much. You're welcome. Our next question comes from Yasmeen Rahimi with Piper Sandler. Hi, Tim. Thank you again for allowing me to ask some follow-up questions. Can you comment on the SAD portion of the study, how high you went on to the doses? And obviously, the monitoring that occurred for liver enzymes? The second question is can you comment on the preclinical data package in terms of how high of dosing did you go? Did you see any liver enzyme elevations in the tox package? So if you could just you know, help us get comfortable that that one patient is more an outlier, that would be helpful. Sure. So, we, in the single phase went up to, four point eight milligrams, which is approximately three times the one point eight milligram dose. And we saw no liver function abnormalities. And regarding the tox program, again, this was only one case that was seen in all the subjects in the SAD and the MAD, just one subject. In addition, in the toxicology program, Yasmin, we saw no adverse events at all. We saw no liver function changes whatsoever. This is something that was not observed. The dose margins in terms of the exposures were higher than the dose margins. Let me rephrase that. The serum concentrations that were obtained in monkeys were a margin higher than the serum concentrations that were obtained in humans. There was a good safety margin and there were no liver function abnormalities seen. Thank you. And is there an opportunity to kind of go back into that patient and that one patient and assess? I mean, study was done during COVID in a 30 year old population. I mean, is there an opportunity to ask if there was significant drinking during that week prior to assessment for the liver enzymes? Is there a way to really or did you get a chance to look at that question just to kind of? Well, we asked the question. We asked about a number of things. And it's a difficult time in Australia and I assume that people were staying at home and drinking. And I don't know when this patient, it was certainly asked. Whether we got a truthful answer is uncertain. But I just want to stress, Yasmin, that we have one case. It resolved quickly. It's not been seen in any of the other subjects despite going to higher doses. It was not seen in our tox studies. It was seen in a type of subject that would be very unlikely. If it was the weight at, the BMI of coming into the study, the subject was barely the acceptable BMI and would not be getting into either an obesity or an NASH trial. We knew that these subjects did not have fatty liver. These subjects would not get into a NASH trial, would not get into an obesity trial. And that's our very strong belief, very strong belief, number one, that we won't see it again. Number two is that we have a very extensive monitoring program, which is not atypical. It's just simply the template DILI or drug induced liver injury program that FDA wants in all NASH studies. And for convenience, we have it in our obesity study as well. But just simply you have it in one, you have it in the other. But, we just don't think it's going to occur again. And if it does occur, think we have a very strong handle on it. So we'll continue to observe it. We'll continue to look for it. But at this point, we have good control over it. We don't we think it's an isolated event and we have very close monitoring systems that will be put in place to capture it. If it does happen, we don't think that there will be any injury here that would result in any consequences here. Thank you, Scott. And then one other comment or question I had for you is, so the baseline weight in this population was ninety kilos and historical rates have been one hundred and five kilos. So obviously achieving a double digit weight loss and a population that weighs less is really, really remarkable. So I mean can you maybe comment on one would speculate that if you had one hundred and five or one hundred and ten kilogram weight group, the magnitude of effect would be significantly higher. So just would love to hear like this data point and how you're thinking about it it's obvious the more you weigh, the more you're going to lose weight. And I think that's being not, I think we should discuss that on the call. We think it's really remarkable that we were able to achieve double digit weight loss in this particular population, Yasmin. And we think as we go to heavier people, the rates of weight loss will probably increase. It's been seen in other studies that you get a higher greater degree of weight loss in people who have a higher BMI. So we think that to achieve this kind of weight loss in a lighter population is very, very positive. You, Scott. Yasmeen, if I could jump in here, I wanted to stress or emphasize one more point. We've mentioned it, but I think it's really important in the context of what we're trying to achieve here is all of this data that we are showing, all of these results that we are showing are in the there is no dose titration involved. So we're doing all this in the absence of dose titration. And we are comparing to everything else that's done with dose titration. So I just want to reemphasize that point that that is also a significant advantage for this molecule, not only the rapid weight loss, the magnitude of weight loss, but also lack of need for dose titration, we think is going to be critical in terms of developing a successful molecule. Let me follow-up on that, Vipin. We think that dose titration is a tremendous advantage. And of course, not titrating leads to faster weight loss. Although we think that a large, if not most of that of the properties of the weight loss are due to the molecule and its unique mechanism rather than the absence of titration. But, dose titration is a problem. And as we shift obesity treatment from endocrinology, because remember these drugs, these GLP-1s have been used predominantly by diabetologists and endocrinologists or specialists. This is now shifting to primary care, where primary care doctors have ten minutes with each patient and they don't want to deal with titration. And there's the ongoing saying that diabetics are non compliant. You're to give them another reason for non compliance. So we think that the acceptability of a compound that's not dose titrated, we don't think we have to. We always could if we ever thought we wanted to. It's always there as an option for us. Companies that are titrating don't have that option anymore. We do have that option. We're not saying we're going to use it, but we have it. But we just really think that this property is important going forward. And the adverse event profile we saw was despite not employing dose titration. We didn't get discontinuations. So we really think that it's a tremendous part of the program. Thank you. Our last question comes from Seamus Fernandez with Guggenheim. Great. Thanks, guys. So one in one hundred ALT rapidly resolved. I think one thing that might be lost here is the fact that this is also a weekly drug. But I wanted to focus in on a little bit more on some of the other benefits. Can you guys talk about the magnitude of blood pressure reduction and the magnitude of lipid reduction, particularly LDL reduction that you're seeing at this early time point relative to some of the other data sets that we've seen elsewhere. This seems to be another unique property of this drug that perhaps is lost in this conversation around a single one in one hundred ALTs. Right. Well, the magnitude of the weight loss of the blood pressure changes the magnitude that you see with blood pressure reducing drugs, I mean, at twelve weeks. And remember, as people continue to lose weight, they're going to continue to, have excellent control and even better control of blood pressure changes. And the drop in blood pressure is known to occur with GLP-one agents is felt to be cardioprotective as in fact, the rationale for the development of GLP-1s for the treatment of congestive heart failure. As I indicated in my response to Mayank's question, we don't have data at twelve weeks, but the amount of lipid reduction we're seeing is comparable to what other drugs are achieving at fifty two weeks. So, the sky is somewhat of the limit here in terms of the amount of lipid improvement we may see as the trial goes forward to a fifty forty eight or fifty two week readout. And then just as one final follow-up. I don't know if folks noticed this in your presentation, but the path of the weight loss curves still seems to be pretty robust at twelve weeks. Just thought I would raise that and any thoughts on the potential incremental magnitude that you would hope to see going forward? Thanks, Seamus. So we're seeing no evidence that the rate of weight loss slows down to twelve weeks. We don't have the data beyond twelve weeks. This is only a twelve week study. But if one plots the rate of weight loss here versus other drugs, it's much faster. Will we plateau at some point? We have to. When will that occur? Well, in animals, it didn't occur until animals returned back to their ideal body weight, the obese animals. Could we achieve 20% weight loss? I think it's possible. But again, we're projecting from 10%. And when would that occur? Would it go out to forty eight weeks? Would it occur by twenty four? I think we're going to have to do, longer term studies. Recognize that with bariatric surgery, you're in the range of about twenty five percent weight loss. The ability to achieve this with drug therapy is very remarkable and it's quite possible that we may get there with longer term studies. Thanks guys. And I'm not showing any further questions at this time. I'd like to turn the call back over to Vipin. Yes. Thank you everyone for joining us today. We look forward to talking to you soon again. Have a wonderful day. Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful