Q4 2024 Altimmune Inc Earnings Call

Operator: [music] Good day, ladies and gentlemen, and welcome to the Altimune fourth quarter and full year 2024 Financial Results Conference call. As a reminder, this call is being recorded.

Operator: Good day, ladies and gentlemen, welcome to the Altimmune Fourth Quarter and Full Year 2024 Financial Results Conference Call. As a reminder, this call is being recorded. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. I would now like to introduce your host for today's conference call, Lee Roth, President of Burns McClellan, investor relations advisor to Altimmune. Lee, you may begin.

Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again.

Lee Roth: I would now like to introduce your host for today's conference call, Lee Roth, President of Burns McClellan, Investor Relations Advisor to Altimune. Lee, you may begin. Thanks, Gigi. Good morning, everyone. And once again, thank you all for joining us for Altimmune's fourth quarter and full year 2024 Financial Results and Business Update conference call. On today's call, you'll hear from Dr. Vipin Garg, our Chief Executive Officer, Dr. Scott Harris, our Chief Medical Officer, and Greg Weaver, our Chief Financial Officer. Dr. Scott Roberts, our Chief Scientific Officer, and Ray Jordt, our Chief Business Officer, will join us for the Q&A.

Lee Roth: Thanks, Gigi. Good morning, everyone. Once again, thank you all for joining us for Altimmune's Q4 and full year 2024 financial results and business update conference call. On today's call, you'll hear from Dr. Vipin Garg, our Chief Executive Officer, Dr. Scott Harris, our Chief Medical Officer, and Greg Weaver, our Chief Financial Officer. Dr. Scot Roberts, our Chief Scientific Officer, and Ray George, our Chief Business Officer, will join us for the Q&A session. Press release covering our Q4 and full year 2024 financial results and corporate update was issued earlier this morning and can be found on the investor relations section of the Altimmune website. Before we begin, I'd like to remind everyone that remarks made about future expectations, plans, and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.

Lee Roth: Press release covering our fourth quarter and full year 2024 financial results and corporate update was issued earlier this morning and can be found on the investor relations section of the Altimmune website.

Lee Roth: Before we begin, I'd like to remind everyone that remarks made about future expectations, plans, and prospects constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Altimmune cautions you that these forward-looking statements are subject to risks and uncertainties that could cause our actual results to differ materially from those expressed today. For a review of the risk factors that could affect our future results and operations, we refer you to the company's filings with the SEC. I direct you to read the forward-looking statements disclaimer in our press release issued this morning, which is also available on our website.

Lee Roth: Altimmune cautions you that these forward-looking statements are subject to risks and uncertainties that could cause our actual results to differ materially from those expressed today. For a review of the risk factors that could affect our future results and operations, we refer you to the company's filings with the SEC. I direct you to read the forward-looking statements disclaimer in our press release issued this morning, which is also available on our website. Any statements made on this conference call speak only as of today's date, 27 February 2025, and the company assumes no obligation to update any of these forward-looking statements to reflect events or circumstances that may occur on or after today's date. As a reminder, this call is being recorded and will be available for replay on the Altimmune website.

Lee Roth: Any statements made on this conference call speak only as of today's date, February 27th, 2025, and the company makes no obligation to update any of these forward-looking statements to reflect events or circumstances that may occur on or after today.

Lee Roth: As a reminder, this call is being recorded and will be available for replay on the Altimmune website.

Lee Roth: With that, it is now my pleasure to turn the call over to Dr. Vipin Garg, Chief Executive Officer of Altimmune. Vipin.

Lee Roth: With that, it's now my pleasure to turn the call over to Dr. Vipin Garg, Chief Executive Officer of Alstom. Vipin? Thank you, Li. Good morning, everyone.

Vipin Garg: Thank you, Lee. Good morning, everyone, and thank you for joining us for our Q4 and full year corporate update. 2024 was a year of significant progress for Altimmune. The milestones we have achieved over the past 12 months have positioned us for transformative catalysts in 2025 and beyond. Following the Q3 2024 completion of enrollment in IMPACT, our phase IIb biopsy-based trial of pemvidutide in MASH, our top-line data readout remains on track for the Q2 of this year. The dual primary endpoints of the study will be MASH resolution and fibrosis improvement at 24 weeks. Pending these results, we will request an end of phase II meeting with the FDA to align on a registrational phase III program.

Vipin Garg: And thank you for joining us for our fourth quarter and full year corporate update. 2024 was a year of significant progress for all. The milestones we have achieved over the past 12 months have positioned us for transformative catalysts in 2025 and beyond. Following the third quarter 2024 completion of enrollment in IMPACT, our Phase 2b biopsy-based trial of pambidutide in MASH, our top-line data readout remains on track for the second quarter of this year. The dual primary endpoints of the study will be MASH resolution and fibrosis improvement at 24 weeks. Pending these results, we will request an end of Phase 2 meeting with the FDA to align on a registration of Phase 3 program.

Vipin Garg: While the timing of that meeting will be determined by the agency, we expect that it will take place before the end of this year, which would position us to initiate a phase III program in MASH in early 2026. With a positive IMPACT readout, pemvidutide would be the first incretin-based agent to achieve fibrosis improvement at 24 weeks and the first therapeutic candidate in any class to achieve both significant fibrosis improvement and meaningful weight loss in a 24-week treatment period. We believe that this unique combination of pemvidutide's direct action on the liver, together with clinically meaningful weight loss, will position pemvidutide to become the treatment of choice in MASH. The ability to reduce fibrosis in only 24 weeks is important because it signals both the potency of pemvidutide and the promise of even greater response rates over the longer treatment durations used by other incretin-based agents.

Vipin Garg: while the timing of that meeting will be determined by the agency. We expect that it will take place before the end of this year. which would position us to initiate a phase three program in MASH in early 2026. With a positive impact readout, Pembidutide would be the first incretin-based agent to achieve fibrosis improvement at 24 weeks. and the first therapeutic candidate in any class to achieve both significant fibrosis improvement and meaningful weight loss. in a 24-week treatment period. We believe that this unique combination of pambiduotide's direct action on the liver, together with clinically meaningful weight loss, will position pambiduotide to become the treatment of choice in MASH.

Vipin Garg: The ability to reduce fibrosis in only 24 weeks is important because it signals both the potency of famidotide and the promise of even greater response rates over the longer treatment durations used by other intratin-based agents. In addition to our progress in MASH, I am thrilled to share that we submitted INDs for family-due diet in two additional indications in the fourth quarter of 2024. Both of these INDs have been cleared by the FDA, and this positions us to start Phase II efficacy trials in mid-2025. We believe that each of these indications represents an attractive and compelling commercial opportunity for which family-due type will be ideally suited.

Vipin Garg: In addition to our progress in MASH, I'm thrilled to share that we submitted INDs for pemvidutide in two additional indications in Q4 2024. Both of these INDs have been cleared by the FDA. This positions us to start Phase II efficacy trials in mid-2025. We believe that each of these indications represents an attractive and compelling commercial opportunity for which pemvidutide would be ideally suited. As we announced this morning in our earnings press release, we will be holding a virtual R&D day on 13 March, at which time we will disclose the additional indications and provide detailed overview of these new opportunities. The R&D event will feature presentations by key opinion leaders specializing in MASH, obesity, and the additional indications. We are extremely excited about this event and look forward to sharing our plans on the future of pemvidutide.

Vipin Garg: as we announced this morning in our earnings press release.

Vipin Garg: We will be holding a virtual R&D day on March 13. at which time we will disclose the additional indications and provide detailed overview of these new opportunities. The R&D event will feature presentations by key opinion leaders. Specializing in MASH, Obesity, and the Additional Indications. We are extremely excited about this event and look forward to sharing our plans on the future of PEMBEDUTA.

Vipin Garg: From an organizational perspective, we are excited by the recent addition of Teri Lawver and Jerry Durso to our board of directors. Notably, they have decades of experience across the pharmaceutical industry, including late-stage clinical development and commercialization of therapeutics in the MASH and metabolic disease space. These areas are highly relevant to Altimmune, and I believe that their expertise and guidance will be invaluable as we embark on our next phase of pemvidutide development. I'm excited to work with them and look forward to their respective contributions. Lastly, I wanted to share with you that Scott Harris, who has served alongside me as our Chief Medical Officer for the last 6 years, recently informed me that he plans to retire a year from now at the end of February 2026.

Vipin Garg: From an organizational perspective, we are excited to invite the recent addition of Terry Lauer and Jerry Durso to our Board of Directors. Notably, they have decades of experience across the pharmaceutical industry, including late-stage clinical development and commercialization of therapeutics in the MASH and metabolic disease space. These areas are highly relevant to Altimmune, and I believe that their expertise and guidance will be invaluable as we embark on our next phase of family-due-type development. I'm excited to work with them and look forward to their respective contributions.

Vipin Garg: Lastly, I wanted to share with you that Scott Harris who has served alongside me as our chief medical officer for the last six years, recently informed me that he plans to retire a year from now at the end of February 2026. Scott has been a valued and trusted colleague whose leadership has been instrumental in advancing Pambithiutai to the cusp of an important data readout. If successful, this readout could position PAMI-DUTA as the foundational therapy in the treatment of MASH and other metabolic disorders. As noted, we are rapidly approaching top-line readout of the 24-week efficacy data.

Vipin Garg: Scott has been a valued and trusted colleague whose leadership has been instrumental in advancing pemvidutide to the cusp of an important data readout. If successful, this readout could position pemvidutide as the foundational therapy in the treatment of MASH and other metabolic diseases. I am grateful that he will remain with us through the IMPACT data readout and the end of phase II FDA meeting for MASH, and that he has given us ample time to find his successor and to ensure a smooth transition. We plan to initiate a search for his successor in the near future. With that, I'll now turn the call over to Scott Harris. Scott?

Scott Harris: Thank you, Vipin. As Vipin mentioned, after 25 years in drug development, including the past 6 years at Altimmune, I've decided to plan for my departure in early 2026. I want to emphasize that I will remain with the company through all important milestones over the next 12 months, and that I'm not going anywhere anytime soon. I'm excited about the upcoming IMPACT readout and the opportunity to lead the medical team through Phase III readiness in MASH, as well as the initiation of the Phase II trials in 2 additional indications. You'll be seeing a lot of me throughout the next 12 months. I want to thank Vipin and Altimmune for letting me shepherd pemvidutide from a preclinical molecule to a Phase III-ready asset in multiple exciting indications. With that, let me turn to our significant progress in MASH.

Scott Harris: As noted, we are rapidly approaching top-line readout of the 24-week efficacy data for the IMPACT trial. Unlike current agents approved or in development for MASH, pemvidutide has the potential to drive both fibrosis reduction and significant weight loss. Essentially, pemvidutide has combined the weight loss effects of the incretins with the liver-directed effects of agents like the FGF21s into a single molecule that we believe will provide a complete solution for the treatment of MASH. Our key metric for the success in the IMPACT trial will be the ability to achieve statistical significance on the fibrosis improvement endpoint at 24 weeks. If successful, pemvidutide will be the first incretin-based agent to achieve fibrosis improvement at 24 weeks and the first therapeutic candidate in any class to achieve fibrosis improvement and meaningful weight loss in a 24-week period. Liver fat reduction is the key driver of fibrosis improvement.

Vipin Garg: for the IMPACT trial. Unlike current agents approved or in development for MASH, pemvidutide has the potential to drive both fibrosis reduction and significant weight loss. Essentially, Pemvidutide has combined the weight loss effects of the incretins with the liver-directed effects of agents like the FGF21s into a single molecule that we believe will provide a complete solution for the treatment of MASH. Our key metric for the success in the IMPACT trial will be the ability to achieve statistical significance on the fibrosis improvement endpoint at 24 weeks. If successful, PEMPA-JUTI will be the first Incretin-based agent to achieve fibrosis improvement at 24 weeks and the first therapeutic candidate in any class to achieve fibrosis improvement and meaningful weight loss in a 24-week period.

Vipin Garg: Liver fat reduction is the key driver of fibrosis improvement. But in addition, we also have preclinical data showing that penvidutide has direct antifibrotic effects. Most importantly, we have greater liver fat reduction at 24 weeks than any of the MASH agents currently in development, regardless of when the reduction was measured. With respect to study power, the two primary treatment arms in PEPACT, pempidutide 1.8 mg and placebo, are larger in comparison to the number of subjects in the successful FGF21 trials that also read out successfully at 24 weeks, albeit without meaningful weight loss. Together, with our greater liver fat reduction, we believe the study has more than adequate power to achieve statistical significance on the fibrosis improvement endpoint at 24 weeks.

Scott Harris: In addition, we also have preclinical data showing that pemvidutide has direct anti-fibrotic effects. Most importantly, we have greater liver fat reduction at 24 weeks than any of the MASH agents currently in development, regardless of when the reduction was measured. With respect to study power, the two primary treatment arms in IMPACT, pemvidutide 1.8 mg and placebo, are larger in comparison to the number of subjects in the successful FGF21 trials that also read out successfully at 24 weeks, albeit without meaningful weight loss. Together, with our greater liver fat reduction, we believe the study has more than adequate power to achieve statistical significance on the fibrosis improvement endpoint at 24 weeks. Controlling the placebo response rate will also assure a higher likelihood of achieving statistical significance at data readout. We've learned a great deal about how to reduce the placebo effect in biopsy-based MASH clinical trials.

Vipin Garg: Controlling the placebo response rate will also assure a higher likelihood of achieving statistical significance at data readout. We've learned a great deal about how to reduce the placebo effect in biopsy-based MASH clinical trials. First, we will be employing three readers and using the mode technique of scoring. Second, we will be rereading all the biopsies in a blinded manner prior to the trial readout, eliminating any bias introduced when pathologists know the biopsy is a pre- or post-treatment sample as a result of when the biopsy is being read. Both of these approaches are similar to those used in the Phase II Pegasovermin trial, which achieved a placebo response rate for fibrosis improvement of only 7%.

Scott Harris: First, we will be employing 3 readers and using the mode technique of scoring. Second, we will be rereading all the biopsies in a blinded manner prior to the trial readout. Eliminating any bias introduced when pathologists know the biopsy is a pre or post-treatment sample as a result of when the biopsy is being read. Both of these approaches are similar to those used in the phase II pegozafermin trial, which achieved a placebo response rate for fibrosis improvement of only 7%. Finally, our pathologists have agreed upon a set of rules by which to align the reading of the biopsies, including, for example, how to read controversial findings like atypical balloon cells. We believe the advantages of pemvidutide do not end there. We have consistently shown that pemvidutide has robust lipid-lowering effects.

Vipin Garg: Finally, our pathologists have agreed upon a set of rules by which to align the reading of the biopsies, including, for example, how to read controversial findings like atypical balloon cells.

Vipin Garg: We believe the advantages of penvadutide do not end there. We have consistently shown that penvadutide has robust lipid-lowering effects. In this context, it is important to note that F2 and F3 patients, cardiovascular events are still the primary cause of mortality. So the reductions in LDL cholesterol and liver fat that we have demonstrated with penvadutide combined with the expected effects in mash and body weight may further reduce the risk of both cardiovascular disease and liver disease. As we've shared previously, the end of Phase II, meaning for obesity, has implications not only for the Phase III velocity trials, but for the entire PEMDU-Tide program.

Scott Harris: In this context, it is important to note that F2 and F3 patients, cardiovascular events are still the primary cause of mortality. The reductions in LDL cholesterol and liver fat that we have demonstrated with pemvidutide, combined with the expected effects in MASH and body weight, may further reduce the risk of both cardiovascular disease and liver disease. As we've shared previously, the end of two Phase II meeting for obesity has implications not only for the Phase III VELOCITY trials, but for the entire pemvidutide program. During those interactions, FDA identified no safety signals related to pemvidutide in its review of over 500 subjects that had been treated with pemvidutide in our prior studies. To date, close to 700 subjects have been treated with pemvidutide across all of our completed and ongoing trials.

Vipin Garg: During those interactions, FDA identified no safety signals related to Penfidutide in its review of over 500 subjects that had been treated with Penfidutide in our prior studies. To date, close to 700 subjects have been treated with PEMDU-TIDE across all of our completed and ongoing trials.

Scott Harris: Turning our attention to the two additional indications, we believe these are areas of significant unmet medical need for which the balanced GLP-1 glucagon dual receptor agonism pemvidutide provides a highly compelling scientific rationale. The recent FDA clearance of our 2 IND applications has us on track to initiate phase II trials in these indications in the middle of this year. We'll be providing detailed and comprehensive information on these indications, including our development plans at our R&D Day on 13 March. You'll be hearing from two of the foremost experts in the treatment of these conditions, who have been instrumental in the formation of our strategy and who share our enthusiasm for the development of pemvidutide in these indications. With that, I'll now hand the call over to our Chief Financial Officer, Greg Weaver, to review our financial results for the Q4 and full year. Greg?

Vipin Garg: Turning our attention to the two additional indications, we believe these are areas of significant unmet medical need for which the balanced GLP-1-glucagon dual receptor agonism panthedutide provides a highly compelling scientific rationale. The recent FDA clearance of our two IND applications has us on track to initiate Phase 2 trials in these indications in the middle of this year. We will be providing detailed and comprehensive information on these indications, including our development plans, at our R&D day on March 13. You will be hearing from two of the foremost experts in the treatment of these conditions who have been instrumental in the formation of our strategy and who share our enthusiasm for the development of PEMDU-TIDE in these indications.

Greg Weaver: With that, I'll now hand the call over to our Chief Financial Officer, Greg Weaver, to review our financial results for the fourth quarter in full year. Greg? Thank you, Scott. I'll be providing a brief review of Altimune's fourth quarter and full year 2024 financial results. We'll have detailed information to be available in our 10-K, which we'll file later this afternoon. We reported our year-end 2024 total cash and investments of $132 million. Current cash position is expected to fund operations well into the second half of 2026.

Greg Weaver: Thank you, Scot. I'll be providing a brief overview of Altimmune's Q4 and full year 2024 financial results, with more detailed information to be available in our 10-K, which we'll file later this afternoon. We reported our year-end 2024 total cash and investments of $132 million. This current cash position is expected to fund operations well into H2 2026 through our key catalyst of the Phase IIb MASH readout next quarter, and also includes funding of the Phase II trials for our additional indications. Moving to the details of the Q4 results, R&D expenses were $19.8 million in Q4 2024, compared to $16.9 million in the same period in 2023. Our R&D expenses in the quarter included $13.6 million in direct costs related to the clinical development activities for pemvidutide, including preparation for the upcoming Phase II trials in the additional indications.

Greg Weaver: through our key catalyst of the Phase 2b MASH readout next quarter, and also includes funding of the Phase 2 trials for our additional indications. Moving to the details of the fourth quarter results, R&D expenses were $19.8 million in the fourth quarter of 2024 compared to $16.9 million in the same period in 2023. Our R&D expenses in the quarter included $13.6 million in direct costs related to the clinical development activities for PEMBA-DUTAI, including preparation for the upcoming Phase 2 trial. in the additional indication. Non-cash stock compensation included in the R&D expenses was $1.6 million in Q4.

Greg Weaver: Non-cash stock compensation included in the R&D expenses was $1.6 million in Q4. G&A expenses, $5.1 million in Q4 2024 versus $4.3 million in the same period of 2023, with a non-cash stock comp included in G&A of $1.8 million in Q4. It's an increase of roughly $500,000 over the same quarter last year. Net loss for the 3 months ended 31 December 2024 was $23.2 million, compared to a net loss of $31.6 million in Q4 2023. That prior year net loss included a one-time non-cash impairment charge of $12.4 million related to a discontinuation of the HepTcell development program. To summarize our full-year results, R&D expenses were $82.2 million in 2024 as compared to $65.8 million in 2023. Our R&D expenses included $53 million in direct costs related to development activities for pemvidutide.

Greg Weaver: GNA expenses $5.1 million in the fourth quarter of 2024 versus $4.3 million in the same period of 2023. with a non-cast stock comp included in GNA of $1.8 million in Q4 to an increase of roughly $500,000 over the same quarter last year. Net loss for the three months ended December 31st, 24 was $23.2 million compared to a net loss of $31.6 million in the fourth quarter of 2023.

Greg Weaver: That prior year net loss included a one-time non-cash impairment charge. 12.4 million related to a discontinuation of the HEP2 cell development program.

Greg Weaver: To summarize our four-year results... R&D expenses were $82.2 million in 2024, as compared to $65.8 million in 2023. Our R&D expenses included $53 million in direct costs related to development activities for PEPA-DUTAI. GNA expenses were $21 million for the full year 2024 compared to $18.1 million in 2023. The increase due primarily to a $2.7 million increase in stock compensation and labor. A total non-cash stock compensation expense for 24 was approximately $14.4 million as compared to $10.6 million in 2020. Net loss for the year 2024 was $95 million compared to a net loss of $88 million in 2020.

Greg Weaver: G&A expenses were $21 million for the full year 2024, compared to $18.1 million in 2023, with the increase due primarily to a $2.7 million increase in stock compensation and labor related expenses. A total non-cash stock compensation expense for 2024 was approximately $14.4 million as compared to $10.6 million in 2023. Net loss for the year 2024 was $95 million, compared to a net loss of $88 million in 2023. The net loss reported for the prior year included the aforementioned non-cash impairment charge of $12 million. I'll close the remarks by highlighting our cash position, which provides runway well into the second half of 2026, based on our OPEX forecast, which includes the cost of launching PEMV trials in 2 additional indications.

Greg Weaver: The net loss reported for the prior year included the aforementioned non-cash impairment charge of $1,290,000.

Greg Weaver: I'll close the remarks by highlighting our cash position, which provides runway into the second half, well into the second half of 2026, based on our OPEX forecast, which includes the cost of launching PEMV trials and two additional indications. Funding through the KeyMASH clinical milestones of both 2025 and 2026. as we anticipate advancing into the Phase III Pivotal program next year.

Greg Weaver: Funding through the key MASH clinical milestones of both 2025 and 2026, as we anticipate advancing into the phase III pivotal program next year. I'll now turn the call back to Vipin. Vipin?

Vipin Garg: I'll now turn the call back to Vipin. Thank you, Greg. We accomplished a great deal in 2024 and have entered 2025 with multiple major inflection points in the near term. As each of these important milestones is achieved, we expect that they'll open the door for new and larger opportunities for us. which I strongly believe we are well equipped to capture.

Vipin Garg: Thank you, Greg. We accomplished a great deal in 2024 and have entered 2025 with multiple major inflection points in the near term. As each of these important milestones is achieved, we expect that they'll open the door for new and larger opportunities for us, which I strongly believe we are well-equipped to capture. I look forward to sharing our next set of updates at the R&D Day on 13 March. The combination of phase II-B readout in MASH and the launch of phase II efficacy trials in two additional indications has us poised for an incredible 2025. That concludes our formal remarks, and we would now like to open the lines to take questions. Operator?

Vipin Garg: I look forward to sharing our next set of updates at the R&D Day on March 13. Combination of phase 2 readout in MASH and the launch of phase 2 efficacy trials in two additional indications has us poised for an incredible 2025.

Vipin Garg: That concludes our formal remarks.

Operator: And we would now like to open the lines to take questions. Operator. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Stand by while we compile the Q&A roster.

Operator: As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Roger Song from Jefferies.

Operator: Our first question comes from the line of Roger Song from Jeffrey.

[Analyst] (Jefferies): Hi. This is Fiona for Roger. Congrats on the year and a lot of new developments. Exciting for this year. Just questions on the new indications. I was wondering if you're going to announce the details, like the pre-clinical data at the R&D Day, and whether if you're going to start the 2 phase II trials simultaneously mid-year.

Fiona Faragher: Hi, this is Fiona Faragher. Congrats on the year and a lot of new developments, exciting for this year. Just some questions on the new indications. I was wondering if you're gonna announce the details like the preclinical data at the R&D day and whether if you're gonna start the two phase two trials simultaneously mid-year. Yeah, so we will we will provide a very comprehensive picture of the two indications at the R&D day that's coming up. As we mentioned, we have two KOLs that will make presentations about both of these indications and we will share our plans in terms of when we would start the phase two programs as well.

Vipin Garg: We will provide a very comprehensive picture of the two indications at the R&D Day that's coming up. As we mentioned, we have two KOLs that will make presentations about both of these indications, and we will share our plans in terms of when we would start the phase II programs as well. Stay tuned, and we're looking forward to providing all that detail.

Fiona Faragher: So stay tuned and we're looking forward to providing all that detail. Thank you, yeah, looking forward to the R&D day and congrats on the year. Thank you.

[Analyst] (Jefferies): Thank you. Yeah, looking forward to the R&D Day, and congrats on the year.

Vipin Garg: Thank you.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Yasmeen Rahimi from Piper Sandler.

Operator: One moment for our next question.

Yasmeen Rahimi: Our next question comes from the line of Yasmeen Rahimi from Piper Sandler. And good morning, team. Thank you for the great updates. And come on, I can't believe you're retiring. You have another 20 years and you have not more. So, but, but I'm happy to know that I get to work with you for another year. So when I say that, and it's been a pleasure working with you.

Yasmeen Rahimi: Good morning, team. Thank you for the great updates. Scott, I can't believe you're retiring. You have another 20 years in you, if not more. I'm happy to know that I get to work with you for another year, so want to say that. It's been a pleasure working with you, honestly. I think one of the questions that we would love to understand is, post the phase II-B data, as you guys are going to be engaging with the agency, is there an opportunity to think about, given the profound defatting of the liver and a lot of data supporting MRI-PDFF as a histological response, should we be thinking about the phase III design very like the typical studies we have seen based on histology, or is there going to be some flexibility on some innovative NIT incorporation into the study?

Scott Harris: Honestly, I, I think one of the questions that we would love to understand is post the face to be data as you guys are going to be engaging with agency. Is there anything, is there an opportunity to think about, given the profound defatting of the liver and a lot of data supporting MRI-PDFF as a histological response, should we be thinking about the phase 3 design very like the typical studies we have seen based on histology, or is there going to be some flexibility on some innovative NIT incorporation into the study? And then also, if you're thinking about, would you be concurrently starting a cirrhosis study in conjunction?

Yasmeen Rahimi: Also, if you're thinking about, would you be concurrently starting a cirrhosis study in conjunction? Just want to love to understand how you're thinking about on sort of the phase III development and what sort of strategy you want to implement. I'll jump back in the queue.

Scott Harris: Just want to love to understand how you're thinking about on sort of the phase 3 development and what sort of strategy you want to implement. And I'll jump back in the queue.

Vipin Garg: Scott?

Scott Harris: Yeah. Thanks, Yasmeen, and thanks for the compliment. I hope I make it 20 years. I will look forward to the prospect. As you know, we're really on the forefront of the NITs with our MRI-PDFF, and this is a potential NIT of great interest to the FDA. At this point in time, we don't really know what the FDA is going to do with the NITs. We think we're right there at the forefront of this discussion when that happens. There's been a lot of discussion about these NITs, but I don't have any new information about what the FDA will do. Regarding a cirrhosis study, we have a great deal of interest in that kind of study. We've talked a lot about it internally. We don't have anything that we can guide you on at this time.

Scott Harris: Scott. Yeah. Thanks, Yasmeen. And thanks for the compliment. I hope I make it 20 years. I will look forward to the prospect. So as you know, we're really on the forefront of the NITs with our MRI-PDFF. And this is a potential NIT of great interest to the FDA. At this point in time, we don't really know what the FDA is going to do with the NITs. We think we're right there at the forefront of this discussion when that happens, but... There's been a lot of discussion about these NITs, but I don't have any new information about what the FDA will do.

Scott Harris: Um...

Scott Harris: Regarding cirrhosis study, we have a great deal of interest in that kind of study. We've talked a lot about it internally. We don't have anything that we can guide you on at this time, but certainly as we get toward our phase three program announcement. um We will, you know, make such a disclosure probably around the time of the end of phase two meeting. I want to say though that we feel very strongly we're going to have success in the cirrhosis population. We believe that we have, we'll have best in class. Fibrosis Improvement on the F2 and F3 population, and we believe that like the recent Afrexa Furman readout, based on our reduction in liver fat and our anti-fibrotic effects, that we have a very high likelihood of success in cirrhosis or F4 as well.

Scott Harris: Certainly, as we get toward our phase III program announcement, we will make such a disclosure, probably around the time of the end of phase II meeting. I want to say, though, that we feel very strongly we're going to have success in the cirrhosis population. We believe that we'll have best-in-class fibrosis improvement on the F2 and F3 population. We believe that, like the recent efruxifermin readout, based on our reduction in liver fat and our anti-fibrotic effects, that we have a very high likelihood of success in cirrhosis or F4 as well. We view cirrhosis in its early stage as simply an extension of F3, and that's as long as patients don't have extensive scarring resulting in clinically significant portal hypertension, the complications of cirrhosis, such as encephalopathy, ascites, variceal bleeding, that this is reversible.

Scott Harris: We view cirrhosis in its early stage as simply an extension of F3. And that's as long as patients don't have extensive scarring resulting in clinically significant portal hypertension, the complications to cirrhosis such as encephalopathy, ascites, variceal bleeding, that this is reversible. And this is the study population that Acuero took in their trial. We simply see that as an extension of F3, and we think our chances of success in cirrhosis are quite high. Thank you so much. I'll jump back in the queue. Thank you.

Scott Harris: This is the study population that Akero took it in their trial. We simply see that as an extension of F3, and we think our chances of success in cirrhosis are quite high.

Yasmeen Rahimi: Thank you so much. I'll jump back in the queue.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Annabel Samimy from Stifel.

Operator: One moment for our next question.

Annabelle Samimi: Our next question comes from the line of Annabelle Samimi from Stiefel. Hi everyone, thanks for taking my questions.

Annabel Samimy: Hi, everyone. Thanks for taking my questions and great progress. I guess, going into this IMPACT trial, can you talk about what your expectations are to consider this not just a clinical success, but a competitive success? Just to follow on from that, we've heard a lot about how the obesity market might evolve, but maybe you can talk about how you expect the MASH market to evolve with semaglutide's ESSENCE data and Rezdiffra and FGF21. Can you just talk about how you think all those programs, as well as pemvidutide, will play in with each other? Thank you.

Vipin Garg: The question is in great progress. you can talk about how you expect the mash market to evolve with. somaglutides, Essence Data, and Rosifera, and FGF21. So Can you just talk about how you think all those... Programs, as well as some of the dudes I will play in with each other. Thank you. Absolutely.

Vipin Garg: Absolutely. Maybe I'll get started, and Scott, you can take from there. In terms of, we've always said that MASH and obesity are linked to each other. People need to lose weight in order to treat their MASH successfully. We are seeing that even the latest data is showing that many people who are taking Rezdiffra, for instance, are also taking GLP-1s. That's really what we have. We have a combination of both a drug that's for obesity as well as for having a direct effect on the liver. Really, it's a complete solution for treating MASH. We view MASH with obesity as really the patient population that we will be treating in the long run. 80% of subjects with MASH have obesity or would benefit from losing weight. Ideal drug would do both.

Scott Harris: Maybe I'll get started and Scott, you can take from there. In terms of, you know, we've always said that MASH and obesity are linked to each other. You know, you need, people need to lose weight in order to treat their MASH successfully and we're seeing that even the latest data is showing that many people who are taking resdrifra for instance are also taking GLP-1s. That's really what we have. We have a combination of both a drug that's for obesity as well as for having a direct effect on the liver. So really it's a complete solution for treating MASH.

Scott Harris: We view MASH with obesity as really the patient population that we will be treating in the long run. Eighty percent of subjects with MASH have obesity or would benefit from losing weight. So ideal drug would do both. It will have a direct impact on the liver as well as people will lose weight and that's exactly what Pembidutide uniquely does. So we think it's very well positioned for addressing both of those comorbidities together, treating MASH as well as people losing weight at the same time.

Vipin Garg: It will have a direct impact on the liver and as well as people will lose weight, and that's exactly what pemvidutide uniquely does. We think it's very well positioned for addressing both of those comorbidities together, treating MASH as well as people losing weight at the same time. Scot?

Scott Harris: Scott? Yeah, thanks for the question, Anabelle. Regarding the competitive success, if we have statistical significance at 24 weeks... will be the only incretin that has even attempted a readout at 24 weeks, let alone has success at 24 weeks. And that's because, unlike semaglutide, which you mentioned, or trizepatide, we have direct effects in the liver. I want to remind you that semaglutide conducted a phase 2 trial about the same size as IMPACT about two years ago, and even going all the way out to 72 weeks. failed to show statistical significance. We expect to show it at just 24 weeks, so it's a much more potent compound.

Scott Harris: Yeah. Thanks for the question, Annabel. Regarding the competitive success, if we have statistical significance at 24 weeks, we'll be the only incretin that has even attempted a readout at 24 weeks, let alone has success at 24 weeks. That's because unlike semaglutide, which you mentioned, or tirzepatide, we have direct effects on the liver. Want to remind you that semaglutide conducted a phase II trial about the same size as IMPACT about 2 years ago, and even going all the way out to 72 weeks, failed to show statistical significance. We expect to show it at just 24 weeks, so it's a much more potent compound. If you listen to the experts out there who are treating MASH, they don't really rely on the anti-fibrotic effect of semaglutide.

Scott Harris: If you listen to the experts out there who are treating MASH, they don't really... rely on the antifibrotic defect of semaglutide. They see it as being weaker than resdifra and there's a lot of concern about using it in their advanced patients. We know, for example, that they failed in a cirrhosis study in which the placebo actually did better than the drug. So regarding all of the incretins, we think we have a more potent effect and simply reading out in statistical significance at 24 weeks will separate us. Now, regarding the FGF21s, which have had successful readouts at 24 weeks and which has guided us to actually make the decision to study the endpoint at 24 weeks, and as I mentioned before, we believe we can be successful because we actually have better liver fat reduction in the FGF21s.

Scott Harris: They see it as being weaker than Rezdiffra, and there's a lot of concern about using it in their advanced patients. We know, for example, that they failed in a cirrhosis study in which the placebo actually did better than the drug. Regarding all of the incretins, we think we have a more potent effect, and simply reading out in statistical significance at 24 weeks will separate us. Regarding the FGF21s, which have had successful readouts at 24 weeks, and which has guided us to actually make the decision to study the endpoint at 24 weeks. As I mentioned before, we believe we can be successful because we actually have better liver fat reduction than the FGF21s. We think our probability of success is even greater, is the FGF21s do not have weight loss, nor does Rezdiffra.

Scott Harris: We think our probability of success is even greater is the FGF21s do not have weight loss, nor does resdifra. So you hear doctors talking about using resdifra for advanced MASH with F3 fibrosis, but when the patient needs weight loss, they add semaglutide. That won't be necessary. With pembidutide, you get both. You get the weight loss and the potent effects in fibrosis. So we think not only in terms of our upcoming readout, but in terms of our competition in the evolving marketplace, that we're gonna have a very successful drug.

Scott Harris: You hear doctors talking about using Rezdiffra for advanced MASH with F3 fibrosis, but when the patient needs weight loss, they add semaglutide. That won't be necessary. With pemvidutide, you get both. You get the weight loss and the potent effects in fibrosis. We think not only in terms of our upcoming readout, but in terms of our competition in the evolving marketplace, that we're going to have a very successful drug.

Annabel Samimy: Great. If I could just ask 1 more question, are you going to be releasing any other exploratory or secondary endpoints on this top-line readout?

Scott Harris: Great. And if I could ask one more question, are you going to be releasing any other exploratory or secondary endpoints on this top line readout? Yeah, we're still planning the readout. Obviously, there's only so much we can do in a top line readout, but we'll try to provide as much data as we can. Great, thank you so much. Thank you.

Scott Harris: Yeah. We are still planning the readout. Obviously, there's only so much we can do in a top-line readout, but we'll try to provide as much data as we can.

Annabel Samimy: Great. Thank you so much.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Liisa Bayko from Evercore.

Operator: One moment for our next question. Our next question comes from the line of Liisa Bayko from Evergreen. Hi there, I'm wondering if you could just talk through the overall strategy of, you know, pursuing Pivotal Studies for PEMBA-DUTAI. in the MASH population, as well as bringing on some new indications. You know, how do you prioritize it and fund all of this stuff from here? Just curious about your thinking and prioritizing all of that as well. I know the obesity is kind of lingering in our background, waiting for partnership, but just love some clarity and thoughts on prioritizing.

Liisa Bayko: Hi there. I'm wondering if you could just talk through the overall strategy of pursuing pivotal studies for pemvidutide in the MASH population, as well as bringing on some new indications. How do you prioritize it and fund all of this stuff from here? Just curious about your thinking in prioritizing all of that as well with the I know the obesity is kind of lingering there in the background waiting for partnership. Just love some clarity and thoughts on prioritization there. Thank you.

Vipin Garg: Good morning, Liisa. Thank you. Thank you for the question. Everything we are doing with pemvidutide, you'll see when we talk about these indications, are really tied to the liver benefits, are tied to really the dual mechanism of action of pemvidutide. It will be all highlighted in our indications. The additional indications, the phase II program, is very inexpensive, relatively speaking. We think that's additional validation of the mechanism and will provide optionality in terms of expanding the indications for pemvidutide beyond MASH. Our focus will continue to be on MASH and executing the phase III program on MASH, which, as you know, we're very excited about. We think we have the best-in-class agent for pursuing that.

Liisa Bayko: Yeah, good morning, Liisa. Thank you. Thank you for the question. Everything we are doing with pemvidutide, you'll see when we talk about these indications, are really tied to the liver benefits, are tied to the really the mechanism, the dual mechanism of action of pemvidutide. So it'll be all highlighted in our indications. The additional indications, the Phase II program is very inexpensive, relatively speaking. We think that's additional validation of the mechanism and will provide optionality in terms of adding, expanding the indications for pemvidutide beyond MASH. Our focus will continue to be on MASH and executing the Phase III program on MASH, which, as you know, we're very excited about.

Vipin Garg: We think we have the best-in-class agent for pursuing that. So when we get to the end of be looking at multiple indications that we could pursue in parallel with MASH by having data, Phase II data, in these additional indications at the same time.

Vipin Garg: When we get to the end of 2026, we could be looking at multiple indications that we could pursue in parallel with MASH by having phase II data in these additional indications at the same time.

Liisa Bayko: Okay. For the upcoming phase IIb data on MASH, can you give us a sense of what you think the bar is to have the competitive profile both on weight loss and fibrosis reversal?

Scott Harris: Okay, and then for the upcoming phase 2b data on MASH, can you give us a sense of what you kind of think the bar is to have the competitive profile both on weight loss and fibrosis? Scott. Yeah. You know, the redox of the FGF21s have had different placebo responses, et cetera, different treatment effects. So it's a bit hard to compare it exactly to that as a percentage. We think the key metric is to achieve statistical significance. because we know that's something that the Inkertons could never get, and then we compete against the FGF21s on weight loss.

Vipin Garg: Scott?

Scott Harris: Yeah. The readouts of the FGF21s have had different placebo responses, et cetera, different treatment effects. It's a bit hard to compare it exactly to that as a percentage. We think the key metric is to achieve statistical significance, because we know that's something that the incretins could never get, and then we compete against the FGF21s on weight loss.

Vipin Garg: The other thing I would add to that is that if we get statistical significance at 24 weeks, we know the response is only going to get better with time. When you go from 24 to 48 to 72 weeks and beyond, we've seen that in other programs, that longer treatment, you will see even additional benefit. More patients will respond. The response rate will become higher with time.

Scott Harris: The other thing I would add to that is that if we get statistical significance at 24 weeks, we know the response is only going to get better with time. So when you go from 24 to 48 to 72 weeks and beyond, we've seen that in other programs that longer treatment, you will see even additional benefit, more patients will respond, the response rate will go, will become higher with time. So achieving statistical significance at 24-week really sets us up well.

Liisa Bayko: Okay.

Vipin Garg: Achieving statistical significance at 24 weeks really sets us up well.

Liisa Bayko: How do you think of survodutide and retatrutide as comps at this juncture?

Scott Harris: And how do you think of Cervidutide and Ritadutide as comps at this juncture? Yeah, well, as you know, there's really no indication at this point that rettature tide is being developed for MASH. That data is over two years old, and we've not seen motion. We think that cervidute tide readout was nice. We think that the effects that were observed were a clear indication of the benefit of glucagon and its direct effects. We think it really confirmed our mechanism. I would emphasize, though, that we'll do better. We have more glucagon in our molecule. That's what drove the additional improvement over the other incretins.

Scott Harris: Well, as you know, there's really no indication at this point that retatrutide is being developed for MASH. That data is over 2 years old, and we've not seen motion. We think the survodutide readout was nice. We think that the effects that were observed were a clear indication of the benefit of glucagon and its direct effects. We think it really confirmed our mechanism. I would emphasize, though, that we'll do better. We have more glucagon in our molecule. That's what drove the additional improvement over the other incretins, and we have greater liver defatting effects. Their defatting effects at 24 weeks is about 62%, ours is 76%, and that's the major driver of MASH resolution and fibrosis improvement. I think even more importantly, we differentiate on safety and tolerability. On the tolerability front, we're giving pemvidutide without dose titration. No other incretin can even approach doing that.

Scott Harris: and we have greater liver defatting effects. Their defatting effects at 24 weeks is about 62%, ours is 76%, and that's the major driver of mass resolution and fibrosis improvement. I think even more importantly, we differentiate on safety and tolerability. On the tolerability front, we're giving PEMVIDUTIB without dose titration. No other incretin can even approach doing that. When that was done in some of the other programs, the rates of GI side effects were enormous. We're not experiencing that. With Cervidutide, even at their lowest dose, they're seeing 20% adverse event discontinuation rates, and that was with 20 weeks of dose titration.

Scott Harris: When that was done in some of the other programs, the rates of GI side effects were enormous. We're not experiencing that. With survodutide, even at their lowest dose, they're seeing 20% adverse event discontinuation rates, and that was with 20 weeks of dose titration. Remember, we're not having dose titration. We believe in the tolerability profile of our compound. In fact, they're now extending their titration up to between 24 and 32 weeks. We clearly differentiate on tolerability, and I want to also remind everyone that we went to an end of phase II meeting with the FDA, where FDA identified no safety signals in our compound and told us to proceed with 4 efficacy trials without a committed cardiovascular safety trial. We don't know the details, but that apparently was not the case with survodutide, where they're doing a cardiovascular safety trial.

Scott Harris: Remember, we're not having dose titration. We believe in the tolerability profile of our compound, and in fact, they're now extending their titration up to between 24 and 32 weeks. So we clearly differentiate on tolerability. And I want to also remind everyone that we went to an end of phase two meeting with the FDA, where FDA identified no safety signals in our compound and told us to proceed with four efficacy trials without a committed cardiovascular safety trial. We don't know the details, but that apparently was not the case with Cervidutide, where they're doing a cardiovascular safety trial.

Scott Harris: It's not like SELECT, where you show the benefit over a placebo for reducing cardiac rates. It's to show that the compound does no harm versus the standard of care. That's a very different look at the molecule. We don't know what conversation they had with the FDA, but we want to emphasize that's not the conversation that we had with FDA. They saw no signals, and they confirmed the safety of the compound. That's an important platform for going forward for all of our trials, not just in obesity, but in MASH and the two indications as well. We've had over 500 subjects in completed trials and close to 700, including the ongoing trials, and we've maintained the safety profile of pemvidutide. You don't get to play in the space without safety.

Scott Harris: It's not like Select, where you show the benefit over a placebo for reducing cardiac rates. It's to show that the compound does no harm versus the standard of care. That's a very, very different look at the molecule. We don't know a conversation they had with the FDA, but we want to emphasize that's not the conversation that we had with FDA. They saw no signals, and they confirmed the safety of the compound. And that's an important platform for going forward for all of our trials, not just in obesity, but in MASH and the two indications as well.

Scott Roberts: We've had over 500 subjects and completed trials, and close to 700 including the ongoing trials, and we've maintained the safety profile of Pembidutide. And you don't get to play in the space without safety. As you recall, with Pembidutide, they saw a signal of arrhythmias, and we know that they have very substantial heart rate increases. We don't have that. Okay, great.

Scott Harris: As you recall, with retatrutide, they saw a signal of arrhythmias, and we know that they have very substantial heart rate increases. We don't have that.

Liisa Bayko: Okay, great. Then just, should we expect any update at your R&D Day on your oral form of pemvidutide? Has there been any progress there? That's my final question. Thanks.

Scott Roberts: And then just, um, what should we expect any update at your R&D day on your oral form of pembidutide? And has there been any progress there? That's my final question.

Vipin Garg: Scot Roberts, do you want to take that?

Scott Roberts: Scott Roberts, you want to take that? Yeah, I think that at the R&D day, we'll be focusing on the new indications. I think that that's where everybody's attention is, and so that'll be the focus of that day. As far as progress on the oral formulations, we're excited about what we're seeing here. As I've mentioned before, we have a number of parallel tracks that we're investigating. I think we're closing in on a bioavailability that makes commercial sense, that's always the consideration when you're talking about a normal formulation, which will always be less efficient as far as the amount of drug that you have to administer.

Scot Roberts: I think that at the R&D day, we'll be focusing on the new indications. I think that that's where everybody's attention is. That'll be the focus of that day. As far as progress on the oral formulations, we're excited about what we're seeing here. As I've mentioned before, we have a number of parallel tracks that we're investigating. I think we're closing in on a bioavailability that makes commercial sense.

Vipin Garg: The consideration when you talk about an oral formulation, which will always be less efficient as far as the amount of drug that you have to administer. Just stay tuned on that, but excited about the progress we're making.

Scott Roberts: So just stay tuned on that, but excited about the progress we're making.

Liisa Bayko: Thanks.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Ellie Merle from UBS.

Operator: Thank you.

Jasmine: One moment for our next question.

Jasmine: Our next question comes from the line of Ellie Merle from UBS.

[Analyst] (UBS): Hi, everyone. This is Jasmine on for Ellie. Thanks so much for taking our question. For the additional indications, I just want to get confirmation. For the 2 phase IIs starting this year, would these be cases where we can potentially see proof of concept data next year? Then I think, previously you had said you were thinking about up to 3 additional indications. Would that potential third one be something we could also see an IND from this year? Will we learn any more about this or any others at the R&D Day? Thanks.

Scott Harris: Hi, everyone, this is Jasmine on for Ellie. Thanks so much for taking our question. So for the additional indications, I just want to get confirmation. So, for the 2 Phase 2s starting this year, would these be cases where we can potentially see proof of concept data next year? And then I think previously you said you were thinking about up to 3 additional indications. So, would that potential 3rd one be something we could also see an IND from this year? And will we learn any more about this or any others at the R&D day? Thanks.

Vipin Garg: Let me take the second part of the question, and Scot can answer the first part. As far as up to three, that's precisely what we said, that we'd look at up to three indications. We've got two on our plate, which we think is plenty for the time being. We'll continue to evaluate additional indications, but at this point, we're very happy having two active INDs and pursuing two additional indications beyond MASH. We're in really good shape there. Scot?

Vipin Garg: Let me take the second part of the question, and Scott can answer the first part. As far as up to three, that's precisely what we said, that we'll look at up to three indications. We've got two on our plate, which we think is plenty for the time being. We'll continue to evaluate additional indications, but at this point, we're very happy having two active INDs and pursuing two additional indications beyond MASH. So we're in really good shape there.

Scott Harris: Yeah. Thanks, Jas. Yes, both of these studies will be phase II proof of concept studies. For at least one of these indications, we expect to have data in 2026. There's the potential for a second, but we're not committing to that at this time. We do expect to have data in at least one of these additional indications from these proof of concept phase II studies in 2026, and we'll have to see about the second, whether that makes the cut by the end of the year.

Scott Harris: Scott? Yeah, and thanks, Jas. So, yes, both of these studies will be Phase II proof-of-concept studies, and for at least one of these indications, we expect to have data in 2026. There's the potential for a second, but we're not committing to that at this time. So we do expect to have data in at least one of these additional indications from these proof-of-concept Phase II studies in 2026, and we'll have to see about the second whether that makes the cut by the end of the year. Great, thank you. Thank you.

[Analyst] (UBS): Great. Thank you.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Mayank Mamtani from B. Riley Securities.

Operator: One moment for our next question.

William: Our next question comes from the line of Mayank Mamtani from B. Riley Security. Hi, yes, and thank you for taking our questions.

[Analyst] (B. Riley Securities): Hi, yes, thank you for taking our questions. This is William on for Mayank. Congratulations on a very nice year, and definitely looking forward to some of the data and events that are coming up. I did just want to dig in just a little bit more on the top-line data at IMPACT. I know that we'll be expecting sort of the fibrosis and liver fat reduction, and please correct me if I'm wrong there. I was also curious if we should be expecting fibrosis improvement and MASH resolution, sort of that combined endpoint. On statistical significance, could you speak to what treatment effect you're thinking that you'll need to hit that stat fibrosis endpoint? I have a follow-up.

Scott Harris: This is William on for Mayank. Congratulations on a very nice year and definitely looking forward to some of the data and events that are coming up. So I did just want to dig in just a little bit more on the top line data at impact. I know that we'll be expecting sort of the fibrosis and liver fat reduction, and please correct me if I'm wrong there, but I was also curious if we should be expecting fibrosis improvement and MASH resolution, sort of that combined end point. And then, you know, on statistical significance. You know, could you speak to what treatment effect you're thinking that you'll need to to hit that that's that Siegel and fibrosis endpoint?

Scott Harris: Well, thanks, William. Yes. The readout will include readouts in both MASH resolution and fibrosis improvement and also the combined endpoint, and we expect to hit all of those endpoints. In terms of the treatment effect, what we would say is that our goal is to hit statistical significance. There's been differences between studies and the actual treatment effects. We would say in terms of the study power, that we've actually powered the study to actually have a higher power for chances of success relative to the other FGF21 studies that have read out at 24 weeks. We have more subjects per treatment arm, and we're also going into the trials with greater liver fat reduction, which is the primary driver of these endpoints.

Scott Harris: Well, thanks, William. Yes, the readout will include readouts in both mass resolution and fibrosis improvement and also the combined endpoint and we expect to hit all of those endpoints. Um… In terms of the treatment effect. What we would say is that our goal is statistical significance. There's been differences between studies and the actual treatment effects. But we would say in terms of the study power, that we've actually powered this study. to actually have a higher power for chances of success relative to the other FGF21 studies that are read out in 24 weeks. We have more subjects per treatment arm, and we're also going into the trials with greater liver fat reduction, which is the primary driver of these endpoints.

Scott Harris: We think both in terms of a better treatment effect and having higher numbers of subjects to show it, that we're sufficiently powered, if not more powered, to achieve the effects that we're seeing by the FGF21s at 24 weeks.

Scott Harris: So we think both in terms of a better treatment effect and having higher numbers of subjects to show it that we're sufficiently powered, if not more powered, to achieve the effects that we're seeing by the FGF21s in 24 weeks.

[Analyst] (B. Riley Securities): Okay, thank you. Then just curious about the two new indications. Is it safe to assume or maybe give us some color, if you could? Should we be expecting these indications to be sort of based on or in the obesity subgroup? Or could they be something more akin to even a MASH or cardiovascular or something outside of obesity directly that may actually surprise us a little bit when you actually unveil these?

Vipin Garg: Okay, thank you. And then, just curious about the two new indications. Is it safe to assume, or maybe give us some color, if you could, should we be expecting these indications to be sort of based on or in the obesity subgroup? Or could they be something more akin to even a mash or cardiovascular or something outside of obesity directly that may surprise us a little bit when you actually unveil these? The only color I can provide, well, let me just say that we're going to be talking about all of this in two weeks' time, so please do stay tuned, and we look forward to seeing you there.

Vipin Garg: Well, let me just say that we're going to be talking about all of this in two weeks' time. Please do stay tuned, and we look forward to seeing you there. The color I can provide is that obesity cuts across all of these indications. It's a comorbidity that results into other comorbidities. People losing weight, there would be a benefit in all of these indications. That's how we're looking at it. One of the critical component of pemvidutide is the ability to achieve meaningful weight loss while also improving liver health. That's really how we are looking at the molecule, and everything we're doing going forward is trying to leverage that differentiation of pemvidutide, this combination of these two features, and you'll see that theme develop through these additional indications as well.

Vipin Garg: But the color I can provide is that obesity cuts across all of these indications. It's a comorbidity that, you know, that results into other comorbidities. So people losing weight, there would be a benefit in all of these indications. So that's how we're looking at it. One of the critical components of pambiduotide is the ability to achieve meaningful weight loss while also improving liver health. So that's really how we're looking at the molecule, and everything we're doing going forward is trying to leverage that differentiation of pambiduotide, this combination of these two features. And you'll see that theme develop through these additional indications as well.

[Analyst] (B. Riley Securities): Excellent. Thank you, and congratulations again on a very nice year. Scott, best of luck for you going forward. Congratulations.

William: Excellent, thank you and congratulations again on a very nice year and Scott, best of luck for you going forward. Thank you, William. Thank you.

Scott Harris: Thank you, Wayne.

Operator: Thank you. Our next question comes from the line of Jonathan Wolleben from Citizens JMP.

Jonathan Wolleben: Our next question comes from the line of Jonathan Wolleben from Citizens JMP. Hey, thanks for taking the questions. For me, in the past, we've talked a little bit about potentially seeing Reduced weight loss in MASH patients due to metabolic dysfunction for the same drugs than in a non-MASH population. I was wondering... Your current thinking there, if it's evolved, since we've seen some more data from other drugs and programs, and then, I guess, the elephant in the room is, you know, real-world adherence. We've seen pretty low discontinuations in Phase III programs from other incretins, but the real-world use not being, you know, sustained long-term.

Jonathan Wolleben: Hey, thanks for taking the questions. Two from me. In the past, we've talked a little bit about potentially seeing reduced weight loss in MASH patients due to metabolic dysfunction for the same drugs than in a non-MASH population. I was wondering your current thinking there, if it's evolved since we've seen some more data from other drugs and programs. I guess the elephant in the room is real-world adherence. We've seen pretty low discontinuations in phase III programs from other incretins, but the real-world use not being sustained long term. How do you think you could buck that trend, if there's anything in the data that could suggest you'll have a different profile in the real world?

Scott Harris: How do you think you could buck that trend? If there's anything in the data that could suggest you'll have a different profile in the real world?

Scott Harris: Jonathan, if I understand your first question, I would answer by saying that we're going to distinguish ourselves from the potent drugs which have direct acting effects in the liver, such as the FGF21s and to some extent Rezdiffra by offering weight loss that also has a meaningful effect on cardiovascular risk. The actual weight loss that we'll achieve in our trials will be probably greater in phase III because we've opted to use the 1.8 mg dose in our trial. That's because the dose response for liver fat reduction, and we believe MASH effects is different than weight loss. To run an efficient trial, we decided to study 1.2 mg and 1.8 mg to study the dose response and to demonstrate that. By the way, that's not been seen with other compounds, that would be a success.

Scott Harris: Jonathan, if I understand your first question. I would answer by saying that we're going to distinguish ourselves. from the potent drugs which have direct acting effects in the liver. such as the FGF21s, and to some extent, RISC-Differer, by offering... Weight Loss That Also Has a Meaningful Effect on Cardiovascular Risk. The actual weight loss that we'll achieve in our trials will be probably greater in phase three because we've opted to use the 1.8 milligram dose in our trial. And that's because the dose response for liver fat reduction, and we believe mass effects is different than weight loss.

Scott Harris: So to run an efficient trial, we decided to study 1.2 and 1.8 milligrams. We're going to study the dose-response and to demonstrate that, and by the way, that's not been seen with other compounds, so that would be a success. But we have the optionality to add the 2.4 milligram dose and back phase three and create a target product profile with not only potent mass effects, but the type of weight loss that we saw in the momentum trial. With regards to real-world adherence, we believe that we're going to have very competitive compliance in this program and also discontinuations.

Scott Harris: We have the optionality to add the 2.4 mg dose in back phase III and create a target product profile with not only potent MASH effects, but the type of weight loss that we saw in the MOMENTUM trial. With regards to real-world adherence, we believe that we're going to have very competitive compliance in this program and also discontinuations. I can't give you a preview of the data. We saw in our MASLD trials and also our diabetes trial, very low adverse event discontinuation rates, and we think this is going to also carry over to the IMPACT trial. I can simply say in terms of the way that trial is going from a view of 10,000 feet, we're very happy with the way that trial is going.

Scott Harris: I can give you a preview of the data we saw in our MASL-D trials and also our diabetes trial, very low adverse event discontinuation rates, and we think this is going to also carry over to the IMPACT trial. I can simply say in terms of the way that trial is going from a view of 10,000 feet, we're very happy with the way that trial is going.

Jonathan Wolleben: Okay. Thanks, Scott. Appreciate it.

Scott Harris: Okay, thanks, Scott. Appreciate it. Thank you.

Operator: Thank you. One moment for our next question. Our next question comes from the line of Patrick Trucchio from H.C. Wainwright & Co.

Operator: One moment for our next question.

Patrick Trucchio: Our next question comes from the line of Patrick Trucchio from HC Wainwright and Company. Thanks. Good morning. A few follow-ups on MASH.

Patrick Trucchio: Thanks. Good morning. A few follow-ups on MASH. First, on IMPACT. Specifically, I was wondering if you could elaborate a little bit more on that triple reader model technique and blinded rereads. How does that compare to approaches used in prior MASH trials to control placebo effects? Secondly, regarding the phase III timing, if the end of phase II meeting occurs by year-end, when could the registrational phase III trial in MASH begin? Last on MASH, regarding phase III planning, will you design the phase III MASH program run in parallel with additional trials and other metabolic indications? How would you prioritize the sequence of development?

Scott Harris: First, on impact, specifically, I was wondering if you could elaborate a little bit more on that triple reader model technique and blinded re-reads. How does that compare to approaches used in prior MASH trials to control placebo effects? Secondly, regarding the phase three timing, at the end of phase two, meeting occurs by year end. When could the registrational phase three trial in MASH begin? And last on MASH, regarding phase three planning, will you design a phase three MASH program run in parallel with additional trials and other metabolic indications? How would you prioritize the sequence of development?

Scott Harris: Patrick, I'll handle the first two, and then I'll turn to Vipin to answer the third. The 3-reader approach that we're using is identical to the approach used by 89bio and pegozafermin in their trial. We think they learned a tremendous amount by their predecessors, this 3-reader approach was advocated by Stephen Harrison. The way it works is that each reader reads individually, then, if there is agreement of all 3, fine. If it's 2 of the 3, you take that, and if none of the 3 agree, then they go to an adjudication. We know that happens very uncommonly, so that's what's called the mode approach. With that, combined with the strict guidances given to the pathologists for reading the biopsy, they were able to get their placebo response rate down to 7%.

Scott Harris: Patrick, I'll handle the first two, and then I'll turn to Vipin to answer the third. So the three-reader approach that we're using is identical to the approach used by 89Bio and Pegasoferman in their trial. We think they learned a tremendous amount. by their predecessors. And this three-reader approach was advocated by Stephen Harrison. and the way it works is that each reader reads individually. And then if there is agreement of all three, fine. If it's two of the three, you take that. And if none of the three agree, then they go to an adjudication. We know that happens very uncommonly.

Scott Harris: So that's what's called the mode approach. And with that, combined. With the strict guidances given to the pathologists for reading the biopsy, they were able to get their placebo response rate down to 7%. using a somewhat similar approach. in the RISC-DFIR program, although it's different, but like. our study. and the Pegasoferman study, rereading all of the biopsies, scrambling them so the pathologists are totally blinded to the time of the biopsy and the sequence. It takes out the bias. of a higher severity score early on because pathologists are trying to help the sponsor by getting the patients into the trial, and a lower score later on when they believe they're reading post-treatment biopsies.

Scott Harris: Using a somewhat similar approach in the Rezdiffra program, although it's different. Like our study and the pegozafermin study, rereading all of the biopsies, scrambling them so the pathologists are totally blinded to the time of the biopsy and the sequence. It takes out the bias of a higher severity score early on because pathologists are trying to help the sponsor by getting the patients into the trial, and a lower score later on when they believe they're reading post-treatment biopsies. You can see without any effects of placebo, simply because of reader bias, you can get placebo responses. We know that in the semaglutide program, when they didn't do that, they had a 30% placebo response.

Scott Harris: You can see without any effects of placebo, simply because of reader bias, you can get placebo responses. And we know that in the semaglutide program, when they didn't do that, they had a 30 percent placebo response. So combined with that, the three mode approach, three reader mode approach, and also the guidance given to pathologists, we believe that we're gonna get very controllable placebo response rates that will aid us in getting statistical significance.

Scott Harris: Combined with that, the 3 reader mode approach, and also the guidance given the pathologists, we believe that we're going to get very controllable placebo response rates that will aid us in getting statistical significance. Regarding your second question, yes, we do expect to have an end of phase II meeting with the FDA by year-end, and that would enable us to commence our phase III program in Q1 of 2026. I'll turn the mic over to Vipin for the third question.

Scott Harris: Regarding your second question, yes, we do expect to have an end-of-Phase II meeting with the FDA by year-end, and that would enable us to commence our Phase III program in the first quarter of 2020. 26.

Vipin Garg: And I'll turn the mic over to Vipin for the third question. Yeah, I think it's also important to remind everyone that it's a 48, the impact trial, even though we are, our primary endpoint is at 24 weeks, it's really a 48 week trial. So the impact trial, we would still be collecting additional data. So we're actually planning to have an end of phase two meeting before all of the data is in, and we'll submit that data once that becomes available, the safety data, as well as biomarker data that we will be collecting all the way through 48 weeks.

Vipin Garg: Yeah, I think it's also important to remind everyone that the IMPACT trial, even though our primary endpoint is at 24 weeks, it's really a 48-week trial. The IMPACT trial, we would still be collecting additional data. We're actually planning to have our end of phase II meeting before all of the data is in, and we'll submit that data once that becomes available, the safety data, as well as biomarker data that we will be collecting all the way through 48 weeks. It's a 48-week trial. That trial is already ongoing, or it's fully enrolled at this point. It's simply a matter of collecting all of the data and compiling it and making it available to the FDA around the time of the phase III meeting or after that. That's how that will play out.

Vipin Garg: So it's a 48 week trial. So that trial is already ongoing, or, you know, it's fully enrolled at this point, it's simply a matter of collecting all of the data and, you know, compiling it and making it available to the FDA around the time of the phase three meeting or after that. So that's how that will play out. You know, we're fully focused on executing that phase three program as efficiently and as quickly as possible in 2026. As far as the additional trial, that's happening right now in parallel while we are waiting for all of the information on impact trial.

Vipin Garg: We're fully focused on executing that phase III program as efficiently and as quickly as possible in 2026. As far as the additional trial, that's happening right now in parallel while we're waiting for all of the information on IMPACT trial. Those are much smaller proof of concept phase II efficacy studies. The goal there, as we've stated all along, is really to create additional expansion of indications for pemvidutide that sort of leverage the mechanism that we've been working with. We think it's easy to sequence them and still have additional data from these studies while we are initiating a phase III program for MASH.

Vipin Garg: And those are much smaller proof of concept phase two efficacy studies. The goal there, as we've stated all along, is really to create additional expansion of indications for Pembidutide that sort of take, leverage the mechanism that we've been working with. So we think, you know, it's easy to sequence them and still have data, additional data from these studies while we are initiating a phase three program for MASH. Great. Thanks so much. Thank you.

Patrick Trucchio: Great. Thanks so much.

Operator: Thank you. At this time, I would now like to turn the conference back over to Vipin Garg for closing remarks.

Vipin Garg: At this time, I would now like to turn the conference back over to Vipin Garg for closing remarks. Thank you everyone for joining our call today. As always, we sincerely appreciate your continued support and interest in Altimmune as we work diligently to advance family duty.

Vipin Garg: Well, thank you, everyone, for joining our call today. As always, we sincerely appreciate your continued support and interest in Altimmune as we work diligently to advance pemvidutide. Thank you again for your time today.

Vipin Garg: Thank you again for your time today.

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

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

Operator: Thank you for watching!