Q4 2024 Amylyx Pharmaceuticals Inc Earnings Call

Operator: Good morning, my name is Jenny, and I will be your conference operator today.

Good morning, My name is Jackie and.

I will be your conference operator today.

Lindsey Allen: At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals 4th Quarter and Full Year 2024 Earnings Conference Call. All participants will be in a listen-only mode. After today's presentation, there will be an opportunity to ask questions. To ask a question, please press star 1 on your telephone keypad. To withdraw your question, please press start. Please limit your questions to one with one follow-up. If you have additional questions, you may rejoin the Q&A.

At this time.

Speaker Change: I would like to welcome everyone.

Speaker Change: <unk> Pharmaceuticals fourth quarter and full year 2024 earnings conference call.

Speaker Change: All participants will be in listen only mode.

Speaker Change: After todays presentation, there will be an opportunity to ask questions to.

Speaker Change: To ask a question. Please press star one on your telephone keypad.

Speaker Change: So we do all your question.

Speaker Change: Press Star two.

Speaker Change: Please limit your questions to one with one follow up.

Speaker Change: If you have additional questions you may rejoin the queue.

Operator: Please be advised that this call is being recorded at the company's request.

Speaker Change: Please be advised that this call is being recorded at the company's request.

Lindsey Allen: I would now like to turn the call over to Lindsey Allen, Head, Investor Relations and Communications. Please proceed.

Lindsay Allen: I'd now like to try to call it back to Lindsay Allen.

Speaker Change: Investor Relations and Communications proceed.

Justin Klee: Good morning, and thank you all for joining us today to discuss our fourth quarter and full year 2024 financial results.

Speaker Change: Good morning, and thank you all for joining us today to discuss our fourth quarter and full year 2024 financial results.

Justin Klee: With me on the call today are Josh Cohen and Justin Klee, our co-CEOs, Dr. Camille Bedrosian, our Chief Medical Officer, and Jim Frates, our Chief Financial Officer.

Speaker Change: With me on the call today are Josh Cohen, and just thankfully our co Ceos, Dr. Camille Bedrosian, Chief Medical Officer, and Jim <unk>, Our Chief Financial Officer before we begin I would like to remind everyone that any statements. We make are information presented on this call that are not historical facts are.

Justin Klee: Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans, and expectations, and are made pursuant to the safe harbors provision of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectation with respect to Avexitide, AMX 35, and AMX 114, statements regarding regulatory and clinical development, the impact thereof, and the expected timing thereof, and statements regarding our cash runway. Actual events and results could differ materially from those expressed or implied by any forward-looking statements.

Speaker Change: We're looking statements that are based on our current beliefs plans and expectations and are made pursuant to the safe harbor's provision of the private Securities Litigation Reform Act of 1995. These statements include but are not limited to our expectation.

Speaker Change: With respect to and back to tide, Amex, 35, and Amex 114 statements regarding regulatory and clinical development the impact thereof, and the expected timing thereof, and statements regarding our cash runway actual events and results could differ materially from those expressed or implied by any forward looking statements.

Justin Klee: You are cautioned not to place any undue reliance on these forward-looking statements, and MLS disclaims any obligation to update such statements unless required by law.

Speaker Change: You are cautioned not to place any undue reliance on these forward looking statements and Emma Emma Watts disclaims any obligation to update such statements unless required by law now ill turn the call over to Justin.

Justin Klee: Now, I will turn the call over to Justin. Good morning, and thank you for joining us. As we look to 2025 and 2026, we're entering a pivotal stage for Amylyx, with key milestones across three assets in four ongoing clinical trials, all targeting orphan diseases with few or no treatment options. We're excited to have started the pivotal study of Avexitide for the treatment of post-bariatric hypoglycemia and anticipate top line results in the first half of next year. We also recently completed a financing, raising approximately $65.5 million to begin commercial preparations for Vexotide and to extend our cash runway through the end of 2026.

Justin: Good morning, and thank you for joining us.

Justin: As we look to 2025 and 2026, we're entering a pivotal stage for analytics with key milestones across three assets in four ongoing clinical trials, all targeting orphan diseases with few or no treatment options.

Justin: We are excited to have started the pivotal study that extra tied for the treatment of post bariatric hypoglycemia and anticipate topline results in the first half of next year.

Justin: We also recently completed a financing raising approximately $65 $5 billion to begin commercial preparations for the extra time and to extend our cash runway through the end of 2026.

Justin Klee: Over the next 12 to 15 months, we are focused on execution as we look forward to three key data readouts. Our lead asset Avexitide is an investigational GLP-1 receptor antagonist with FDA breakthrough therapy designation in post-bariatric hypoglycemia, or PBH, as well as orphan drug designation. PBH is a debilitating condition that leads to persistent and often progressive hypoglycemia. There are no treatments approved for the approximately 160,000 people living with PBH in the U.S. today. Avexitide has already been studied in five clinical trials of PVH that showed consistent dose-dependent statistically significant reductions in hypoglycemia. We started recruiting Lucidity, our pivotal 16-week phase 3 clinical trial, in mid-February and expect that the first study participant will be dosed in March or April.

Justin: Over the next 12 to 15 months, we are focused on execution as we look forward to three key data readouts.

Our lead asset <unk> is an investigational G O P. One receptor antagonist with FDA breakthrough therapy designation in post bariatric hypoglycemia or PVH as well as orphan drug designation.

Justin: PVH is a debilitating condition that leads to persistent and often progressive hypoglycemia.

There are no treatments approved for the approximately 160000 people living with PVH and the U S. Today.

Justin: That's the tide has already been studied in five clinical trials with PVH that showed consistent dose dependent statistically significant reductions in hypoglycemia.

Justin: We started recruiting lucidity, our pivotal 16 week phase III clinical trial in mid February and expect that the first study participant will be dosed in March or April.

Justin Klee: We expect to complete recruitment of the approximately 75 participants by the end of this year and anticipate top-line data in the first half of 2026.

Justin: We expect to complete recruitment of the approximately 75 participants by the end of this year and anticipate top line data in the first half of 2026.

Justin Klee: Next in our pipeline is AMX35, a combination small molecule that is designed to target endoplasmic reticulum, or ER, stress, and mitochondrial dysfunction. AMX-35 is currently being evaluated in Wolfram syndrome and progressive supernuclear palsy, or PSP, two diseases characterized by ER stress and mitochondrial dysfunction. Wolfram syndrome is a rare, fatal, monogenic, progressive, diabetic and neurodegenerative disease affecting an estimated 3000 people in the US. There are no approved treatments. Like many childhood onset monogenic diseases, the pathophysiology of Wolfram syndrome is well characterized. Our program is focused on people who carry mutations in the WFS1 gene, which encodes a protein called Wolframin that spans the membrane of the endoplasmic reticulum.

Justin: Next in our pipeline is amex 35, a combination small molecule that is designed to target endoplasmic reticulum or E are stressed and mitochondrial dysfunction.

Justin: M. F 35 is currently being evaluated in Wolfram syndrome in progressive Supranuclear palsy, or PSP chew diseases characterized by ear stress and mitochondrial dysfunction.

Justin: Wolfram syndrome is a rare fatal monogenic progressive diabetic and neurodegenerative disease affecting an estimated 3000 people in the U S.

Justin: There are no approved treatments.

Justin: Like many childhood onset ontogenetic diseases, the pathophysiology of Wolfram syndrome is well characterized.

Justin: Our program is focused on people, who carry mutations in the <unk>, one gene, which encodes the protein called we'll frame that spans the membrane of the endoplasmic reticulum.

Justin Klee: These mutations in Wolframin directly cause ER stress and mitochondrial dysfunction. Last year, we reported our first clinical data in people with Wolfram syndrome. In our 12-person Phase 2 Open Label Helios study, participants showed improvement or stabilization across all measured outcomes. We are continuing to follow participants in the ongoing Helios trial and expect to share the week 48 data in the coming months. These data, along with regulatory interactions, will inform the design of a phase three trial. We are also anticipating an interim readout of our Phase 2b3 Orion trial, evaluating AMX35 and PSP in the third quarter 2025.

Justin: These mutations and we'll frame and directly cause ER stress and mitochondrial dysfunction.

Justin: Last year, we reported our first clinical data in people with Wolfram syndrome.

Justin: And our 12 person phase two open label Helios study participants showed improvement or stabilization across all measured outcomes.

Justin: We are continuing to follow the participants in the ongoing Helios trial and expect to share the week 48 data in the coming months.

Justin: These data along with regulatory interactions will inform the design of the phase III trial.

Justin: We are also anticipating an interim readout of our phase two b III Orion trial evaluating a M F 35, and PSP in the third quarter 2025.

Justin Klee: PSP is a rare, progressive, fatal neurodegenerative disease that affects an estimated 23,000 people in the U.S. at any one time and has no currently approved treatment. PSP is the most well-characterized pure tauopathy because all people with PSP have tau protein buildup in the brain. Genetics and model systems show that this abnormal tau buildup causes a characteristic brain degeneration and clinical presentation observed in the disease. AMX 35 previously demonstrated that it reduced tau measured in the cerebrospinal fluid of people with Alzheimer's disease. We believe AMX 35 is the first brain and cell penetrant agent that has previously shown significant tau protein reduction in CSF to be tested in PSP.

Justin: PSP is a rare progressive fatal neurodegenerative disease that affects an estimated 23000 people in the U S. At any one time and has no currently approved treatments.

Justin: PSP is the most well characterized curious how apathy because all people with PSP have tau protein buildup in the brain.

Justin: Genetics in model systems showed that this abnormal buildup causes a characteristic brain degeneration and clinical presentation observed in the disease.

Justin: Amex 35, previously demonstrated that it reduced Cal measured in this to reverse spinal fluid of people with Alzheimer's disease.

Justin: We believe a M. F 35 is the first brain and sell penetrate agent that has previously shown significant tau protein reduction in CSF to be tested in P. S T.

Justin Klee: The Phase 2b portion of our Phase 2b3 Orion trial evaluating AMX 35 and PSP was fully enrolled in January with a total of 139 participants randomized. We expect safety and efficacy data from an unblinded interim analysis in the third quarter of this year. These data will inform our decision whether or not to move into the phase three portion of the trial. Powering analyses published in the PSP literature estimate approximately 80% power to detect a 30% slowing in the rate of decline of PSPRS with this sample size.

Justin: The phase II portion of our phase two b III Orion trial evaluating <unk> five and P. S. T was fully enrolled in January with a total of 139 participants randomized.

Justin: We expect safety and efficacy data from an unblinded interim analysis in the third quarter of this year.

Justin: These data will inform our decision whether or not to move into the phase II portion of the trial.

Justin: Powering analysis published in the PSD literature estimate approximately 80% power to detect a 30% slowing the rate of decline of P. S. P. R S with the sample size.

Justin Klee: Our fourth clinical program is evaluating AMX 114 for the treatment of ALS. AMX 114 is an antisense oligonucleotide that knocks down Calpain-2, one of the key proteases driving axonal degeneration. Last month, the Phase I Multiple Ascending Dose Lumina Trial of AMX- and Recruiting in Canada. We are working diligently to open additional sites in Canada and the U.S. We started recruiting Lumina and expect the first participant host in March or April. We look forward to early cohort data from our Phase I Lumina trial expected later this year.

Speaker Change: Our fourth clinical program is evaluating <unk> hundred 14 for the treatment of ALS.

Speaker Change: M. S 114 is an antisense oligonucleotide that knocks down helping to one of the key protease is driving axonal degeneration.

Speaker Change: Last month, the phase one multiple ascending dose lumina trial of Amish.

Speaker Change: And recruiting in Canada.

Speaker Change: We are working diligently to open additional sites in Canada and the U S.

Speaker Change: We started recruiting lumina and expect our first participant dosed in March or April.

Speaker Change: We look forward to early cohort data from our phase one Lumina trial expected later this year.

Justin Klee: We're also actively working to build our pipeline in PBH and other rare diseases that may benefit from GLP-1 antagonism. Of particular note, at the end of last year, we announced a collaboration to develop a novel, long-acting GLP-1 receptor antagonist with Gubra. Gubra is an industry leader in peptide-based drug discovery. We will continue to focus on clinical execution as we look forward to milestones in each of our programs over the next 12 to 15 months.

Speaker Change: We're also actively working to build our pipeline and PVH and other rare diseases that may benefit from G. L. P. One antagonism.

Speaker Change: Of particular note at the end of last year, we announced the collaboration to develop a novel long acting G. O P. One receptor antagonist with Google.

Speaker Change: <unk> is an industry leader and peptide based drug discovery.

Speaker Change: We will continue to focus on clinical execution as we look forward to milestones in each of our programs over the next 12 to 15 months.

Camille Bedrosian: I will now pass it to Camille to speak further on our Phase III lucidity clinical trial of Avexitide and TBH. Thanks, Justin. We are very excited about the potential of Avexitai to become the first approved treatment for people living with PBH. This debilitating condition is believed to result from an excessive GOP1 response following bariatric surgery, leading to persistent, recurrent and debilitating hypoglycemic events that take a profound toll on a person's quality of life. There are no approved treatments for PBA. Despite dietary modifications and rescue measures, such as glucagon, people with P.B.H. still experience persistent symptoms with no sustainable management options.

Speaker Change: I will now pass the Camille to speak further on our phase III lucidity clinical trial, although that's the tide and PVH.

Speaker Change: Thanks, Justin we are very excited about the potential exit tied to become the first approved treatment for people living with PVH.

Speaker Change: This debilitating condition is believed to result from an excessive G. L. P. One response, following bariatric surgery, leading to persistent recurrent and debilitating hypoglycemic events.

Speaker Change: Take a profound toll on a person is quality of life there.

Speaker Change: There are no approved treatments for PVH.

Speaker Change: Despite dietary modifications and rescue measures such as glucagon people with PVH still experienced persistent symptoms with no sustainable management option.

Camille Bedrosian: and a potential first-in-class GLP-1 receptor antagonist, Avexitide is designed to bind to the GLP-1 receptor on pancreatic islet beta cells and inhibit the effects of excessive GLP-1 and PBH, mitigating hyperglycemia by decreasing insulin secretion and stabilizing blood glucose levels.

Speaker Change: And a potential first in class G. L. P. One receptor antagonist of exercises designed to bind to the G. L. P. One receptor on pancreatic islet beta cells and inhibits the effects of excessive G. L. P. One P. B H mitigating hyperglycemia by decreasing insulin secretion and stabilizing blood glucose levels.

Camille Bedrosian: In December 2024, we presented the design of our Pivotal Phase 3 lucidity clinical trial, evaluating Avexitide in participants with PBH following Roux-en-Y gastric bypass surgery. In February of this year, we started recruiting lucidity and expect to dose the first participant in March or April. The Phase 3 study is designed to have similar inclusion and exclusion criteria to the previous successful Phase 2 PREVENT trial that led to breakthrough therapy status, and the subsequent Phase 2B trial of Avexitide in PBH. Lucidity will evaluate the FDA-agreed-upon primary outcome of a reduction in the composite of Level 2 and Level 3 hypoglycemic events.

Speaker Change: In December 2024, we presented the design of our pivotal phase III and the city of the clinical trial evaluating of extra tied in participants with PVH following wrong Y gastric bypass surgery.

Speaker Change: In February of this year, we started recruiting lucidity and expect to dose the first participant in March or April.

Speaker Change: The phase III study is designed to have similar inclusion and exclusion criteria to the previous successful phase III trial that led to breakthrough therapy status and the subsequent phase two b trial of extra tired and PVH.

Speaker Change: Lucidity will evaluate the F D. A agreed upon primary outcome.

Speaker Change: There was a reduction in the composite of level, two and level III hypoglycemic events.

Camille Bedrosian: We believe there are many contributing factors for overall optimism for the study. We are encouraged by the engagement of the sites as they are activated, as well as the responsiveness of potential participants. The study team is fully engaged with the carefully chosen sites as they provide comprehensive training materials and facilitate site activation. Furthermore, the study has a number of blinded touch points and monitoring elements that will serve to support the study site staff and by extension the participants throughout the study.

Speaker Change: We believe there are many contributing factors for overall optimism for this study we are encouraged by the engagement of the sites as they are activated as long as the responsiveness of potential participants.

Speaker Change: The study team is fully engaged with the carefully chosen sites as they provide comprehensive training materials and facilitate site activation.

Speaker Change: Furthermore, the study has a number of blinded touch points and monitoring elements that will serve to support the study site staff and by extension the participants throughout the study.

Camille Bedrosian: Strength of the substantial clinical data generated to date for Vexotide underpins our confidence in the potential of this program. Across five clinical trials of Avexatide in people with PBH, there have been consistent dose dependent effects that we believe support its potential to become the first approved treatment option for PBH. and multiple early-stage trials in PBH and in healthy volunteers, Avexatide had a clear pharmacodynamic effect. Avexatide showed a rapid, statistically significant decrease in post-meal insulin levels and stabilization in plasma-glucose nadir. Data from two phase two trials of Avexatai demonstrated statistically significant and clinically meaningful reductions in hypoglycemic events and improvements in glucose control in PBH following Roux-en-Y gastric bypass surgery.

Speaker Change: The strength of the substantial clinical data generated to date from extra tie underpins our confidence in the potential of this program.

Across five clinical trials, there's extra tired and people with PVH never been consistent dose dependent effects that we believe support its potential to become the first approved treatment option for PVH.

Speaker Change: Multiple early stage trials and PVH N in healthy volunteers and that's the tie is a clear pharmacodynamic effects.

Speaker Change: <unk> showed a rabbits statistically significant decrease in post meal, and some levels and stabilization in plasma glucose nadir.

Speaker Change: Data from two phase two trials and as <unk> demonstrated statistically significant and clinically meaningful reductions in hypoglycemic events.

Speaker Change: And improvements in glucose control and PVH following raw y gastric bypass surgery.

Camille Bedrosian: In the Phase 2b trial, participants received 90 milligrams once daily of Avexatibe, the dose we are evaluating in our pivotal Phase 3 lucidity trial. Most notably, treatment with 90 milligrams of Avexatibe led to a statistically significant reduction in hyperglycemic amounts. Specifically, a 53% reduction in level 2 events with a p-value of 0.004, a 66% reduction in level 3 events with a p-value of 0.0003. 90 milligrams once daily of Avexatide also has demonstrated a favorable pharmacokinetic profile, maintaining exposure in the therapeutic range through 24 hours, supporting daily dosing. This property translated to a similar meaningful improvements in nadir glucose levels as measured by CGM, both during the day and overnight.

Speaker Change: In the phase II B trial participants received 90 milligrams once daily of extra tie the dose we are evaluating in our pivotal phase III, who Sydney trial.

Speaker Change: Most notably treatment with 90 milligrams of those extra time led to a statistically significant reduction in hypoglycemic events.

Speaker Change: Typically at 53% reduction in level two of them with a P value of 0.00 for a.

Speaker Change: A 66% reduction in level three events with a P value of 0.0003.

Speaker Change: 90 milligrams once daily of exercise also has demonstrated a favorable pharmacokinetic profile maintaining exposure in the therapeutic range through 24 hours supporting daily dosing.

Speaker Change: This property translate into a similar meaningful improvements and NATO glucose levels as measured by CGM, both during the day and overnight.

Camille Bedrosian: Abexotide was generally well tolerated, with a favorable safety profile replicated across the clinical trial.

Speaker Change: If extra tie was generally well tolerated with a favorable safety profile replicated across the clinical trial.

Camille Bedrosian: In summary, we are executing this important Phase 3 trial supported by compelling and consistent Evexa-Ti data and a dedicated study team.

Speaker Change: In summary, we are executing this important phase III trials supported by compelling and consistent as extra tie data and a dedicated study team.

Jim Frates: I will now turn over the call to Jim. Jim? Thanks, Camille. We ended 2024 in a solid cash. with $176.5 million, which does not include the approximately $65.5 million in net proceeds. from our public offering, which closed on January 13th.

Jim: I will now turn over the call to Jim.

Speaker Change: Jim.

Jim: Thanks Camille.

Jim: We ended 2024, and a solid cash position of $176 $5 million, which does not include the approximately $65 5 million in net proceeds from our public offering which closed on January 13 2025.

Jim Frates: With these resources, we expect our cash runway to take us through 2020.

Jim: With these resources, we expect our cash runway to take us through 2026.

Jim Frates: Now turning to the financial results for the quarter. Total operating expenses for Q4 were $39.9 million, down 62% from the same period in 2023. Research and development expenses were $22.9 million compared to $44.9 million in Q4 2020. primarily due to a decrease in spending on AMX 35 for the treatment of ALS, payroll and personnel related costs, and a decrease in preclinical development. Felling General and Administrative Expenses were $17.1 million. compared to $52.2 million in Q4 2020. primarily due to a decrease in payroll and personnel-related costs and a decrease in consulting and professional During the quarter, our ongoing operating expenses used roughly $27 million in cash.

Jim: Now turning to the financial results for the quarter.

Jim: Operating expenses for Q4 were $39 $9 million down 62% from the same period in 2023.

Jim: Research and development expenses were $22 9 million.

Jim: Compared to $44 9 million in Q4, 2023, primarily due to a decrease in spending on Amex 35 for the treatment of ALS payroll and personnel related costs and a decrease in preclinical development activities.

Jim: Selling general and administrative expenses were $17 1 million compared to $52 2 million in Q4 2023.

Jim: Primarily due to a decrease in payroll and personnel related costs and a decrease in consulting and professional services.

Jim: During the quarter, our ongoing operating expenses used roughly $27 million in cash.

Jim Frates: In addition, we used roughly $31 million in cash for previously recognized items related to our voluntary discontinuation of Rolivrio Albrioza in April of last year. These included payments for product returns and rebates and the final settlements of previous purchase commitments for AMEX 35 for commercial production. Going forward, we have approximately $7.8 million of these obligations remaining, which we expect will be paid through 2025.

Jim: In addition, we use roughly $31 million in cash for previously recognized items related to our voluntary discontinuation of <unk> in April of last year.

Jim: These included payments for product returns and rebates and the final settlements of previous purchase commitments for <unk> 35 for commercial production.

Jim: Going forward, we have approximately $7.8 million of these obligations remaining which we expect will be paid through 2025.

Jim Frates: Looking ahead, we believe we have the necessary cash to support our progress and to deliver on our planned clinical milestones through the end of 2020. These milestones are data from the Phase III lucidity trial of Avexitide and PBH. Data at week 48 from the ongoing Helios trial and Wolfram syndrome. The Unblinded Interim Analysis of the Phase IIb portion of our Orion Trial in PSP. and data from our Phase I Lumina trial of AMX114 and ALS. along with commercial preparations for the potential first-to-market launch of Avexitide.

Jim: Looking ahead, we believe we have the necessary cash to support our progress and to deliver on our planned clinical milestones through the end of 2026.

Jim: These milestones are data from the phase III, the Sydney trial of a versatile and PVH.

Data at week 48 from.

Jim: From the ongoing Helios trial in <unk> syndrome.

Jim: The unblinded interim analysis of the phase <unk> portion of our Orion trial in PSP.

Jim: And data from our phase one lumina trial of Amex, $1 14 and al.

Jim: Along with commercial preparations for the potential first to market launch of a versatile and PVH.

Josh Cohen: With that, I'll turn the call over to Josh to provide some closing remarks. Thank you, Jim. We are entering this year with strong momentum. We are focused on executing our clinical trials and making meaningful progress on preparing for a potential commercial launch of a GLP-1 receptor and tag.

Jim: With that I'll turn the call over to Josh to provide some closing remarks.

Josh Cohen: Thank you Jim we are entering this year with strong momentum we are focused on executing our clinical trials and making meaningful progress on preparing for a potential commercial launch of a G. O P. One receptor antagonist.

Josh Cohen: At the start of the year, we appointed Dan Monaghan as Chief Commercial Officer. Dan is leading our commercialization strategy across our portfolio, beginning with Avexiton. He brings more than two decades of commercial leadership experience launching industry-leading medicines at Otsuka, Novartis, and Santa Fe. With a proven commercial and medical team in place, we believe we are well positioned for a potential first of Avexatide and PBA. We estimate based on our projections from published literature and claims-based work that there are about 160,000 people in the United States who are living with PBH today, who have persistent symptoms despite dietary modifications, and who face a significant unmet need.

Josh Cohen: At the start of the year, we appointed Dan Monahan as Chief commercial officer.

Speaker Change: Dan is leading our commercialization strategy across our portfolio beginning with his expertise.

Speaker Change: He brings more than two decades of commercial leadership experience launching industry, leading medicines at Osaka Novartis in Santa Fe.

Speaker Change: With a proven commercial and medical team in place. We believe we are well positioned for a potential first.

Speaker Change: Although the extra tide and PVH.

Speaker Change: We estimate based on our projections from published literature and claims based work that there are about 160000 people in the United States, who are living with PVH today, who have persistent symptoms despite dietary modifications and in face of significant unmet need.

Josh Cohen: There is a new slide with these details in our updated corporate deck. PBH is rare. The condition doesn't happen to most of the millions of people who undergo bariatric surgery, and PBH does not present immediately. On average, symptoms appear approximately one to three years following bariatric surgery. Once people have PBH, the condition is chronic, debilitating, and often progressive. It can mean loss of work, inability to drive, and a state of disability. Bariatric surgery remains standard of care for addressing obesity, particularly for people who require significant and sustained weight loss, meaning the unmet need in PBH is only expected to continue to grow.

Speaker Change: There is a new slide with these details in our updated corporate deck.

Speaker Change: PVH is rare the condition doesn't happen to most of the millions of people, who undergo bariatric surgery and PVH does not present immediately.

Speaker Change: On average symptoms appear approximately one to three years following bariatric surgery.

Speaker Change: Once people have PVH the condition is chronic debilitating and often progresses it.

It can mean loss of work and ability to drive in a state of disability.

Speaker Change: Bariatric surgery remains standard of care for addressing obesity, particularly for people, who require significant and sustained weight loss meaningly unmet need and PVH is only expected to continue to grow.

Josh Cohen: We're preparing diligently ahead of the Avexatide Phase 3 top-line data, expected in the first half of next year, and, if approved, we anticipate commercial launch in 2027. In addition to Avexitide and PBH, we have exciting milestones ahead this year that have the potential to make a meaningful, positive impact on the other communities that we aim to serve. For AMX 35 and PSP, we expect top-line data from an unblinded interim analysis of the phase 2b portion of the Orion trial in the third quarter of this year. For AMX 35 and Wolfram syndrome, we are continuing to follow participants in the ongoing phase 2 Helios trial and expect to share week 48 data in the coming months.

Speaker Change: We're preparing diligently ahead of the <unk> phase III top line data expected in the first half of next year and if approved we anticipate commercial launch in 2027.

Speaker Change: In addition to <unk> and PVH, we are exciting milestones ahead. This year that have the potential to make a meaningful positive impact on the other communities that we aim to serve.

Speaker Change: <unk> 35 in PSP, we expect topline data from an unblinded interim analysis of the phase two b portion of the Orion trial in the third quarter of this year.

Speaker Change: For Amex 35, and Wolfram syndrome, we are continuing to follow the participants in the ongoing phase II Helios trial and expect to share a week 48 data in the coming months. These.

Josh Cohen: These data, along with regulatory interactions, will inform the design of a phase three trial. And we expect early cohort data from our Phase I Lumina ALS trial in 2025.

Speaker Change: These data along with regulatory interactions will inform the design of a phase III trial.

Speaker Change: And we expect early cohort data from our phase one alumina AOS trial in 2025.

Josh Cohen: We appreciate your continued support and look forward to keeping you updated on our progress toward developing novel therapies for people living with serious and fatal neurodegenerative diseases and endocrine conditions.

We appreciate your continued support and look forward to keeping you updated on our progress towards developing novel therapies for people living with serious and fatal neurodegenerative diseases and endocrine conditions now I would like to open the call up for questions.

Operator: Now I would like to open the call up for questions. Thank you. Ladies and gentlemen, we will now begin the question and answer session. To ask a question, please press star 1 on your telephone keypad. To withdraw your question, please press star 2. Please limit your questions to one with one follow-up. If you have additional questions, you may rejoin the Q&A.

Speaker Change: Yeah.

Speaker Change: Thank you.

Speaker Change: Ladies and gentlemen, we will now begin the question and answer session to ask a question.

Speaker Change: Press Star one on your telephone keypad.

Speaker Change: To withdraw your question. Please press star two.

Speaker Change: Please limit your questions to one with one follow up.

Speaker Change: Additional questions you may rejoin the queue.

Operator: At this time, we will pause momentarily to assemble our roster.

Speaker Change: At this time, we will pause momentarily to assemble our roster.

Speaker Change: Yeah.

Michael DiFiore: Your first question is from Michael DiFiore from Evercore ISI. Your line is now open. Hi, guys. Thanks so much for taking my questions, and congrats on all the progress.

Speaker Change: Your first question is from Michael Cherny from Evercore ISI. Your line is now open.

Michael Cherny: Hi, guys. Thanks, so much for taking my questions and congrats on all the progress two for me one on the PVH phase III, Oh, why limit the entry criteria to just ruin Y gastric bypass procedures are not included.

Michael DiFiore: Two for me, one on the PBH phase 3, why limit the entry criteria to just ruin-wide gastric bypass procedures and not include sleeve gastrectomy, especially when considering the greater prevalence of sleeve procedures?

Michael Cherny: Sleeve gastrectomy, especially when considering the greater prevalence of sleep procedures.

Michael DiFiore: And my follow-up is on the PSP Orion study. Could you remind us how efficacy will be interpreted in this study across regions given the use of the 10-item PSP rating scale in the U.S. as a primary and the 28-item PSP rating scale in ex-U.S. jurisdictions?

Michael Cherny: And my follow up is on the PSP.

Michael Cherny: PSP Orion study could you remind us how efficacy will be interpreted.

Michael Cherny: In this study across regions given the use of the item.

Michael Cherny: <unk> rating scale in the U S. As the primary and the 28 item PSP rating scale in ex U S jurisdictions. Thank you.

Camille Bedrosian: Thank you. Yes. Hi, Mike.

Michael Cherny: Yes, Hi, Mike. This is Camille. Thank you for the question with regard to rule on why and our lucidity trial.

Camille Bedrosian: This is Camille. Thank you for the question. With regard to Roux-en-Y in our lucidity trial, we have the most experience with Avexitibes from people who have experienced Roux-en-Y and then developed PBH. Having said that, we recognize that the pathophysiology is consistent across bariatric surgeries.

Speaker Change: Uh huh.

Michael Cherny: We have the.

Michael Cherny: The most experience with his expertise.

Michael Cherny: His experience on one and then develop PD.

Michael Cherny: Having said that we recognize that.

Michael Cherny: Does the Allergan is consistent.

Michael Cherny: Across bariatric surgery.

Josh Cohen: To minimize heterogeneity, though, we are limiting the enrollment to the alumni of Vexercide Health and expect later for Vexercide to be available for people with PBH generally. Yeah, and just going to the, you know, market dynamics as well. So I think first is underscoring Camille's point that we think that pathophysiology is the same, is really for trial criteria. So we'll have those discussions when appropriate with, with FDA. But, you know, Roux-en-Y gastric bypass, there have been about 600,000 people who've gotten Roux-en-Y gastric bypass over the each year who get a Roux-en-Y gastric bypass. So with, you know, 8%, we estimate about of people who get a bariatric procedure who get, who will develop PVH in the years following surgery, that's still a very substantial market.

Michael Cherny: To minimize heterogeneity, though we are limiting the amendment.

Speaker Change: Thanks Thats helpful.

Michael Cherny: And.

Michael Cherny: That's later.

Michael Cherny: Okay.

Michael Cherny: Applied to be available for people with PVH.

Michael Cherny: Hello.

Michael Cherny: Yeah, and just going to the <unk>.

Michael Cherny: Market dynamics as well so I think first is underscoring <unk> point that we think that pathophysiology is the same it was really for trial criteria.

Michael Cherny: So we'll have those.

Michael Cherny: Discussions when appropriate with with FDA.

Michael Cherny: But.

Michael Cherny: We wouldnt lie gastric bypass there've been about 600000 people who've gotten ruined Y gastric bypass over the past 10 years.

Michael Cherny: And they're roughly 60000 people each year forget it ruined like gastric bypass so 8% we estimate about.

Michael Cherny: People, who get a bariatric procedure.

Michael Cherny: <unk>, who will develop PVH and in the years following surgery, that's still a very substantial market but.

Josh Cohen: But, you know, but to say as well, you know, we think the pathophysiology is the same. So our, you know, ultimate intention is we think that this should be a treatment that would be used for PVH period.

Michael Cherny: But to say as well.

Michael Cherny: Thank the pathophysiology of the same so our ultimate intention is we think that this should be a treatment that.

Michael Cherny: That would be used for PVH period.

Camille Bedrosian: Yeah, and on your question on PSP, you know, about the 10-item versus the 28-item, so different, you know, regulators in different regions are, you know, interested in different ways of analyzing the PSP rating scale, as you mentioned. Our experience, however, is that these are pretty consistent, you know, it's not a, you know, big divergence to kind of look at the PSP 10-item versus the PSP 28-item. So, you know, frankly, in the study, we'll be looking at both, but again, we expect the results from both to be, you know, very similar. Got it, thank you. Thank you.

Michael Cherny: Yeah and on your question on PSP.

Michael Cherny: About the 10 item versus the 28 item so different regulators and different regions are interested in in different ways of analyzing the PSP rating scale as you mentioned.

Michael Cherny: Our experience. However is that these are pretty consistent it's not a big divergence to kind of look at the PSP 10 item versus the PSB 28 item.

Michael Cherny: So frankly in the study we'll be looking at both but again, we expect the results from both to be very similar.

Michael Cherny: Yeah.

Speaker Change: Got it thank you.

Michael Cherny: Yeah.

Speaker Change: Thank you. Your next question is from Tim Anderson from Bank of America. Your line is now open.

Susan: Your next question is from Tim Anderson from Bank of America. Your line is now open. Hi, good morning.

Steven: Hi, Good morning. This is Steven on for Tim Anderson <unk> two questions from Us the first one.

Susan: This is Susan on for Tim Anderson. Two questions from us. The first one, what is the target profile that you guys are looking to? with the long acting JLP. And if you can, how does this profile compare to other long acting jail people? like M. Jansmaritide and MatserisMet0979.

Steven: What is the target profile that you guys are looking to achieve with the long acting G. L. P. One.

Steven: And if you can how does this profile compared to other long acting GOP line.

Steven: Like Amgen's maritime terrorism that youre, the ninth of an eye.

Josh Cohen: Yeah, so maybe I'll take those in reverse, actually. So this is a GLP-1 antagonist. Those are GLP-1 agonists. So today, Avexacide is the only GLP-1 antagonist that has consistently shown reductions in insulin, raising the glucose nadir, reductions in hypoglycemia in people with PBH. And we think that a GLP-1 antagonist may have not just application in people with PBH, but potentially other diseases as well that are either characterized or accelerated by hyperinsulinemic hypoglycemia. You know, because we're quite excited about the mechanism, we think it makes sense to invest for the future. So that's why we started the research partnership with Gubra to develop a potential long-acting GLP-1 antagonist.

Steven: Yeah, So maybe I'll kick those in reverse actually so this is the <unk> antagonist are those are GOP one agonists.

Steven: So today.

Steven: <unk> is the only <unk> antagonist that has consistently shown reductions in insulin raising the glucose nadir.

Steven: Reductions in hypoglycemia and people with PVH.

Steven: And we think that a <unk> antagonist may.

Steven: They have not just application in people with PVH, but potentially other diseases as well that are either characterized or accelerated by hyper insulin EMEA hyperglycemia.

Steven: Because we're quite excited about the mechanism.

Steven: It makes sense to invest for the future.

Steven: So that's why we started the research partnership with Google.

Steven: To develop a potential long acting guilty one antagonist.

Josh Cohen: But we also think Avexacide has great potential. So we really see this as investing for the future.

Steven: We also think of <unk>. It has great potential so we really see this as investing for the future.

Steven: Okay.

Steven: Okay, and just one more so on your PVH market sizing a how are you guys forecasting.

Josh Cohen: And just one more, so on your PBH market sizing, how are you guys forecasting future patient numbers?

Josh Cohen: I guess I'm just trying to understand, I think the market will shrink, right, over time, given current use of GLP-1s, which would mean that fewer patients probably get bariatric surgery, and of course, bariatric surgery is a once and done type of procedure. Yeah, so maybe a couple of things. So first, our information actually is that the market will continue to grow, and maybe breaking that down. So first, bariatric surgery started becoming common in the United States in the early 2000s. And it's typically done in some, you know, to folks who are generally in their early 40s.

Speaker Change: Future patient numbers, I guess I'm, just trying to understand and I think the market. It will shrink rate over time, given current use of DLP, one which would.

Speaker Change: I mean that your patients probably get very I check surgery, and then of course aortic surgery as a one and done type of procedure.

Speaker Change: Yeah. So maybe a couple of things. So first artist nation actually is that the market will continue to grow and maybe breaking that down. So first bariatric surgery started becoming common in the United States and the early two thousands.

Speaker Change: Typically done.

Speaker Change: To folks who are generally in their early forty's.

Josh Cohen: So the population who have had bariatric surgery, you know, in the US today are generally in their 40s or 50s. PBH is chronic. You know, once people have PBH, they generally have it for the rest of their life. So all of those folks who have had bariatric surgery and now have PBH will have it for, you know, multiple upcoming decades. Then, you know, talking about kind of the ongoing bariatric surgeries, one, in talking to, you know, physicians and bariatric surgeons, we do hear that there continue to be, you know, there continues to be significant demand for bariatric surgeries.

Speaker Change: So the population, who how bariatric surgery.

Speaker Change: And in the U S. Today are generally in their forty's or fifty's.

Speaker Change: PVH is chronic.

Speaker Change: Once people have PVH, they generally habit for the rest of their life.

Speaker Change: So all of those folks who have had bariatric surgery and now have PVH will have it for multiple upcoming decades.

Speaker Change: And then talking about kind of the ongoing bariatric surgeries won in talking to.

Speaker Change: Physicians bariatric surgeons, we do hear that there continue to be there continues to be significant demand for bariatric surgeries and a lot of people described that there is a differentiation.

Josh Cohen: And a lot of people describe that there is a differentiation, you know, that the bariatric surgery is often used for those who are looking for very significant, you know, deep weight loss, in some cases, looking for over a hundred pounds of weight loss, whereas they might use the GLP-1, you know, in cases that, you know, maybe are less significant in terms of total weight loss. So, one, we hear that this, you know, continues to be, you know, quite in demand, which, you know, will continue to grow that pool that, you know, already exists today and will have it for the rest of their lives.

Speaker Change: That's a bariatric surgery is often used for those who are looking for very significant deep.

Speaker Change: Deep weight loss in some cases looking for over 100 pounds.

Speaker Change: Weight loss, whereas they might use the G. L P. One.

Speaker Change: In cases that maybe are less significant in terms of total weight loss. So.

Speaker Change: One we hear that this continues to be.

Speaker Change: Quite in demand.

Speaker Change: Which will continue to grow that pool that already exists today, and we will have it for the rest of their lives.

Josh Cohen: Yeah, and just underscoring that last point. So we estimate there are 160,000 people with post-bariatric hypoglycemia today. PBH does not go away. For example, we're working with someone who's had PBH for 18 years. So PBH is persistent. It doesn't go away. So the market will only continue to grow, not shrink. Thank you.

Speaker Change: Just just underscoring that last point. So we estimate there are 160000 people with post bariatric hypoglycemia todays PVH does not go away. For example, we're working with someone who said PVH for 18 years. So PVH is persistent it doesn't go away. So the market will only continue to grow.

Speaker Change: Not shrink.

Speaker Change: Thank you.

Speaker Change: Thank you. Our next question is from Joe <unk> from Baird. Your line is now open.

Joel Beatty: Your next question is from Joel Beatty from Baird. Your line is now open. Hi, thanks for taking the questions.

Speaker Change: Okay.

Speaker Change: Hi, Thanks for taking my questions.

Joel Beatty: For the Wolfram syndrome trial, could you discuss what you're looking for in the week 48 data that will help inform regulatory interactions?

Speaker Change: For the Wolfram syndrome trial could you discuss what youre looking for in a week 48 that will help inform our regulatory interactions and then for a vaccine tied.

Camille Bedrosian: And then for a Vox fatide, can you discuss the potential to develop that agent for other indications beyond PBH? Thank you. Thank you, Joel. This is Camille. Yes, as we described in October of last year, the week 24 data, and some individuals out to week 36 and week 48, we saw improvements in C-peptide response to a mixed meal, which is indicative of improved beta cell function, which is uncharacteristic for a disease that is neurodegenerative and beta cell degenerative. All other hypoglycemic control measures also moved in the same direction. And we are anticipating and looking forward to the possibility that at week 48, we'll see continued sustained improvements in all those measures, in addition to which the visual acuity, an indication of retinal ganglia cell health.

Speaker Change: Discuss the potential to develop the agent for other indications beyond PVH. Thank you.

Speaker Change: Yep. Thank you Joel this is <unk>.

Speaker Change: Yes, as we described in October of last year, There's a week 24 data and some individuals out to week 36 and week 48.

We saw improvements in C. Peptide response to a mixed meal, which is indicative of improved beta cell function, which is uncharacteristic for a disease that has narrowed degenerative in beta cell degenerative.

Speaker Change: All other hyperglycemia control measures also moved in the same direction and we are anticipating and looking forward to the possibility that at week 48 will see continued sustained improvements in all of those measures in addition to which the visual acuity.

Speaker Change: Ah indication of retinal ganglion cell health.

Camille Bedrosian: We expect that and look forward to the possibility of seeing stabilization or improvement in visual acuity as well. Recall that these individuals are adults having lived with this genetic disorder all their lives. So we're looking forward to that possibility. And that should also provide the FDA with continued confidence in the potential of AMX 35 for people living with wolfram who have nothing at this time to treat their condition.

Speaker Change: We expect that and look forward to the possibility of seeing a stake.

Speaker Change: Stabilization or improvement in visual acuity as well recall that these individuals are adults having lived with this genetic disorder. All their lives. So we're looking forward to that possibility and that should also provide the FDA with continued confidence in the potential of amex.

Speaker Change: <unk> 35 for people living with Wolfrom, who have nothing at this time to treat their condition.

Camille Bedrosian: And then speaking to vexatide and other indications, so first I'll say, PBH is already a large and exciting area and a significant unmet need, so certainly our first focus is in PBH. We do believe, though, that there are multiple other indications where the mechanism of a GLP-1 antagonist could be important, including diseases of hyperinsulinemic hyperglycemia and potentially diseases where, you know, other elements of the GLP-1 pathway may be helpful. But again, our focus for right now is on PBH. Thank you.

And then speaking to <unk> and other indications. So first I'll say PVH is already a large and exciting area and a significant unmet need. So certainly our first focus is in PVH. We do believe though that there are multiple other indications where the mechanism of a G. L. P. One and two.

Speaker Change: <unk> could be important.

Speaker Change: <unk> diseases of hyperinsulinism, hyperglycemia, and potentially diseases, where other elements of the G. L. P. One pathway may be helpful. But again, our focus for right now is on is on PVH.

Speaker Change: Thank you.

Speaker Change: Thank you once again that is star one could you wish to ask a question.

Operator: Once again, that is far one to do is to ask a question.

Madhu: Your next question is from Mark Goodman from Lyrinc. Your line is now open. Hi, thanks, this is Madhu on the line for Mark. We've heard from some physicians that there are some patients who exhibit PBH without the postprandial hyperinsulinism. So we're curious if you're screening for patients who specifically show a spike in insulin levels post-meal. Has your research shown like a specific proportion of patients who show this in PBH? And then also how should we be thinking of pricing for Avexitide? We know it's early, but just wanted to get like a ballpark idea. Thanks.

Operator: Our next question is from Marc Goodman from Leerink. Your line is now open.

Speaker Change: Hi. Thanks. This is my view on the line from Mark we've heard from some physicians that there are some patients who.

Marc Goodman: Who exhibit PVH without the postprandial hyperinsulinism, so I'm curious if you're screening for patients, who specifically show a spike in insulin levels post meal.

Speaker Change: Does your research show like a specific proportion of patients who show that's N P B H.

And then also how should we be thinking of pricing of exit had we know it's early but just wanted to get like a ballpark idea.

Josh Cohen: Sure, so maybe starting with the postprandial hyperinsulinism, so one, I think we have generally seen the hyperinsulinism, you know, going through at least our review of the literature, you see that across, you know, quite a number of studies and quite a number of patients, but I think also important to note, our inclusion exclusion criteria are, you know, very similar, nearly identical to what was used in Phase 2 and Phase 2B, where we saw large effect size and high statistical significance. So, we think we're well-positioned for that as we go into the Phase 3 study, and then on the pricing side, you know, of course, too early to, you know, give anything definitive on pricing quite yet before we have our data, but I encourage you to, you know, look at other orphan analogs, this is an orphan drug, and additionally, you know, of course, the efficacy will drive things, and I do think, you know, it is quite an impact in people's lives to bring their glucose control to a much more, you know, normal measure.

Speaker Change: Sure So maybe starting with the postprandial hyperinsulinism.

Speaker Change: One I think we have generally seen the hyperinsulinism gone through at least our review of the literature, you see that across.

Speaker Change: Quite a number of studies of quite a number of patients, but I think also important to note. Our inclusion exclusion criteria are very similar nearly identical.

Speaker Change: What was used in phase two and phase two b, where we saw large effect size in high statistical significance.

Speaker Change: We are well positioned for that as we go into the phase III study.

Speaker Change: And then on the pricing side.

Speaker Change: Of course too early to give anything definitive on pricing quite yet before we ever data, but I encourage you to look at other orphan analogues. This is an orphan drug and.

Speaker Change: And Additionally of course, the efficacy will drive things and I do think you know.

Speaker Change: It is quite an impact in people's lives to bring their glucose control to a much more.

Josh Cohen: You know, these patients do describe, you know, being in kind of an ongoing state of disability and being able to bring that, you know, back more near towards normal would be a, you know, a huge change for these individuals.

Speaker Change: Normal measure you know these patients do describe being in kind of an ongoing state of disability and being able to bring that back more near towards normal would be a huge change for these individuals' yes.

Josh Cohen: Yeah, and just going back to the first question as well, so, and just to talk through the pharmacology a little bit. So, hypoglycemia can happen certainly as a result, after a meal, postprandial, but it can happen at any time, it can happen for a variety of different triggers, so that's, you know, very true. So, we think that's why it's important that you want to have a molecule that can protect against these hypoglycemic events throughout the day, and so, with 90 mg once daily dosing, we are in the therapeutic range for 24 hours, so preventing those hypoglycemic events for the full day with daily dosing.

Speaker Change: Just going back to the first question as well, so and just to talk through the pharmacology a little bit.

Speaker Change: Hypoglycemia can happen.

Certainly as it was after a meal postprandial, but it can happen at any time it can happen for a variety of different triggers.

Speaker Change: So that's that's very true.

Speaker Change: That's why it's important that you want to have a molecule that can protect against these hypoglycemic events throughout the day and so with 90 Migs 90, Meg once daily dosing.

Speaker Change: We are in the therapeutic range for 24 hours, so preventing those hypoglycemic events.

Speaker Change: For the full day with daily dosing.

Josh Cohen: With PBH, though, what we know from a pharmacology perspective is the reason for these very precipitous blood glucose drops is because there's a very strong insulin response that seems to be due to a very strong endogenous GLP-1 response. So, GLP-1 levels can be up to 10 times normal in people with PBH. That causes very significant insulin secretion, which then lowers glucose very precipitously, and that's why, of course, the GLP-1 antagonist makes a lot of sense for this indication. Won't you? There are no further questions at this time.

Speaker Change: PVH, though what we know from a pharmacology perspective is the reason for these very precipitous blood glucose drops is because there's a very strong insulin response that seems to be due to very strong endogenous GOP. One response, so GOP one levels can be up to 10 times normal and people with TVA.

Speaker Change: H that causes very significant insulin secretion, which then lowers glucose very precipitously and that's why of course, the <unk> antagonist makes a lot of sense for the syndication.

Speaker Change: Thanks.

Speaker Change: Thank you.

Speaker Change: There are no further questions at this time I will now turn the call back to Mr. Li.

Josh Cohen: I will now turn the call back to Mr. Thank you, Operator, and thank you all for your time. We look forward to seeing many of you in the coming weeks and months.

Speaker Change: Thank you operator, and thank you all for your time, we look forward to seeing many of you in the coming weeks and months. If you have any follow up questions. Please reach out to Lindsay.

Lindsey Allen: If you have any follow up questions, please reach out to Lindsey.

Operator: I hope you have a great rest of your day. Thank you.

Speaker Change: I Hope you have a great rest of your day.

Speaker Change: Thank you.

Operator: Ladies and gentlemen, the conference has now ended. Thank you all for joining. You may all disconnect your lines.

Speaker Change: Ladies and gentlemen, the conference has now and.

Speaker Change: Thank you all for joining you may all disconnect your lines.