Q1 2024 Amylyx Pharmaceuticals Inc Earnings Call

Morgan: Good morning. My name is Morgan, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals First Quarter 2024 Earnings Conference Call. All participants will be in a listen-only mode.

Good morning, My name is Morgan and I will be your conference operator today at this time I would like to welcome everyone to the analytics Pharmaceuticals first quarter 2024 earnings conference call. All participants will be in a listen only mode. After today's presentation, there will be an <unk>.

Morgan: After today's presentation, there will be an opportunity to ask questions. To ask a question, please press star, then the number one on your telephone keypad. If you wish to withdraw your question after you have entered the queue, please press star, then the number one again. Please limit your questions to one with one follow-up.

Opportunity to ask questions to ask a question. Please press Star then the number one on your telephone keypad. If you wish to withdraw your question. After you have entered the queue. Please press Star then the number one again.

Please limit your questions to one with one follow up if you have additional questions you may rejoin the queue. Please.

Morgan: If you have additional questions, you may rejoin the queue. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to your host, Lindsey Allen, Head of Investor Relations and Communications.

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

I would now like to turn the call over to your host Lindsay Atlan head of Investor Relations and Communications. Please proceed.

Lindsey Allen: Good morning, and thank you for joining us today to discuss our first quarter 2024 financial results. With me on the call are Josh Cohen and Justin Klee, our co-CEOs, Jim Frates, our chief financial officer, and Dr. Camille Bedrosian, our chief medical officer.

Good morning, and thank you for joining us today to discuss our first quarter of 2024 financial results.

Lindsey Allen: Me on the call are Josh Cohen, and Justin <unk>, our co CEO, Jim <unk>, our Chief Financial Officer, and Dr. Camille Bedrosian, Chief Medical Officer.

Lindsey Allen: 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 forward looking statements that are made by our current beliefs plans and expectations and are made pursuant to the safe Harbor provision of the private Securities Litigation Reform Act.

Lindsey Allen: 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 made based on our current beliefs, plans, and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our plans with respect to AMX 35 and AMX 114, statements regarding current and planned clinical trials, statements regarding regulatory developments and the expected timing thereof, our business strategy and outlook, and our expected financial performance and cash runway.

Lindsey Allen: Act of 1995.

Lindsey Allen: Statements include but are not limited to our plans with respect to Amex 35, and Amex 114 statements regarding current and planned clinical trials.

Lindsey Allen: Statements regarding regulatory developments and the expected timing thereof, our business strategy and outlook and our expected financial performance and cash runway.

Lindsey Allen: Actual events and results could differ materially from those expressed or implied by any forward-looking statement as a result of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law. Now, I will turn the call over to Justin.

Lindsey Allen: Actual events and results could differ materially from those expressed or implied by any forward looking statements as a result of various risks uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC you are cautioned not to place any undue.

Lindsey Allen: Reliance on these forward looking statements and analytics disclaims any obligation to update such statements unless required by law now I will turn the call over to Justin.

Justin B. Klee: Good morning, and thank you all for joining us today. The first quarter of this year was a difficult one for Amylyx as an organization and especially for the ALS community. The top line results from the Phoenix trial of Amex 35 and ALS were deeply disappointing and surprising, given the prior central trial results that showed a meaningful benefit of Amex 35 for people living with ALS and supported an FDA approval. But as a mission journey, the next steps were clear.

Justin: And thank you all for joining us today.

Justin: The first quarter of this year was a difficult one for analysts as an organization and especially for the ALS community.

Justin: The topline results from the Phoenix trial of Amex 35 at AOS for deeply disappointing and surprising given the prior centric trial results that had showed a meaningful benefit of amex 35 for people living with ALS and supported an FDA approval.

Justin: But as I mentioned, just the next steps for clear we moved quickly to restructure our organization in order to continue our work for one day ending the suffering caused by neuro degenerative diseases.

Justin B. Klee: We moved quickly to restructure our organization in order to continue our work for one day ending the suffering caused by neurodegenerative diseases. Not long after the Phoenix trial results, in early April, we announced the planned interim analysis results from our study of AMX 35 and Wolfram syndrome, a program we have been developing for nearly seven years. The data showed stabilization or even improvement across the major outcomes in the trial. These data strengthen our belief that we've been investigating for over a decade that targeting cell death mechanisms is an important approach across many different diseases.

Justin: Not long after the Phoenix trial results in early April we announced the planned interim analysis results from our study of an F 35, and Wolfram syndrome a.

Justin: The program, we have been developing for nearly seven years.

Justin: Data showed stabilization or even improvement across the major outcomes in the trial.

Justin: Data strengthen our belief that we have been investigating for over a decade, the targeting cell death mechanisms as an important approach across many different diseases.

Justin B. Klee: It is therefore critical to continue to focus our resources on matching the mechanism of our treatment candidates with the mechanisms of disease and, ideally, incorporating measurable biomarkers in our development that are consistent with disease progression. In that spirit, and in pursuit of our mission, we continue to advance our three key programs that have been in the works for several years. AMX 35 for the treatment of Wolfren syndrome, AMX 35 for the treatment of progressive supernuclear palsy or PSP, and AMX-114, our anti-sense oligonucleotide targeting Calpain-2 for the treatment of ALS. For Wolfram, we are seeing early evidence of benefit across multiple organ systems based on well-established outcomes such as C-peptide response. These results are consistent with our prior preclinical studies.

Justin: It is therefore critical to continue to focus our resources on matching the mechanism of our treatment candidates with the mechanisms of disease and ideally incorporating measurable biomarkers in our development that are consistent with disease progression.

Justin: In that spirit and in pursuit of our mission, we continue to advance our three key programs that had been in the works for several years.

Justin: <unk> 35 for the treatment of <unk> syndrome.

Justin: <unk> 35 for the treatment of progressive Supranuclear palsy, or PSP and.

Justin: <unk> 2014, our antisense oligonucleotide targeting <unk> two for the treatment of AOS.

Justin: For Wolfram, we are seeing early evidence of benefit across multiple organ systems based on well established outcomes such as C. Peptide response.

Justin: Results are consistent with our prior preclinical studies.

Justin B. Klee: We plan to meet with FDA to discuss next steps in the program. The PSP community continues to be excited about our trial because of the tau-lowering effects we saw with AMX 35 in a prior Alzheimer's study. We expect to have data from an interim analysis of this study mid-next year. AMX-114 is a potent antisense oligonucleotide targeting inhibition of Calpain-2, a well-established target in a number of neurological diseases, and published data suggest Calpain-2 is the primary protease that cleaves neurofilament light chains.

Justin: We plan to meet with FDA to discuss next steps in the program.

Justin: The PSP community continues to be excited about our trial because of the Tau lowering effects, we saw with Amex 35 in the prior Alzheimer's study.

We expect to have data from an interim analysis of this study mid next year.

Justin: <unk> hundred 14 is a potent anti sense oligonucleotide targeting inhibition of helping to a well established target in a number of neurological diseases and published data suggest counting two is the primary protease <unk> neuro filament light chain.

Justin B. Klee: We expect to enroll the first participants in our ALS trial later this year. All of these programs address neurodegenerative diseases with well-defined mechanistic rationales, well-defined and measurable biomarkers, and a foundation of rigorous preclinical data upon which we have based our clinical work, all with the goal of bringing important therapies to communities with high unmet need. And critically, we currently have the cash runway into 2026 through meaningful milestones in each of these programs.

Justin: We expect to enroll the first participants in our ALS trial later this year.

Justin: Each of these programs address neurodegenerative diseases with well defined mechanistic rationale.

Justin: Well defined and measurable Biomarkers and the foundation of rigorous preclinical data upon which we base our clinical work all with the goal of bringing important therapies to communities with high unmet need.

Justin: And critically we currently have the cash runway into 2026 through meaningful milestones in each of these programs.

Justin B. Klee: Since founding Amylyx more than 10 years ago, we have built a foundation focused on the science behind what drives cell death and degeneration. These pathways remain critically important across many diseases of high unmet medical need, and we will continue the work to further our mission. I will now turn the call over to Camille to provide an update on these key clinical programs.

Justin: Since founding and much more than 10 years ago, we have built a foundation focused on the science behind what drives cell death and degeneration.

Justin: These pathways remain critically important across many diseases of high unmet medical need.

Justin: We'll continue to work to further our mission.

Justin: I will now turn the call over to Camille to provide an update on the key clinical programs.

Camille L. Bedrosian: Thank you, Justin, and I wish all of you a good morning. I'm going to begin today by providing an overview of the mechanistic rationale for AMX 35 at a cellular level and share why we are so excited to continue studying it in Wolfram syndrome and PSP. I will also discuss the mechanistic rationale of AMX 114 and neurodegenerative diseases. AMX 35 was designed to mitigate neurodegeneration by simultaneously targeting and reducing endoplasmic reticulum (ER) stress and mitochondrial dysfunction.

Camille L. Bedrosian: Thank you Dustin and I wish all of you a good morning.

Camille L. Bedrosian: I'm going to begin today by providing an overview of the mechanistic rationale for Amex 35 at a cellular level and share why we are so excited to continue studying it and Wolfram syndrome and PSP.

Camille L. Bedrosian: I also will discuss the mechanistic rationale of them excellent 14, and neuro degenerative diseases.

Camille L. Bedrosian: Amex 35 was designed to mitigate neuro degeneration by simultaneously targeting and reducing endoplasmic reticulum or E R stress and mitochondrial dysfunction.

Camille L. Bedrosian: ER stress is activated when protein homeostasis is disrupted, leading to the accumulation of misfolded and unfolded proteins in the ER. This activation leads to an adaptive response in order to restore homeostasis. The Unfolded Protein Response Pathway is activated by initiating three protein cascades, IRE 1, Perk, and ATF6.

Camille L. Bedrosian: ER stress is activated when protein homeostasis is disrupted leading to the accumulation of misfolded and unfolded proteins and the E. R.

Camille L. Bedrosian: This activation leads to an adaptive response in order to restore homeostasis.

Camille L. Bedrosian: From the literature, these protein cascades act to put the cell in a defensive mode where most new protein and RNA synthesis is slowed or halted, and the cell prioritizes production of chaperone proteins and phagocytic activity. Prolonged ER stress is the cause of cell death; mitochondrial dysfunction that occurs in response to stress results in BATS protein activation to open a pore through which cytochrome c is This release, in turn, activates Caspase 3, which is known to be the execution protein that causes apoptotic cell death.

Camille L. Bedrosian: Folded protein response pathway is activated by initiating three protein cascades.

Speaker Change: Sorry, one.

Speaker Change: Park and ATF six.

Speaker Change: From the literature. These protein Cascades act to put the sell in a defensive mode, where most new protein and RNA synthesis has slowed or halted.

Speaker Change: And the sell prioritizes production of chaperone protein and phagocytic activity.

Speaker Change: Prolonged ER stress is it causes cell death.

Speaker Change: Mitochondrial dysfunction that occurs in response to stress this.

Speaker Change: <unk> and bats protein activation to open a poor two which cytochrome C is released.

This release and turn activates caspase, three which is known to be the execution protein that causes apoptotic cell death.

Camille L. Bedrosian: Based on existing literature and our preclinical data, there is a wealth of evidence that sodium central butyrate, or PD, and torusadiol, or TRSO, can prevent activation of these pathways and reduce the resulting cell death. In our experiments, we have repeatedly shown that the combination of TB and TERSO outperforms the individual agents.

Speaker Change: Based on existing literature, and our preclinical data there is a wealth of evidence and sodium saddle Butte rate, our PV and tourists the dial our tercel can prevent activation of these pathways and reduce the resulting cell death.

Speaker Change: In our experiments we have repeatedly show that the combination of Pbms herself outperformed the individual.

Speaker Change: Agents.

Camille L. Bedrosian: This research has led us to Wolfram syndrome, a monogenetic disease in which ER stress and mitochondrial dysfunction are driving the underlying disease pathophysiology, aligning with the mechanism of action of AMX 35. Individuals with Wolfram syndrome generally have mutations in the WFS1 gene that encodes the protein Wolframin. Wolframen spans the ER membrane and is thought to play a role in protein folding and aid in the maintenance of ER function by regulating calcium levels.

Speaker Change: Okay.

Speaker Change: This research has led us to Wolfram syndrome.

Monogenetic disease, and with ER stress and mitochondrial dysfunction are driving the underlying disease pathophysiology.

Speaker Change: Aligning with the mechanism of action of Amex 35.

Speaker Change: Individuals with Wolfram syndrome generally have mutations in the W. S. S. One gene that encodes the protein well from them.

Speaker Change: Well frame and spans the E. R membrane and is thought to play a role in protein folding and aid in the maintenance of ear function by regulating calcium levels.

Camille L. Bedrosian: Therefore, Wolfram syndrome is often characterized in the literature as a prototypical disease of ER stress, given the observed activation of the three-protein arms of the ER stress cascade. Additionally, there is evidence in the literature for mitochondrial dysfunction and the activation of Caspase 3. Wolfram's disease is generally characterized by childhood-onset diabetes mellitus, optic nerve atrophy, deafness, diabetes insipidus, and neurodegeneration, ultimately resulting in premature death. The disease is thought to impact approximately 3,000 people in the US and possibly more.

Speaker Change: Therefore, Wolfram syndrome is often characterized in the literature as a prototypical disease of ER stress given the observed activation of the <unk> protein onto the ER stress cascade.

Speaker Change: Also there is evidence in the literature for mitochondrial dysfunction and the activation of caspase three.

Speaker Change: Warfront is generally characterized by childhood onset diabetes mellitus optic nerve accuracy deafness diabetes, insipidus and neuro degeneration.

Speaker Change: Ultimately, resulting in premature death.

Speaker Change: The disease is thought to impact approximately 3000 people in the U S and possibly more.

Camille L. Bedrosian: Over the last seven years, we have been collaborating with Dr. Fumihiko Urano and his team at Washington University School of Medicine in St. Louis on preclinical research to evaluate the effect of AMX 35 on wolfram. The main data from this collaboration are published in JCI Insights.

Over the last seven years, we have been collaborating with Dr. Freeman <unk> co. Your Arnaud and his team at Washington University School of Medicine in St. Louis and preclinical research.

Speaker Change: The effect of Amex 75 or more for them.

Speaker Change: The main data from this collaboration are published in GCI insight.

Camille L. Bedrosian: We studied the compounds in people-derived beta cells and neurons harboring clinical mutations in the WSS1 gene and then in an animal model harboring a double knockout of the WSS1 gene. We observed sizable reductions in cell death and increased insulin production upon glucose administration in beta cells, and substantially reduced cell death in neurons. In WFS1 knockout mice, we observed that AMX35 halted the progression of the diabetic phenotype in these animals.

Speaker Change: We studied the compounds and people derive beta cells and neurons harboring the clinical mutations in <unk> gene.

Speaker Change: And then in an animal model harboring a double knockout of the W. S. S. One gene.

Speaker Change: We observed sizable reductions in cell death, and increased insulin production upon glucose administration in beta cells.

Speaker Change: And substantially reduce cell death and neurons.

Speaker Change: And the W. S. S. One knockout mice, we observed that an F 35 halt the progression of the diabetic phenotype in these animals.

Camille L. Bedrosian: We initiated our Phase 2 Wolfram Syndrome clinical study called Helios in April 2023 following these findings. And in April of this year, we announced promising data from a planned interim analysis of eight of the 12 participants enrolled who had their week 24 assessed.

Speaker Change: We initiated our phase two Wolfram syndrome clinical study called Helios in April 2023, following the findings.

Speaker Change: In April of this year, we announced promising data from a planned interim analysis of eight of the 12 participants enrolled who had their week 24 assessments.

Camille L. Bedrosian: Our hypothesis a priori was that AMX 35 could slow beta cell decline, slow deterioration of glycemic control, and slow progression of other characteristics of the disease. In actuality, based on the interim data, treatments with ANX35 resulted in an improvement in beta cell function as evidenced by an increase from baseline in the C-peptide response to a mixed meal challenge, the primary outcome. Improvements and other measures of glycemic control also were reported as part of the interim data.

Speaker Change: Our hypothesis Arpey Ari was it an F 35 could slow beta cell decline some deterioration of glycine it control and slow progression of other characteristics of the disease.

Speaker Change: In actuality based on the interim data two months with an F. 35 resulted in an improvement in beta cell function as evidenced by an increase from baseline and the C. Peptide response to a mixed meal challenge the primary outcome.

Speaker Change: Improvements and other measures the blessing of control also were reported as part of the interim data.

Camille L. Bedrosian: In addition, we reported some improvement in vision in a subset of participants, which was unexpected given that visual acuity worsens over time, often leading to blindness, according to Natural History. These results were supported by improvement or disease stability as measured by clinician and patient-reported outcomes. AMX 35 was generally well tolerated in all participants, and they all continue in the study. Based on the strength of these interim data and the lack of approved treatment options for people living with Wolfram syndrome, we are planning to engage the FDA as soon as we can, initially with these interim data.

Speaker Change: In addition, we reported some improvement in vision in a subset of participant.

Speaker Change: Which was unexpected given the visual acuity worsens over time, often leading to blindness. According to natural history.

Speaker Change: These results were supported by improvement or disease stability as measured by clinician and patient reported outcomes.

Speaker Change: <unk> 35 was generally well tolerated in all participants and all continue in the study.

Speaker Change: Based on the strength of these interim data and the lack of approved treatment options for people living muscle from syndrome.

Speaker Change: We are planning to engage the FDA as soon as we can initially with these interim data.

Camille L. Bedrosian: Turning to our work in PSP, we continue to plan for an interim analysis and expect data in mid-2025. PSP impacts approximately 7 in 100,000 people worldwide and affects eye movement, walking, and balance, as well as speech and swallowing, and Cognitive Function.

Speaker Change: Turning to our work in PSP, we continue to plan for an interim analysis and expect data in mid 2025.

Speaker Change: P S P.

Speaker Change: Ultimately seven and 100000 people worldwide and effects I movement, walking imbalance speech and swallowing and cognitive function.

Camille L. Bedrosian: There are no approved treatments for this fatal disease. There is a strong genetic linkage of tau to the disease and clear tau pathology when brains from people with PSP were observed postmortem. Multiple pathways, including ER stress and mitochondrial dysfunction, have been implicated as contributors to tau dysfunction and aggregation. In a clinical trial of Alzheimer's disease, AMX 35 has been shown to target multiple pathways of neurodegeneration and significantly reduced CSF, total tau, and FOXO tau levels. Out of 288 measured proteins, tau was the most changed by AMX 35. We believe AMX 35 has strong scientific rationale and PSP based on these considerations.

Speaker Change: There are no approved treatments for this failed disease.

Speaker Change: There is a strong genetic linkage of tau to the disease and clear Tau pathology when brain from people with PSP were observed postmortem.

Speaker Change: Multiple pathways, including ER stress and mitochondrial dysfunction have been implicated as contributors to Tao dysfunction and aggregation.

Speaker Change: In a clinical trial in Alzheimer's disease, Amex 35 has been shown to target multiple pathways of neuro degeneration and significantly reduced CSF total tau and phosphor <unk> levels.

Speaker Change: Out of 288 measured proteins, how was the most change by Amex 35.

Speaker Change: We believe Amex 35 has strong scientific rationale and PSP based on these considerations.

Camille L. Bedrosian: We also remain committed to the ALS community and are developing AMX114, our antisense oligonucleotide, or ASO, targeting inhibition of Calpain-2. Decades of scientific literature support an essential role for Calpain-2 in the process of axonal degeneration. Calpain-2 inhibition has been studied in models of multiple sclerosis, Huntington's disease, Parkinson's disease, chemotherapy-induced peripheral neuropathy, spinal cord injury, and Alzheimer's disease, to name a few, with repeatedly positive effects across the literature. In considering targeting Calpain 2, specificity and cellular localization are critical, given that there are at least a dozen Calpains.

Speaker Change: We also remain committed to the ALS community and are developing Amex 114, our antisense oligonucleotide or ASO targeting inhibition of calpain too.

Speaker Change: Decades of scientific literature support and a central role for Calpine to in the process of axonal degeneration.

Speaker Change: <unk> two inhibition has been studied in models of multiple sclerosis Huntington's disease.

Speaker Change: Since disease chemotherapy induced peripheral neuropathy spinal cord injury, and Alzheimer's disease to name a few.

Speaker Change: With repeatedly positive effects across the literature.

Speaker Change: And considering targeting calpain, two specificity and cellular localization are critical given that there are at least a dozen campaigns.

Camille L. Bedrosian: We leveraged ASO technology targeting the CNS or central nervous system by intrathecal delivery to initiate a program designed to effectively and specifically inhibit Calpain 2. In our hands, and with collaborators, we have observed rescue of cellular degeneration and neurofilament biology in multiple cellular experiments. Having well-defined biomarkers is also essential as we progress this compound into the clinic. Calpain-2 is a protease known to cleave many substrates, including neurofilament, tau, and TGP-43 proteins.

Speaker Change: We leveraged <unk> technology targeting the CNS.

Speaker Change: Nervous system by into a single delivery to initiate a program designed to effectively.

Speaker Change: Typically inhibits calpain too.

Speaker Change: And our hands and with collaborators we have observed rescue settled or degeneration, and neuro filling that biology.

Speaker Change: Multiple cellular experiments.

Speaker Change: Having well defined Biomarkers is also essential as we progress this compound into the clinic.

Speaker Change: How phase two is a protease known to create many substrates, including neuro filament Tau and TDP 43 proteins.

Camille L. Bedrosian: These proteins, in addition to neurofilament light, provide important disease and target engagement biomarkers. We are planning to file an IND, and our team is poised to initiate a multiple ascending dose clinical trial of AMX 114 in people living with ALS in the second half of this year when the IND is cleared. Now, I will turn the call over to Jim to discuss financial updates from the quarter.

Speaker Change: These proteins in addition to neural filling up right.

Speaker Change: Important disease and target engagement biomarker.

Speaker Change: We are planning to file an IND.

Speaker Change: And our team is poised to initiate a multiple ascending dose clinical trial of an excellent 2014 and people living with ALS.

In the second half of this year when the IND is cleared.

Speaker Change: Now I will turn the call over to Jim to discuss financial updates from the quarter.

James M. Frates: Thank you, Camille. As you know, over the last two months, we took swift and comprehensive action to restructure our organization, including an approximately 70% workforce reduction to focus on delivering data from our three key programs in Wolfram Syndrome, PST, and ALS. These actions provide us with the expected crash runway into 2026, giving us time to report additional data from each of our clinical trials. I'll now review our financial results for the quarter and our expectations for the impact of the restructuring on the quarters ahead.

Jim: Thank you Camille as you've heard over the last two months, we took swift and comprehensive action to restructure our organization, including an approximately 70% workforce reduction to focus on delivering data from our three key programs and Wolfram syndrome, PST and ALS.

Jim: These actions provide us with the expected cash runway into 2026, giving us time to report additional data from each of our clinical trials.

Jim: I will now review, our financial results for the quarter and our expectations on the impact of the restructuring on the quarters ahead.

James M. Frates: Net product revenues were $88.6 million for the first quarter, down from $108.4 million in the fourth quarter of 2023. For context, the rate of new prescriptions being written, as well as refills of existing prescriptions, started to decline immediately after our announcement on March 8 that our Phoenix study did not meet its primary or secondary end point.

Jim: Net product revenues were $88 6 million for the first quarter down from $108 $4 million in the fourth quarter of 2023.

Jim: For context, the rate of new prescriptions being written as well as refills of existing prescriptions started to decline immediately after our announcement on March eight through our Phoenix study did not meet its primary or secondary endpoints.

James M. Frates: For modeling purposes, you should anticipate us reporting no meaningful revenues after March 8. The cost of sales was $116.4 million for the quarter. This included non-cash charges of approximately $110.5 million associated with the write-down of inventory and the loss on CMO purchase commitments related to the decision to voluntarily discontinue marketing authorizations in the U.S. and Canada. We may report revenue in COGS in the months ahead due to the timing of true-ups related to our final accrual estimates as we wrap up sales for Rolivrio and Albrioza, but the expectation is that any future revenues in COGS will be immaterial as we have discontinued our commercial sales.

Jim: For modeling purposes.

Jim: Should anticipate us reporting no meaningful revenues aftermarket.

Jim: Cost of sales were $116 $4 million for the quarter.

Jim: This included noncash charges of approximately $110 $5 million associated with the write down of inventory and the loss on CMO purchase commitments related to the decision to voluntary.

Antero discontinue the marketing authorizations in the U S and Canada.

Jim: We may report revenue in Cogs in the months ahead due to the timing of true ups related to our final accrual estimates as we wrap up sales for <unk> and Albert Joseph.

Jim: But the expectation is that any future revenues and costs will be immaterial as we have discontinued our commercial sales.

James M. Frates: Research and development expenses were $36.6 million, and selling general and administrative expenses were $57.8 million for the quarter. With our restructuring, we expect our total operating spend to move down over the next few quarters as we wind down commercial operations and focus on R&D. As we move into the next year, we expect total spend on R&D and SG&A to be in the range of $30 to $40 million per quarter, in line with our spend prior to the build out of our commercial organization, which happened in the first two quarters of 2022 in preparation for potential approvals in the U.S. and Canada.

Jim: Research and development expenses were $36 6 million and selling general and administrative expenses were $57 8 million for the quarter.

Jim: With our restructuring we expect our total operating spend to move down over the next few quarters as we wind down commercial operations and focus our R&D.

Jim: As we move into the next year, we expect total spend on R&D and SG&A will be in the range of $30 million to $40 million per quarter.

Jim: In line with our spend prior to the build out of our commercial organization, which was happening in the first two quarters of 2022 in preparation for potential approvals in the U S and Canada.

James M. Frates: As a result of the changes to our organization announced on April 4th, we also expect to incur severance and related expenses of roughly $19.1 million. These charges will be largely recorded in the second quarter, with some occurring in Q3. As a result of these actions, in the first quarter, we recorded a net loss of $118.8 million, or a net loss per share of $1.75. We had $373.3 million in cash and investments as of March 31, 2024, with an expected cash runway into 2026. Funding us through key milestones, including anticipated data readouts for AMX 35 in Wolfram Syndrome and PSP and AMX 114 in ALS. I'll now turn the call over to Josh to provide some closing remarks.

Jim: As a result of the changes to our organization announced on April four we also expect to incur severance and related expenses of roughly $19 $1 million.

Jim: These charges will be largely recorded in the second quarter with some occurring in Q3.

Jim: As a result of these actions in the first quarter, we recorded a net loss of $118 $8 million.

Jim: Or a net loss per share of $1 75.

Jim: We had $373 $3 million in cash and investments as of March 31, 2024.

Jim: With an expected cash runway into 2026 funding us through key milestones, including anticipated data Readouts for Amex, 35, and Wolfram syndrome in PST and Amex $1 14 in ALS.

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

Joshua B. Cohen: Thanks, Jim.

Joshua B. Cohen: In closing, we believe we are well positioned to advance our compelling, science-driven pipeline forward to key value-generating milestones. For example, the interim data from our Phase 2 Helios trial of AMX35 for the treatment of Wolfram syndrome demonstrated early evidence of benefit on well-established outcomes such as C-peptide that are supported by prior results, including in the mouse model of the disease. Based on these compelling interim data, we are acting swiftly to engage with the FDA to discuss next steps for the program. We expect top-line data on all 12 participants at week 24 in the fall of this year.

Joshua B. Cohen: In closing, we believe we are well positioned to advance our compelling science driven pipeline forward to key value generating milestones.

Joshua B. Cohen: The interim data from our phase two Helios trial of Amex 35 for the treatment of Wolfram syndrome demonstrated early evidence of benefit on well established outcomes such as C. Peptide that are supported by prior results, including in the mouse model of the disease.

Joshua B. Cohen: Based on these compelling interim data, we are acting swiftly to engage with the FDA to discuss next steps for the program.

Joshua B. Cohen: We expect top line data on all 12 participants at week 24 in the fall of this year.

Joshua B. Cohen: Our Phase 3 Orion trial of AMX-35 for the treatment of PSP is progressing, and we continue to anticipate data from an interim analysis in mid 2025. And we are excited to advance AMX 114 into the clinic for the treatment of ALS in the second half of this year. CALPING-2 is a well-recognized target, with decades of scientific literature supporting its essential role in the process of axonal degeneration.

Joshua B. Cohen: Our phase III Orion trial of Amex 35 for the treatment of PSP is progressing and we continue to anticipate data from an interim analysis in mid 2025.

Joshua B. Cohen: And we are excited to advance amex $1 14 into the clinic for the treatment of ALS in the second half of this year.

Joshua B. Cohen: Helping to as a well recognized target with decades of scientific literature supporting its essential role in the process of external generation.

Joshua B. Cohen: We have an opportunity with this study to assess safety, as well as biomarkers of target engagement and the disease process. We are in a strong financial position to deliver on all of these milestones and generate important data for each of our programs. Our pipeline is supported by more than a decade of our own research and bolstered by promising preclinical and clinical data. Our strategy from here is clear: we continue to follow the science, advance our pipeline, and work tirelessly for communities that continue to wait for new solutions and better support. Now, we'd be happy to take your questions. Operator, please open the call to Q&A.

Joshua B. Cohen: We have an opportunity with this study to assess safety as well as biomarkers of target engagement in the disease process.

Joshua B. Cohen: We are in a strong financial position to deliver on all of these milestones and generate important data for each of our programs.

Joshua B. Cohen: Our pipeline is supported by more than a decade of our own research and bolstered by promising preclinical and clinical data.

Joshua B. Cohen: Our strategy from here is clear we continue to follow the science advanced our pipeline and worked tirelessly for communities that continue to wait for new solutions and better support.

Now we'd be happy to take your questions. Operator, please open the call up to Q&A.

Morgan: We will now begin the Q&A session. To ask a question, please press star, then the number one on your telephone keypad. If you wish to withdraw your question after you have entered the queue, please press star, then number one again. Please limit your questions to one with one follow-up. If you have additional questions, you may rejoin the queue. At this time, we will pause momentarily to assemble our roster. Your first question comes from Corinne Johnson with Goldman Sachs. Your line is open.

Speaker Change: We will now begin the Q&A session.

Speaker Change: To ask a question. Please press Star then the number one on your telephone keypad. If you wish to withdraw your question. After you have entered the queue. Please press Star then the number one again please limit your questions to one with one follow up if you have additional questions you may rejoin the queue.

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

Speaker Change: Your first question comes from Korean Johnson with Goldman Sachs. Your line is open.

Corinne Johnson: Good morning, guys. Maybe a couple from us.

Korean Johnson: Good morning, guys.

Korean Johnson: Maybe a couple from US just first in terms of the cash runway guidance into 'twenty, because I guess what specific.

Corinne Johnson: Just first, in terms of the cash runway guidance into 26, I guess what specific trials and then readouts would be embedded within that guidance? And then how should we think about the trial design and your expectations for the phase one study of AMX0014? And then when can we get that data? Thanks.

Korean Johnson: Trials, and then Readouts would be embedded within that guidance and then how should we think about the trial design and your expectations for the phase one study of Amex Theyre 014.

Speaker Change: And then when could we get that data. Thanks.

James M. Frates: Hey, Corinne, maybe I'll start, it's Jim. Maybe I'll start with the expectations that are built into the numbers. And, you know, as we outlined, that will, we expect that that will give us a kind

Speaker Change: Hey, maybe I'll start it's Jim maybe I'll start with the expectations that are built into the numbers.

Jim: As we outlined that will we expect that that will give us kind of sort of continued operating.

James M. Frates: of, you know, sort of continued operating mode in each of the programs that we have. So, you know, with Wolfram's continuing to move forward with this study.

Uh huh.

Jim: Continued operating mode in each of the programs that we have so.

Jim: Well firms continue to move forward with this study that we're in now and an additional study between now and the end of 2020.

James M. Frates: And an additional study between now and the end of 2020, you know, into 2026. It'll allow us to continue to execute on the PSP study and to begin the clinical studies on 1.14, you know, with, of course, some cushion in there as well as we move forward. So I think, you know, sort of full operations moving forward on the three programs we've outlined.

Jim: 2026, it will allow us to continue to execute on the PSP study and to begin the clinical studies on one 2014.

Jim: Or some.

Jim: Some cushion in there as well.

Jim: As we move forward, so I think sort of full operations moving forward on the three programs we've outlined.

Jim: Great.

Joshua B. Cohen: And I might just add, too, we do expect the cash runway to be enough to have, you know, important data milestones for each of the programs during that time frame. Well, that's the Camille on 114. Yeah, thanks, Josh.

Speaker Change: I'd just add too we do expect the cash runway would be enough to have important data milestones for each of the programs during that timeframe robotic meal in 114, yes. Thanks, Josh. Thanks, Karen Yes, 114, as we said in the prepared remarks will be a multiple ascending dose study in individuals with ALS.

Camille L. Bedrosian: Thanks, Josh. Thanks, Corinne. Yes, so 1.14, as we said in the prepared remarks, will be a multiple ascending dose study in individuals with ALS. And in terms of when we'll have data, we'll report along the way and keep you updated on when we expect to have the data. Yeah, I might just

Speaker Change: And in terms of when we'll have data, we'll report along the way and.

Speaker Change: Keep you updated when we expect to have the data.

Joshua B. Cohen: Yeah, and I might just add, too, that one thing nice with the 114 program, in general, too, is Calpain-2 is a protease, so there are many proteins that it's known to cleave, which provide important biomarkers of target engagement. And also, biomarkers in the ALS field have generally moved along quite a lot, particularly with neurofilament, which Calpain-2's biology has So I think as we go forward with the study, I think we have a lot of promising things to measure, and that can even be measured fairly early.

Speaker Change: Yes, I might just add to that one thing nice with the 114 program in general too is coming to us a protease. So theres many proteins that it's known to cleave, which provide important biomarkers of target engagement and also biomarkers in the AOS field generally moved along quite a lot, particularly with narrow filament.

Which <unk> biology has been heavily linked to so I think as we go forward into this study I think we have a lot of <unk>.

Speaker Change: Promising things to measure and Matt can even be measured fairly early.

Speaker Change: Okay. Thank you.

Speaker Change: Okay.

Marc Harold Goodman: Your next question comes from Mark Goodman with Lyrinc. Your line is open.

Speaker Change: Your next question comes from Marc Goodman with Leerink. Your line is open.

Rudy: All right, thanks for taking the question. This is Rudy on the line for Mark.

Marc Harold Goodman: Alright, Thanks for taking the question. This is Rudy on the life of mine.

Rudy: Can you maybe provide more color on the measurement of disease progression in Warfarin syndrome and in a Phase II Helios study, which of the measured endpoints are the most important, and how do you decide which one will be used in a potential, like, pivotal program? Thanks.

Marc Harold Goodman: Can you maybe provide more color on the measurement of disease progression and Wolfram syndrome and.

Rudy: As to Helios study, we feel commended endpoints.

Rudy: Most important and how do you decide which one will be used in a potential pivotal program. Thanks.

Camille L. Bedrosian: Right, thank you. So, as we described in the prepared remarks and actually during our webinar as well, we had a number of endpoints that we evaluated. And in fact, the natural history study by Ray et al. showed that there was an inevitable progression and deterioration of beta cell function, deterioration of neurons leading to vision, visual loss, and retinal ganglion cell loss. And so those are important considerations with Wolfram syndrome. And what we showed in the interim data for Helios was that, in fact, not only did we flow progression, but we actually improved beta cell function through an increase in C-peptide, which is a well-established and objective endpoint and measure of beta cell function used extensively in the diabetes field.

Speaker Change: Alright. Thank you. So as we described in the prepared remarks, and actually doing a webinar as well we had a number of endpoints that we evaluated and in fact in the natural history study by Ray at all showed that there was inevitable progression of <unk>.

Speaker Change: And deterioration of beta cell function deterioration of neurons leading to.

Speaker Change: Vision visual loss retinal ganglion cells.

Speaker Change: Loss and so those are important considerations with Wolfram syndrome, and our what we showed in that the interim data for Helios was that in fact, not only did we.

Speaker Change: Slow progression, but we actually improve beta cell function to an increase in C peptide, which is a well established an objective endpoint in measure of beta cell function used extensively in the diabetes field.

Speaker Change: So that will be an important consideration as well as.

Camille L. Bedrosian: So that will be an important consideration as well, and to our excitement, we actually saw some improvement in vision as well in these adult individuals who've had many years of progressive visual loss. So, you know, we will, as we said, meet with the FDA shortly to be able to understand how they view the Totality of Evidence and Substantial Evidence of Improvement. So certainly, we will be keeping an eye on those measures going forward.

Speaker Change: Quite.

Speaker Change: Two are.

Speaker Change: Excitement, we actually saw some improvement in vision as well in these adult individuals who had many years of progressive visual loss.

Speaker Change: So yeah.

Speaker Change: Well, we will as we said meet with the FDA.

Speaker Change: Shortly to be able to understand how they view they they.

Italian of evidence and substantial evidence of improvement. So certainly we will be keeping an eye on those measures going forward.

Rudy: Got it. Thanks for the caller.

Got it thanks for the color.

Graig C. Suvannavejh: Your next question comes from Craig Suvannavejh with Mizzou Securities. Your line is open.

Speaker Change: Your next question comes from Craig Savannah edge with Mizuho Securities.

Unknown Executive: Securities Your line is open.

Scott: Good morning. Thank you for taking the questions that I have, Scott. One just in particular around the expectation of getting the final data with respect to Wolfram, and I'm just wondering, is there any potential that what you see in the final could change the interpretation of the findings of your interim data? And then secondly, just maybe in your Calpain program, you mentioned that there are perhaps a dozen different Calpains, and you've chosen Calpain 2, so I'm just wondering, among the dozen, what gives you the confidence that Calpain 2 is the right one to go after in ALS?

Unknown Executive: Hi, Good morning, Thank you for taking the questions that I have got.

Unknown Executive: One just in particular around the expectation of getting the.

Final.

Data.

Unknown Executive: With respect to Wolfram and I'm, just wondering is there any potential that what <unk> seen the final changes the interpretation of the findings of your interim data.

Unknown Executive: And then secondly, just maybe on your Calpain program. You had mentioned that there are perhaps a dozen different campaigns and you've chosen calpain too. So I'm just wondering.

Unknown Executive: Of the dozen what gives you the confidence that <unk> two is the right one to go after.

Unknown Executive: Thanks.

Camille L. Bedrosian: Yeah, sure. So on Wolfram, we continue to be very encouraged by the data that we've seen with the eight of the 12 patients who are in the study and expect, as we said, in the second half of this year and fall, we'll have data at 24 weeks for all 12 participants. We continue to encourage. So, you know, And as Dr. Urano said during the webinar, he is also very encouraged not only by what has been seen in the eight individuals at 24 weeks, but going forward as well. So stay tuned, and we look forward to sharing those data with you. With regard to Calpain, maybe Josh will start, and then I'll continue. Sure.

Speaker Change: Yeah sure so well from we continue very encouraged by the data that we've seen with the eight of the 12 patients who are in the study and expect as we said second half of this year and they'll have the date.

Speaker Change: Data at 24 weeks for all trial participants we continue to encourage so that.

Speaker Change: You know that.

Speaker Change: And as Doctor Hirano said during the webinar.

Speaker Change: He also has very encouraged not only by what has been seen in the eight individuals at 24 weeks, but going forward as well so stay.

Speaker Change: Stay tuned and we look forward to sharing those data with you.

Joshua B. Cohen: So with regard to Calpain, I think it's mostly, you know, literature based on that choice. You know, Calpain 2 is, you know, the most neuronally expressed Calpain, and also the Calpain that is, you know, most associated with, you know, axonal degeneration. When people talk about Calpains being associated with axonal degeneration, they're usually referring to Calpain 2, you know, from time to time Calpain 1, but typically Calpain 2.

Speaker Change: With regard to Cal pay maybe Josh I'll start and then I'll concern you.

Joshua B. Cohen: With regard to Calpine I think it's mostly literature based on that choice.

<unk> two is the most of our early expressed campaign and also the campaign that is most associated with external degeneration. When people talk about compounds being associated with axonal degeneration, but usually referring to helping to from time to time, calpain, one, but but typically calpain too and I'd say the.

Joshua B. Cohen: And I'd say the other thing that, you know, just gets us very excited about this target; it is one of these targets with just decades of literature. You know, there's so much, you know, kind of lab to lab replication. There are so many different models and experiments that have shown that, you know, inhibiting this can slow axonal degeneration, as well as connecting this to neurofilm and biology. So I think that certainly makes us quite excited to go after the target and quite excited to, hopefully, move into the clinic later this year. And I'll just add that, you know, we've

Joshua B. Cohen: Other thing that just gets us very excited with this target. It is one of these targets with just decades of literature.

Joshua B. Cohen: So much.

Joshua B. Cohen: <unk> application with so many different models and experiments that have shown that inhibiting this ken kinslow axonal degeneration as well as connecting this generic film and biology, So I think with that.

Joshua B. Cohen: Certainly makes us quite excited to go after the target.

Speaker Change: And quite excited to hopefully move into the clinic later this year and I'll just add that you know we.

Camille L. Bedrosian: And I'll just add that, you know, we've presented some posters, we'll continue to present the preclinical data on 1.14, and what you can see is that targeting Calpain-2 in a variety of model systems has quite a substantial effect on lowering neurofilament levels, as well as on helping with cell viability, so I think it's just further confirmation of the literature that Josh was saying that inhibiting Calpain-2 is, in fact, the Calpain that you'd like to inhibit, and I think what one of the challenges has been historically is your point that there are a large variety of Calpains, and so targeting just one specifically has been challenging. We think that's the strength of using an antisense oligonucleotide, is that we can be very certain that we are targeting Calpain-2, not the other Calpains. This is also a very potent ASO, and it's delivered intrathecally, so we expect to have good brain exposure as well.

Speaker Change: We've Ah.

Speaker Change: Presented some posters will continue to present the preclinical data on 114, and what you can see is that are getting calpain too in variety of model systems has quite a substantial effect on lowering your film at levels as well as on helping with Silva.

Speaker Change: The ability so I think it just further confirmation of the literature that Josh was saying that inhibiting <unk>. Two is in fact, the calpain that you'd like to inhibit and I think what one of the challenges has been historically is your point that there are a large variety of calpain and so targeting just one specifically.

Speaker Change: It has been challenging.

Speaker Change: We think that's the strength of using an antisense oligonucleotide is that we can be very certain that we are targeting calpain too not the other calpain.

Speaker Change: This is also a very potent ASO.

Speaker Change: And it's delivered interests equally so we have we expect to have good brain exposure as well.

Speaker Change: Thanks Joseph.

Morgan: Once again, to ask a question, please press star, then the number one on your telephone keypad. If you wish to withdraw your question after you have entered the queue, please press star, then the number one again.

Once again to ask a question. Please press Star then the number one on your telephone keypad. If you wish to withdraw your question. After you. After you have entered the queue. Please press Star then the number one again.

Joel Beattie: Your next question comes from Joel Beattie with Baird. Your line is open. Hi, this is Ben Palucciano for Joel Beattie. Thanks for taking the question.

Speaker Change: Your next question comes from Joel Beatty with Baird. Your line is open.

Speaker Change: Hi, This is Ben Blue Jon on for Joe. Thanks for taking the question on the company's plan to engage with the FDA.

Speaker Change: Is that meeting been scheduled yet.

Ben Palucciano: As we said, we're moving swiftly to meet with the FDA based on the interim data of eight individuals out of the 12 in our Helios study. And when we have the information from our meeting, we certainly will share that.

Speaker Change: As we said, we're moving swiftly to meet with the FDA based on the interim data of eight individuals of the 12 and our Helios a study and when we have the information from our meeting we certainly will share those with you.

Speaker Change: Got it thank you.

Morgan: Thank you. There are no further questions at this time. I'll turn the call back to Mr. Klee.

Speaker Change: Thank you there are no further questions at this time I'll turn the call back to Mr. Klee.

Justin B. Klee: Thank you, operator. And thank you all for joining us on our call today and for your support. We hope you have a good day. Thank you for attending Amylyx Pharmaceuticals' first quarter 2024 earnings conference call. This concludes the call. You may now disconnect. Have a wonderful rest of your day.

Justin B. Klee: Thank you operator, and thank you all for joining us on our call today and for your support and hope you have a good day.

Justin B. Klee: Yeah.

Mr. Klee: Okay.

Operator: The host has ended this call. Goodbye.

Speaker Change: Thank you for attending analytics Pharmaceuticals first quarter 2024 earnings Conference call. This concludes the call. You may now disconnect have a wonderful rest of your day.

Speaker Change: The host has ended this call good.