Core Viewpoint - Shares of Amylyx Pharmaceuticals, Inc. (AMLX) have increased by 26.7% over the past four weeks, closing at $5.36, with a mean price target of $11 indicating a potential upside of 105.2% [1] Price Targets - The average price target consists of five estimates ranging from a low of $8 to a high of $16, with a standard deviation of $3, suggesting a variability in analyst estimates [2] - The lowest estimate indicates a potential increase of 49.3%, while the highest suggests an upside of 198.5% [2] Analyst Consensus and Earnings Estimates - Analysts show strong agreement in revising earnings estimates higher, which is a positive indicator for potential stock upside [4][11] - The Zacks Consensus Estimate for the current year has risen by 4.7% over the past month, with two estimates increasing and no negative revisions [12] - AMLX holds a Zacks Rank 2 (Buy), placing it in the top 20% of over 4,000 ranked stocks based on earnings estimate factors, indicating strong potential for near-term upside [13]

Summary of Amylyx Pharmaceuticals (AMLX) Conference Call Company Overview - **Company**: Amylyx Pharmaceuticals (AMLX) - **Focus**: Development of therapies for rare diseases, particularly those related to hypoglycemia and neurodegenerative conditions Key Points Industry and Product Pipeline - **Lead Program**: Focus on post-bariatric hypoglycemia (PBH) with the drug Vexatide, which has received FDA breakthrough therapy designation [1][16] - **Current Trials**: Phase III trial for Vexatide is ongoing, with recruitment expected to complete by the end of 2025 and data anticipated in the first half of 2026 [2][17] - **Other Programs**: - **AMX-35**: Targets endoplasmic reticulum stress and mitochondrial dysfunction, with promising Phase II data in Wolfram syndrome [2][6] - **AMX-114**: An antisense oligonucleotide targeting calpain 2 in ALS, with early cohort data expected by the end of 2025 [3] Wolfram Syndrome Insights - **Disease Overview**: Wolfram syndrome is a rare genetic disorder characterized by early-onset diabetes, vision loss, and hearing loss, affecting approximately 3,000 people in the U.S. [6][8] - **Clinical Data**: AMX-35 showed stabilization or improvement in insulin production (C-peptide levels) over a year, marking a significant finding in diabetic conditions [7][11] - **FDA Discussions**: Ongoing discussions with the FDA regarding trial design for a Phase III study based on positive data from the HELIOS trial [10][13] Vexatide and PBH - **Patient Population**: Approximately 160,000 people in the U.S. suffer from PBH, with no approved treatments currently available [16][21] - **Phase II Results**: Vexatide demonstrated a 53% reduction in level II hypoglycemic events and a 66% reduction in level III events, indicating significant clinical benefits [19][21] - **Patient Feedback**: High satisfaction rates among trial participants, with most rating their experience positively, highlighting improvements in energy and overall well-being [24][25] Upcoming Data and Market Insights - **Upcoming Presentations**: Data on pharmacokinetics and Phase II modeling will be presented at the Endo conference, providing further insights into Vexatide's efficacy [27][28] - **Market Research**: New abstract on the prevalence of PBH aligns with the company's estimates, reinforcing the market potential for Vexatide [28] Conclusion - **Future Outlook**: The company is optimistic about the potential of Vexatide and AMX-35 to address significant unmet medical needs in their respective patient populations, with ongoing trials and data expected to support their market entry [17][26]

Financial Data and Key Metrics Changes - The company ended the first quarter with a cash position of $204.1 million, which includes approximately $65.5 million in net proceeds from a public offering closed in January 2025 [23] - Total operating expenses for the quarter were $37.8 million, down 82% from the same period in 2024 [25] - Research and development expenses were $22.1 million compared to $36.6 million in Q1 2024, primarily due to decreased spending on AMX-thirty five and reduced payroll costs [25] - Selling, general and administrative expenses were $15.7 million compared to $57.8 million in Q1 2024, mainly due to decreased payroll and consulting costs [25] Business Line Data and Key Metrics Changes - The company is advancing three potential therapies across four clinical trials, including Avexatide for post bariatric hypoglycemia (PBH), AMX-thirty five for Wolfram syndrome and progressive supranuclear palsy (PSP), and AMX-one hundred fourteen for ALS [7][8] - Avexatide has shown promise in treating PBH, with a pivotal Phase III trial (Lucidity) initiated, and the first participant dosed [10][18] - AMX-thirty five is being evaluated in two indications, with positive Phase II data reported for Wolfram syndrome and ongoing trials for PSP [12][14] Market Data and Key Metrics Changes - There are approximately 160,000 people in the U.S. living with PBH, a condition with no approved treatment options [9][19] - The American Society for Metabolic and Bariatric Surgery reported around 270,000 new bariatric surgeries in 2023, indicating a stable market for potential PBH patients [20] - The company estimates that 8% of patients who undergo bariatric surgery will develop PBH within one to three years [48][50] Company Strategy and Development Direction - The company aims to develop novel therapies for diseases with high unmet needs, focusing on execution across its clinical trials [28] - The company is preparing for a potential commercial launch of Avexatide in 2027 if approved [10] - The company is actively engaging with clinical trial sites and expects to complete recruitment for the Lucidity trial by the end of 2025 [22] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in achieving clinical milestones through the end of 2026, supported by a strong cash position [23][24] - The company is focused on educating the medical community and patients about PBH, given the lack of awareness and treatment options [34][46] - Management highlighted the importance of access to treatments for patients suffering from debilitating conditions like PBH [65] Other Important Information - The company plans to present week 48 data from the HELIOS trial in Wolfram syndrome at an upcoming conference [12][28] - The company is preparing for potential FDA discussions regarding trial designs for its various programs [56] Q&A Session Summary Question: Will a large patient education campaign be required for Avexatide? - Management acknowledged the need for education due to the rarity of PBH and the lack of prior treatments, emphasizing the importance of informing both medical professionals and patients [32][34] Question: What is the expected efficacy for the PSP trial? - Management stated the study has 80% power to detect a 30% effect on the PSP rating scale, with multiple endpoints being considered for decision-making [37][39] Question: How many of the 160,000 PBH patients are seeking treatment? - Management indicated that a larger group, potentially up to 1 million, may experience hypoglycemia post-bariatric surgery, but only about 160,000 have persistent symptoms warranting treatment [46][47] Question: What are the remaining questions with the FDA regarding trial design? - Management noted that the week 48 data will inform the Phase III program, but specific details of FDA discussions were not disclosed [56] Question: Will there be subgroup analysis in the Avexatide study? - Management confirmed that the study will focus on a population experiencing frequent hypoglycemic events, with no anticipated step therapy restrictions [61][62] Question: What gives confidence that Avexatide won't cause safety issues? - Management highlighted the good safety profile observed in both non-clinical and clinical data, noting that Avexatide is a competitive antagonist rather than a GLP-1 agonist [70] Question: How does Avexatide compare to other drugs in the space? - Management emphasized Avexatide's strong profile and breakthrough therapy designation, noting that other programs are earlier in development and face hurdles [82][84]

Financial Data and Key Metrics Changes - The company ended the first quarter with a cash position of $204.1 million, which includes approximately $65.5 million in net proceeds from a public offering closed in January 2025 [23] - Total operating expenses for the quarter were $37.8 million, down 82% from the same period in 2024 [25] - Research and development expenses were $22.1 million compared to $36.6 million in Q1 2024, primarily due to decreased spending on AMX-thirty five and reductions in payroll and personnel costs [25] - Selling, general and administrative expenses were $15.7 million compared to $57.8 million in Q1 2024, mainly due to decreased payroll and consulting costs [25] Business Line Data and Key Metrics Changes - The company is advancing three potential therapies across four clinical trials, including Avexatide for post-bariatric hypoglycemia (PBH), AMX-thirty five for Wolfram syndrome and progressive supranuclear palsy (PSP), and AMX-one hundred fourteen for ALS [7][8] - Avexatide has shown promise in treating PBH, with a pivotal Phase III trial (Lucidity) initiated, and the first participant dosed [10][18] - AMX-thirty five is being evaluated in two indications, with positive Phase II data reported for Wolfram syndrome and ongoing trials for PSP [12][14] Market Data and Key Metrics Changes - There are approximately 160,000 people in the U.S. living with PBH, a condition with no approved treatment options [9][19] - The American Society for Metabolic and Bariatric Surgery reported approximately 270,000 new bariatric surgery procedures in 2023, indicating a stable market for potential PBH patients [20] Company Strategy and Development Direction - The company aims to execute across its clinical programs, focusing on diseases with high unmet needs [28] - The anticipated commercial launch of Avexatide is planned for 2027, contingent on successful trial outcomes [10] - The company is preparing for potential market entry and is focused on educating healthcare providers and patients about PBH [34][66] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in achieving clinical milestones through the end of 2026, supported by a strong cash position [23][29] - The company is optimistic about the potential of its therapies, particularly Avexatide, given the high unmet need in PBH [84] - Management highlighted the importance of education and access for patients suffering from PBH, emphasizing the need for awareness in the medical community [34][66] Other Important Information - The company plans to present week 48 data from the HELIOS trial in Wolfram syndrome and expects to share unblinded Phase 2b data from the ORION trial in PSP in the third quarter [28] - The company is also preparing for early cohort data from the Phase I LUMINA trial of AMX-one hundred fourteen in ALS by the end of the year [28] Q&A Session Summary Question: Will a large patient education campaign be required for Avexatide in PBH? - Management acknowledged the need for education due to the rarity of treatments for PBH and the importance of informing both medical professionals and patients about the condition and potential treatment options [31][34] Question: What is the expected efficacy bogey on the PSP rating scale? - Management indicated that the study has 80% power to detect a 30% effect on the PSP rating scale, with multiple endpoints being considered for decision-making [35][37] Question: How many of the 160,000 PBH patients are seeking treatment? - Management clarified that while 160,000 represent those with persistent hypoglycemia, a larger group of 500,000 to 1 million may experience hypoglycemia post-bariatric surgery [44][46] Question: What are the remaining questions with the FDA on trial design? - Management stated that the week 48 data will inform the Phase III program, but specific details of discussions with the FDA were not disclosed [53][56] Question: Will there be subgroup analysis within the Avexatide study? - Management confirmed that the study is focused on a population experiencing frequent hypoglycemic events, and they do not anticipate step therapy restrictions due to the lack of approved therapies for PBH [61][62] Question: What gives confidence that GLP-one antagonists like Avexatide won't cause safety issues? - Management highlighted the good safety profile observed in both non-clinical and clinical data for Avexatide, noting that it is a competitive antagonist rather than a full agonist [69][71] Question: How does the company compare Avexatide to other drugs in the space? - Management emphasized that Avexatide is in Phase III with breakthrough therapy designation, and they believe it has a strong profile compared to earlier-stage programs [82][84]

Financial Data and Key Metrics Changes - The company ended Q1 2025 with a cash position of $204.1 million, which includes approximately $65.5 million in net proceeds from a public offering closed in January 2025 [21] - Total operating expenses for the quarter were $37.8 million, down 82% from the same period in 2024 [22] - Research and development expenses were $22.1 million compared to $36.6 million in Q1 2024, primarily due to decreased spending on AMX-35 for ALS treatment [22] - Selling, general and administrative expenses were $15.7 million compared to $57.8 million in Q1 2024, mainly due to reduced payroll and consulting costs [22] Business Line Data and Key Metrics Changes - The lead asset, Avexatide, is in a pivotal Phase III trial for post-bariatric hypoglycemia (PBH), with the first participant dosed in April 2025 [6][8] - AMX-35 is being evaluated for Wolfram syndrome and progressive supranuclear palsy (PSP), with positive Phase II data reported for Wolfram syndrome [10][12] - AMX-114, targeting ALS, has initiated a Phase I trial with the first participant dosed in April 2025 [13] Market Data and Key Metrics Changes - Approximately 160,000 people in the U.S. are estimated to be living with PBH, a condition with no approved treatment options [7][17] - The American Society for Metabolic and Bariatric Surgery reported around 270,000 new bariatric surgeries in 2023, indicating a stable market for potential PBH patients [18] Company Strategy and Development Direction - The company aims to advance three potential therapies across four clinical trials, focusing on diseases with high unmet needs [6] - The anticipated commercial launch of Avexatide, if approved, is expected in 2027 [8] - The company is preparing for a potential first-to-market launch of Avexatide in PBH, emphasizing the need for patient education and market access strategies [31][60] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in achieving clinical milestones through the end of 2026, supported by a strong cash position [21][22] - The company is focused on executing its clinical programs and is optimistic about the upcoming data releases from ongoing trials [25][26] Other Important Information - The company has received FDA breakthrough therapy designation for Avexatide, highlighting the high unmet need in PBH [8][82] - The Phase III Lucidity trial is designed to evaluate the reduction in hypoglycemic events, with a robust body of data supporting Avexatide's efficacy [19][20] Q&A Session Summary Question: On Avexatide and patient education needs - Management acknowledged the need for a patient education campaign due to the rarity of PBH and the lack of prior treatments [28][31] Question: Efficacy expectations for PSP - Management indicated the study is powered to detect a 30% effect on the PSP rating scale, with multiple endpoints being considered [34][36] Question: Treatment-seeking behavior in PBH population - Management clarified that while 160,000 are estimated to have PBH, a larger group experiences hypoglycemia post-bariatric surgery, with many seeking treatment [40][42] Question: FDA discussions on trial design - Management stated that the week 48 data will inform the Phase III program, but specific details of FDA discussions were not disclosed [50][54] Question: Subgroup analysis in Avexatide study - Management confirmed that the study focuses on a population with frequent hypoglycemic events, and they do not anticipate step therapy restrictions from payers [58][60] Question: Safety concerns regarding GLP-1 antagonists - Management reassured that Avexatide has shown a good safety profile in clinical trials, with no significant adverse events reported [66][68] Question: Business development activities - Management emphasized a focus on executing current clinical trials rather than pursuing new business development opportunities at this time [70] Question: Inclusion criteria regarding NfL levels in ALS trial - Management explained that while NfL levels are high in ALS patients, they did not set specific high NfL level criteria for trial inclusion to avoid missing important signals [73][75] Question: Comparison of Avexatide to other drugs - Management highlighted Avexatide's strong profile and breakthrough therapy designation, noting that it is well-positioned compared to earlier-stage competitors [80][82]

Investigational Therapies - The company is developing three investigational therapies: avexitide for PBH and congenital hyperinsulinism, AMX0035 for Wolfram syndrome and PSP, and AMX0114 for ALS[80][87]. - Avexitide has received Breakthrough Therapy Designation from the FDA for both PBH and congenital hyperinsulinism, impacting approximately 160,000 people in the U.S.[81][82]. - The Phase 3 LUCIDITY trial for avexitide began recruiting in February 2025, with topline data expected in the first half of 2026 and a potential commercial launch in 2027[83]. - In the Phase 2 PREVENT trial, avexitide demonstrated a 21% and 26% increase in mean plasma glucose nadir after treatment compared to placebo, with statistical significance (p=0.001 and p=0.0002)[84]. - AMX0035 showed improvement in pancreatic beta cell function in the Phase 2 HELIOS trial, with sustained improvement observed over time[91]. - The ORION trial for AMX0035 in PSP completed enrollment in January 2025 with 139 participants, and efficacy data is anticipated in Q3 2025[94]. - AMX0114, targeting calpain-2, is currently in the Phase 1 LUMINA trial, with early cohort data expected in 2025[97]. - The company announced a collaboration with Gubra A/S in December 2024 to develop a novel long-acting GLP-1 receptor antagonist[87]. - The company is actively engaging with the congenital HI community to develop a path forward for treatments[86]. Financial Performance - The company reported no product revenue for the three months ended March 31, 2025, a 100% decrease from $88.6 million in the same period of 2024 due to the discontinuation of RELYVRIO®/ALBRIOZA™[108][109]. - Total operating expenses for the three months ended March 31, 2025, were $37.8 million, an 82% decrease from $210.8 million in the same period of 2024[108]. - Selling, general and administrative expenses were $15.7 million for the three months ended March 31, 2025, a 73% decrease from $57.8 million in the same period of 2024[113]. - The company recorded approximately $110.5 million in charges related to inventory impairment and losses on firm purchase commitments for the three months ended March 31, 2024[110]. - The company reported a net loss of $35.9 million for the three months ended March 31, 2025, compared to a net loss of $118.8 million in the same period of 2024[122][124]. Research and Development Expenses - Research and development expenses primarily include costs for avexitide, AMX0035, AMX0114, and other potential candidates, with expenses incurred as they arise[98]. - Research and development expenses decreased to $22.1 million for the three months ended March 31, 2025, down 40% from $36.6 million in the same period of 2024[111]. - The company expects to increase research and development expenses in connection with ongoing clinical development activities, particularly for avexitide and AMX0035[118]. - The company is focused on developing additional product candidates and may incur significant costs related to clinical trials and regulatory approvals[119]. Cash Flow and Financing - As of March 31, 2025, the company had cash, cash equivalents, and marketable securities totaling $204.1 million, with an accumulated deficit of $642.6 million[115]. - The January 2025 Offering resulted in proceeds of approximately $65.5 million, net of underwriting discounts and offering expenses[114]. - The company anticipates financing near-term operations through existing cash and potential future equity or debt financing[117]. - For the three months ended March 31, 2025, the net cash used in operating activities was $39.8 million, a significant increase from $0.5 million in the same period of 2024, reflecting a $39.3 million change[121][122]. - The net cash used in investing activities for the three months ended March 31, 2025, was $43.7 million, compared to a net cash provided of $0.8 million in 2024, indicating a $44.5 million change[121][126]. - Net cash provided by financing activities increased to $65.7 million in the three months ended March 31, 2025, from $0.1 million in 2024, representing a $65.6 million change[121][128]. - The company plans to finance future cash needs through equity offerings, debt financings, and collaborations, which may dilute current ownership interests[120]. - The company may face challenges in raising additional funds, which could impact its product development and commercialization efforts[120]. Workforce and Restructuring - The restructuring plan announced in April 2024 reduced the workforce by approximately 70% and is expected to impact future general and administrative expenses[104]. - The company experienced a $0.7 million decrease in prepaid expenses and other current assets during the three months ended March 31, 2025[123].

[Company Overview and First Quarter Highlights](index=1&type=section&id=1.%20Company%20Overview%20and%20First%20Quarter%20Highlights) The company reports Q1 2025 results, highlighting clinical pipeline progress and an extended cash runway through 2026 [First Quarter 2025 Business and Financial Highlights](index=1&type=section&id=1.1.%20First%20Quarter%202025%20Business%20and%20Financial%20Highlights) Amylyx Pharmaceuticals reported Q1 2025 results, highlighting significant clinical pipeline progress and a strengthened financial position - **Pivotal Phase 3 LUCIDITY trial** of avexitide for post-bariatric hypoglycemia (PBH) is underway; completion of recruitment expected in 2025, with topline data anticipated in the first half of 2026[6](index=6&type=chunk) - Week 48 data from the ongoing **Phase 2 HELIOS trial** of AMX0035 in Wolfram syndrome to be presented from May 10-13[6](index=6&type=chunk) - **Phase 1 LUMINA trial** of AMX0114 for amyotrophic lateral sclerosis (ALS) is underway; early cohort data expected in 2025[6](index=6&type=chunk) - **Cash runway expected through the end of 2026**[6](index=6&type=chunk) Cash Position (as of March 31, 2025) | Metric | Amount (Millions) | | :----- | :---------------- | | Cash, cash equivalents, and marketable securities | $204.1 | [Co-CEOs' Strategic Outlook](index=1&type=section&id=1.2.%20Co-CEOs%27%20Strategic%20Outlook) The Co-CEOs expressed confidence in pipeline progress and achieving goals with the extended cash runway through 2026 - Continued progress across the pipeline, including strong clinical execution of the **pivotal Phase 3 LUCIDITY trial** of avexitide in post-bariatric hypoglycemia[4](index=4&type=chunk) - Completion of enrollment for LUCIDITY expected in 2025 and **topline data in the first half of 2026**[4](index=4&type=chunk) - First patient dosed in **Phase 1 LUMINA trial** of AMX0114 in ALS, with early cohort data expected later this year[4](index=4&type=chunk) - Anticipated **cash runway through the end of 2026**, supporting confidence in achieving current goals and upcoming milestones[4](index=4&type=chunk) [Pipeline and Clinical Development Updates](index=1&type=section&id=2.%20Pipeline%20and%20Clinical%20Development%20Updates) The company details advancements in its key clinical programs for avexitide, AMX0114, and AMX0035 across various indications [Avexitide Program (Post-Bariatric Hypoglycemia - PBH)](index=1&type=section&id=2.1.%20Avexitide%20Program%20(Post-Bariatric%20Hypoglycemia%20-%20PBH)) The avexitide program for PBH is advancing with the pivotal Phase 3 LUCIDITY trial, which has begun dosing participants - Avexitide is an investigational, first-in-class **glucagon-like peptide-1 (GLP-1) receptor antagonist**[16](index=16&type=chunk) - FDA has granted avexitide **Breakthrough Therapy Designation** for both PBH and congenital hyperinsulinism (HI), Rare Pediatric Disease Designation in congenital HI, and Orphan Drug Designation for hyperinsulinemic hypoglycemia[16](index=16&type=chunk) - Post-bariatric hypoglycemia (PBH) affects approximately **8% of people in the U.S. (around 160,000 people)** who underwent bariatric surgery, with no approved therapies[17](index=17&type=chunk) [LUCIDITY Trial (Phase 3)](index=1&type=section&id=2.1.1.%20LUCIDITY%20Trial%20(Phase%203)) - Pivotal Phase 3 LUCIDITY clinical trial of avexitide for PBH has begun dosing, with the **first participant dosed in April 2025**[6](index=6&type=chunk)[7](index=7&type=chunk) - The trial is an approximately **75-participant, randomized, double-blind, placebo-controlled study** evaluating efficacy and safety of avexitide in participants with PBH following Roux-en-Y gastric bypass (RYGB) surgery at approximately 20 sites in the U.S[7](index=7&type=chunk)[18](index=18&type=chunk) - Primary efficacy objective: **reduction in the composite of Level 2 and Level 3 hypoglycemic events** through Week 16, as agreed upon with the FDA[12](index=12&type=chunk)[19](index=19&type=chunk) - Completion of enrollment expected in 2025, with **topline data anticipated in the first half of 2026**, and potential commercial launch in 2027 if approved[6](index=6&type=chunk)[12](index=12&type=chunk) [Other Avexitide Data Presentations](index=2&type=section&id=2.1.2.%20Other%20Avexitide%20Data%20Presentations) - Amylyx plans to present additional data from the Phase 2 PREVENT and Phase 2b trials of avexitide in PBH at the **Endocrine Society's annual meeting (ENDO) 2025** on July 12-15 in San Francisco, CA[12](index=12&type=chunk) [AMX0114 Program (Amyotrophic Lateral Sclerosis - ALS)](index=1&type=section&id=2.2.%20AMX0114%20Program%20(Amyotrophic%20Lateral%20Sclerosis%20-%20ALS)) Amylyx has initiated the Phase 1 LUMINA trial for AMX0114, an investigational antisense oligonucleotide targeting calpain-2 for people living with ALS [LUMINA Trial (Phase 1)](index=1&type=section&id=2.2.1.%20LUMINA%20Trial%20(Phase%201)) - Phase 1 LUMINA clinical trial of AMX0114, an investigational antisense oligonucleotide (ASO) targeting knockdown of calpain-2, for people living with ALS has begun dosing, with the **first participant dosed in April 2025**[6](index=6&type=chunk)[7](index=7&type=chunk) - The multinational, randomized, double-blind, placebo-controlled, multiple ascending dose trial is designed to evaluate the **safety and biological activity of AMX0114**, and will assess ALS biomarkers, including changes in neurofilament light (NfL) levels[7](index=7&type=chunk) - **Early cohort data** from the LUMINA trial are expected in 2025[6](index=6&type=chunk)[12](index=12&type=chunk) [AMX0035 Program (Wolfram Syndrome & Progressive Supranuclear Palsy - PSP)](index=1&type=section&id=2.3.%20AMX0035%20Program%20(Wolfram%20Syndrome%20&%20Progressive%20Supranuclear%20Palsy%20-%20PSP)) Amylyx continues to advance AMX0035 for Wolfram syndrome and PSP, with key data readouts expected in 2025 [HELIOS Trial (Wolfram Syndrome - Phase 2)](index=1&type=section&id=2.3.1.%20HELIOS%20Trial%20(Wolfram%20Syndrome%20-%20Phase%202)) - **Data through Week 48** from the ongoing Phase 2 HELIOS trial of AMX0035 in Wolfram syndrome to be presented at the Joint Congress of the European Society for Pediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE) from May 10-13[6](index=6&type=chunk)[12](index=12&type=chunk) - Data from participants at Week 48 and ongoing discussions with the FDA will inform the **design of a Phase 3 trial** of AMX0035 in Wolfram syndrome[12](index=12&type=chunk) [ORION Trial (Progressive Supranuclear Palsy - Phase 2b/3)](index=2&type=section&id=2.3.2.%20ORION%20Trial%20(Progressive%20Supranuclear%20Palsy%20-%20Phase%202b%2F3)) - **Unblinded analysis** of the Phase 2b portion of the Phase 2b/3 ORION trial evaluating AMX0035 for progressive supranuclear palsy (PSP) expected in the **third quarter of 2025**[12](index=12&type=chunk) - The Phase 2b portion was **fully enrolled in January 2025** with a total of 139 participants randomized[12](index=12&type=chunk) - Efficacy and safety Phase 2b data from an unblinded analysis will be used to inform a **go/no-go decision on the Phase 3 portion** of the trial[12](index=12&type=chunk) [Financial Performance and Outlook](index=2&type=section&id=3.%20Financial%20Performance%20and%20Outlook) The company reports a reduced net loss for Q1 2025, a strengthened cash position, and an extended operational runway [First Quarter 2025 Financial Results](index=2&type=section&id=3.1.%20First%20Quarter%202025%20Financial%20Results) Amylyx reported a significantly reduced net loss for Q1 2025, driven by lower operating expenses following the discontinuation of RELYVRIO®/ALBRIOZA™ Key Financial Highlights (Three Months Ended March 31) | Metric | 2025 (in thousands) | 2024 (in thousands) | Change (YoY) | | :--------------------------------------- | :------------------ | :------------------ | :----------- | | Product revenue, net | $— | $88,643 | -100% | | Total operating expenses | $37,803 | $210,773 | -82.1% | | Loss from operations | $(37,803) | $(122,130) | -70.0% | [Research and Development (R&D) Expenses](index=2&type=section&id=3.1.1.%20Research%20and%20Development%20(R&D)%20Expenses) - Decrease primarily due to a decrease in spending on AMX0035 for the treatment of ALS, payroll and personnel-related costs, and a decrease in preclinical development activities[10](index=10&type=chunk) R&D Expenses (Three Months Ended March 31) | Period | Amount (in thousands) | Change (YoY) | | :----- | :-------------------- | :----------- | | Q1 2025 | $22,119 | -39.6% | | Q1 2024 | $36,608 | | Stock-Based Compensation Expense (R&D) | Period | Amount (in millions) | | :----- | :------------------- | | Q1 2025 | $1.8 | | Q1 2024 | $2.7 | [Selling, General and Administrative (SG&A) Expenses](index=2&type=section&id=3.1.2.%20Selling,%20General%20and%20Administrative%20(SG&A)%20Expenses) - Decrease primarily due to a decrease in payroll and personnel-related costs and a decrease in consulting, professional services, and other expenses[11](index=11&type=chunk) SG&A Expenses (Three Months Ended March 31) | Period | Amount (in thousands) | Change (YoY) | | :----- | :-------------------- | :----------- | | Q1 2025 | $15,684 | -72.8% | | Q1 2024 | $57,759 | | Stock-Based Compensation Expense (SG&A) | Period | Amount (in millions) | | :----- | :------------------- | | Q1 2025 | $5.0 | | Q1 2024 | $7.2 | [Net Loss](index=2&type=section&id=3.1.3.%20Net%20Loss) Net Loss (Three Months Ended March 31) | Period | Net Loss (in thousands) | Net Loss Per Share | | :----- | :---------------------- | :----------------- | | Q1 2025 | $(35,907) | $(0.42) | | Q1 2024 | $(118,793) | $(1.75) | [Cash Position and Runway](index=1&type=section&id=3.2.%20Cash%20Position%20and%20Runway) Amylyx's cash position increased to $204.1 million, which is expected to fund operations through the end of 2026 - Based on current operating plans, Amylyx expects its **cash runway to be through the end of 2026**[6](index=6&type=chunk)[13](index=13&type=chunk) - The cash position reflects payments of **$6.0 million in Q1 2025** related to product rebates and settlement of purchase commitments for AMX0035, established prior to the voluntary discontinuation of RELYVRIO®/ALBRIOZA™ sales in April 2024[13](index=13&type=chunk) - Residual cash obligations related to the discontinuation of RELYVRIO/ALBRIOZA are **$3.1 million**, expected to be paid through 2025[13](index=13&type=chunk) Cash, Cash Equivalents, and Marketable Securities | Date | Amount (in thousands) | | :--- | :-------------------- | | March 31, 2025 | $204,068 | | December 31, 2024 | $176,501 | [Public Offering and Cash Runway Extension](index=2&type=section&id=3.3.%20Public%20Offering%20and%20Cash%20Runway%20Extension) A January 2025 public offering generated net proceeds of approximately $65.5 million, extending the company's cash runway - Amylyx closed its underwritten public offering of **19.7 million shares** of its common stock in January 2025[8](index=8&type=chunk) - The offering **extended the company's expected cash runway through the end of 2026**[8](index=8&type=chunk) Public Offering Details | Metric | Value | | :----- | :---- | | Net proceeds to Amylyx | ~$65.5 million | [Additional Company Information](index=3&type=section&id=4.%20Additional%20Company%20Information) This section provides details on investor communications, the company's mission, and important forward-looking statements [Investor Conference Call and Available Information](index=3&type=section&id=4.1.%20Investor%20Conference%20Call%20and%20Available%20Information) Amylyx hosted a conference call on May 8, 2025, and directs investors to its corporate websites for periodic disclosures - Amylyx' management team hosted a conference call on **May 8, 2025, at 8:00 a.m. ET** to discuss financial results and provide a business update[14](index=14&type=chunk) - A live audio webcast of the call is available under 'Events and Presentations' on the Investor section of the Company's website, with an **archived replay available for 90 days**[14](index=14&type=chunk) - The company periodically provides information for investors on its corporate and investor relations websites, including press releases, financial performance, corporate governance, and SEC filings, and intends to use its website for disclosing material non-public information[15](index=15&type=chunk) [About Amylyx Pharmaceuticals](index=4&type=section&id=4.2.%20About%20Amylyx%20Pharmaceuticals) Amylyx Pharmaceuticals is dedicated to treating diseases with high unmet needs, focusing on three investigational therapies - Amylyx's mission is to usher in a new era of **treating diseases with high unmet needs**[20](index=20&type=chunk) - The company is currently focused on **three investigational therapies** across several neurodegenerative and endocrine diseases[20](index=20&type=chunk) [Forward-Looking Statements](index=4&type=section&id=4.3.%20Forward-Looking%20Statements) The report contains forward-looking statements regarding clinical programs, financial performance, and strategy, which are subject to risks and uncertainties - Statements in the press release regarding matters that are not historical facts are **'forward-looking statements'** subject to risks and uncertainties[21](index=21&type=chunk) - Risks include the success, cost, and timing of program development activities; ability to execute regulatory development plans; ability to fund operations; and the impact of global macroeconomic uncertainty, geopolitical instability, and public health events[21](index=21&type=chunk) - Amylyx **undertakes no obligation to update such statements** to reflect events or circumstances after the date they were made, except as required by law[21](index=21&type=chunk) [Condensed Consolidated Financial Statements](index=5&type=section&id=5.%20Condensed%20Consolidated%20Financial%20Statements) This section presents the unaudited condensed consolidated balance sheets and statements of operations as of March 31, 2025 [Condensed Consolidated Balance Sheets](index=5&type=section&id=5.1.%20Condensed%20Consolidated%20Balance%20Sheets) The balance sheet shows increased total assets and stockholders' equity, driven primarily by a higher cash position as of March 31, 2025 Condensed Consolidated Balance Sheets (Unaudited, in thousands) | Item | March 31, 2025 | December 31, 2024 | | :-------------------------------- | :------------- | :---------------- | | **Assets** | | | | Cash, cash equivalents and marketable securities | $204,068 | $176,501 | | Accounts receivable, net | $300 | $447 | | Prepaid expenses and other current assets | $11,776 | $12,484 | | Other assets | $3,532 | $4,202 | | **Total assets** | **$219,676** | **$193,634** | | **Liabilities and Stockholders' Equity** | | | | Accounts payable and accrued expenses | $16,877 | $26,888 | | Other liabilities | $1,382 | $1,981 | | **Total liabilities** | **$18,259** | **$28,869** | | **Stockholders' equity** | **$201,417** | **$164,765** | | **Total liabilities and stockholders' equity** | **$219,676** | **$193,634** | [Condensed Consolidated Statements of Operations](index=5&type=section&id=5.2.%20Condensed%20Consolidated%20Statements%20of%20Operations) The statement of operations reflects zero product revenue and a substantially reduced net loss for Q1 2025 compared to the prior year Condensed Consolidated Statements of Operations (Unaudited, in thousands, except share and per share data) | Item | Three Months Ended March 31, 2025 | Three Months Ended March 31, 2024 | | :--------------------------------------- | :-------------------------------- | :-------------------------------- | | Product revenue, net | $— | $88,643 | | Operating expenses: | | | | Cost of sales | $— | $5,945 | | Cost of sales - inventory impairment and loss on firm purchase commitments | $— | $110,461 | | Research and development | $22,119 | $36,608 | | Selling, general and administrative | $15,684 | $57,759 | | **Total operating expenses** | **$37,803** | **$210,773** | | **Loss from operations** | **$(37,803)** | **$(122,130)** | | Other income, net | $1,896 | $3,579 | | Loss before income taxes | $(35,907) | $(118,551) | | Provision for income taxes | $— | $242 | | **Net loss** | **$(35,907)** | **$(118,793)** | | Net loss per share — basic and diluted | $(0.42) | $(1.75) | | Weighted-average shares used in computing net loss per share — basic and diluted | 85,697,108 | 67,854,356 |

Financial Data and Key Metrics Changes - The company ended 2024 with a solid cash position of $176.5 million, excluding approximately $65.5 million in net proceeds from a public offering that closed on January 13, 2025 [28] - Total operating expenses for Q4 were $39.9 million, down 62% from the same period in 2023 [29] - Research and development expenses were $22.9 million compared to $44.9 million in Q4 2023, primarily due to decreased spending on AMX0035 and other cost reductions [29] - Selling, general and administrative expenses were $17.1 million compared to $52.2 million in Q4 2023, reflecting a decrease in payroll and consulting costs [29] Business Line Data and Key Metrics Changes - The lead asset, avexitide, is in a pivotal Phase III clinical trial targeting post-bariatric hypoglycemia (PBH) with top line results expected in the first half of 2026 [6][7] - AMX0035 is being evaluated in Wolfram syndrome and progressive supranuclear palsy (PSP), with ongoing trials showing promising early data [9][12] - AMX0114 is in a Phase I trial for ALS, with recruitment expected to begin in March or April [16][17] Market Data and Key Metrics Changes - There are approximately 160,000 people in the U.S. living with PBH, a condition with no approved treatments [8][36] - The company estimates that about 8% of individuals who undergo Roux-en-Y gastric bypass will develop PBH, indicating a substantial market opportunity [46] Company Strategy and Development Direction - The company is focused on executing clinical trials and preparing for a potential commercial launch of avexitide in PBH, with a target launch anticipated in 2027 [34][39] - A collaboration with Gubra aims to develop a novel long-acting GLP-1 receptor antagonist, indicating a strategic expansion of the company's pipeline [18] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the upcoming data readouts and the potential impact of avexitide as the first approved treatment for PBH [19][39] - The company is preparing for significant milestones in 2025 and 2026, including data from multiple ongoing trials [32][40] Other Important Information - The company has approximately $7.8 million in obligations remaining from previously recognized items related to the discontinuation of RELYVRIO/ALBRIOZA, expected to be paid through 2025 [31][32] - The company appointed Dan Monahan as Chief Commercial Officer to lead commercialization efforts, highlighting a strengthened leadership team [35] Q&A Session Summary Question: Why limit the entry criteria to just Roux-en-Y gastric bypass procedures for the PBH Phase III trial? - Management noted that they have the most experience with avexitide in patients who have undergone Roux-en-Y gastric bypass, but they recognize the pathophysiology is consistent across bariatric surgeries [45] Question: How will efficacy be interpreted in the PSP ORION study across regions? - Management indicated that both the 10-item and 28-item PSP rating scales will be analyzed, and they expect similar results from both [48] Question: What is the target profile for the long-acting GLP-1? - Management clarified that avexitide is a GLP-1 antagonist, which has shown reductions in insulin and hypoglycemia, differentiating it from GLP-1 agonists [51] Question: How is the market for PBH forecasted to change over time? - Management believes the market will continue to grow due to the chronic nature of PBH and ongoing demand for bariatric surgeries [55][59] Question: What are the expectations for the week 48 data in the Wolfram syndrome trial? - Management is looking for sustained improvements in C-peptide response and visual acuity, which would support regulatory confidence in AMX0035 [64] Question: Is there potential for avexitide to be developed for other indications beyond PBH? - Management acknowledged the potential for avexitide in other diseases characterized by hyperinsulinemic hypoglycemia but emphasized that the current focus remains on PBH [65]

Financial Performance - Product revenue, net for the year ended December 31, 2024, was $87.4 million, a decrease of 77% from $380.8 million in 2023[506]. - Net loss for the year ended December 31, 2024, was $301.7 million, compared to a net income of $49.3 million in 2023, representing a 712% decline[505]. - Cash, cash equivalents, and marketable securities as of December 31, 2024, totaled $176.5 million, supplemented by net proceeds of $65.5 million from a January 2025 offering[490]. - As of December 31, 2024, the company had cash, cash equivalents, and marketable securities totaling $176.5 million, with an accumulated deficit of $606.7 million[517]. - Net cash used in operating activities was $167.6 million in 2024, compared to a cash provided of $11.9 million in 2023, reflecting a change of $179.6 million[524][525]. - Net cash provided by investing activities decreased to $75.7 million in 2024 from $92.1 million in 2023, a decline of $16.4 million or 18%[529][530]. Operating Expenses - Total operating expenses increased by 18% to $402.1 million in 2024, compared to $342.0 million in 2023[505]. - Research and development expenses decreased by 19% to $104.1 million in 2024, down from $128.2 million in 2023[505]. - Selling, general and administrative expenses decreased by 39% to $114.3 million in 2024, compared to $188.4 million in 2023, following a restructuring plan that reduced the workforce by approximately 70%[502]. - Direct research and development expenses for AMX0035 - ALS dropped by $24.1 million (40%) to $36.7 million, while expenses for AMX0035 - PSP increased by $10.5 million (164%) to $16.9 million[510][511]. - Restructuring expenses amounted to approximately $22.9 million in 2024, including $21.9 million for employee severance and termination benefits[513]. Product Discontinuation - The RELYVRIO/ALBRIOZA product was discontinued in April 2024 following the failure of the Phase 3 PHOENIX trial to meet its primary and secondary endpoints[492]. - The company recorded approximately $118.7 million in charges related to inventory write-downs and losses on firm purchase commitments due to the discontinuation of RELYVRIO/ALBRIOZA[507]. Future Outlook - The company anticipates that existing cash and proceeds will be sufficient to meet operating and capital expenditure requirements through 2026[490]. - The company expects to finance near-term operations through existing cash and potential equity or debt financing, with no assurances of additional funding availability[519][523]. - The January 2025 Offering is expected to generate approximately $65.5 million in proceeds, which will support ongoing operations[516]. Accounting and Reporting - The company prepares its consolidated financial statements in accordance with U.S. GAAP, requiring estimates and judgments that affect reported amounts of assets and liabilities[534]. - Revenue recognition prior to the discontinuation of RELYVRIO®/ALBRIOZA™ involved significant estimates related to gross-to-net adjustments, which have not materially differed from actual activity to date[536]. - The company estimates accrued research and development expenses based on open contracts and service provider communications, with adjustments made as necessary[539]. - The estimate of accrued research and development expenses relies on timely reporting from third-party service providers, with no material adjustments to prior estimates reported[540]. - The company is classified as a smaller reporting company and is not required to provide certain market risk disclosures[543].

Financial Performance - Net loss for Q4 2024 was $37.5 million, or $0.55 per share, compared to a net income of $4.7 million, or $0.07 per share in Q4 2023; for the full year, net loss was $301.7 million, or $4.43 per share, compared to a net income of $49.3 million, or $0.70 per share in 2023[11] - Product revenue for the three months ended December 31, 2024, was $(665,000), compared to $108,449,000 in the same period of 2023, indicating a significant decrease[24] - The net loss for the year ended December 31, 2024, was $(301,743,000), compared to a net income of $49,271,000 in 2023, marking a substantial decline[24] - The company reported a basic net loss per share of $(0.55) for the three months ended December 31, 2024, compared to a profit of $0.07 in the same period of 2023[24] Expenses - Research and development expenses for Q4 2024 were $22.9 million, down from $44.9 million in Q4 2023, and total R&D expenses for the year were $104.1 million compared to $128.2 million in 2023[9] - Selling, general, and administrative expenses for Q4 2024 were $17.1 million, a decrease from $52.2 million in Q4 2023, with total SG&A expenses for the year at $114.3 million compared to $188.4 million in 2023[10] - Total operating expenses for the year ended December 31, 2024, were $402,102,000, up from $341,984,000 in 2023, reflecting an increase of approximately 17.5%[24] - Research and development expenses for the three months ended December 31, 2024, were $22,892,000, compared to $44,914,000 in the same period of 2023, showing a decrease of approximately 48.9%[24] Cash Position - Cash position at December 31, 2024, was $176.5 million, down from $234.4 million at September 30, 2024; the company raised $65.5 million in January 2025, extending the cash runway through the end of 2026[12] - Cash, cash equivalents, and marketable securities decreased to $176,501,000 as of December 31, 2024, down from $371,362,000 in 2023, a decline of approximately 52.5%[22] Clinical Trials and Development - The pivotal Phase 3 LUCIDITY trial of avexitide for post-bariatric hypoglycemia is underway, with completion of recruitment expected in 2025 and topline data anticipated in the first half of 2026[5] - The LUCIDITY trial will evaluate the FDA-agreed-upon primary outcome of reducing hypoglycemic events through Week 16, with a total of approximately 75 participants[18] - Amylyx appointed Dan Monahan as Chief Commercial Officer to lead the commercialization strategy for avexitide, which is expected to launch in 2027 if approved[6] - The company began the Phase 1 LUMINA clinical trial of AMX0114 for ALS, with dosing expected to begin in March or April 2025[6] - Amylyx plans to share Week 48 data from the ongoing Phase 2 HELIOS trial of AMX0035 in Wolfram syndrome in the coming months[12] - The company anticipates the announcement of Week 48 data from the Phase 2 HELIOS trial of AMX0035 for the treatment of Wolfram syndrome in the near future[20] - Amylyx is currently conducting a Phase 3 trial of avexitide for PBH, with expectations regarding recruitment completion and topline data readout[20] - The company is exploring the potential of AMX0114 as a treatment for ALS, with an expected timeline for data readout forthcoming[20] Asset Position - As of December 31, 2024, total assets decreased to $193,634,000 from $517,454,000 in 2023, representing a decline of approximately 62.6%[22] - The company entered into a collaboration with Gubra A/S to develop a novel long-acting GLP-1 receptor antagonist, aiming to identify a lead development candidate for IND-enabling studies[6]