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Maggie, living with Post-Bariatric Hypoglycemia (PBH) Pancreatic islet cells JUNE 2025 We have an audacious mission to develop novel therapies for diseases with high unmet needs, with a focus on serious and fatal neurodegenerative diseases and endocrine conditions.
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2 DISCLAIMER Statements contained in this presentation regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, the Company’s plans to explore the use of avexitide as a treatment for post-bariatric hypoglycemia (PBH) and congenital hyperinsulinism, AMX0035 for neurodegenerative diseases, including progressive supranuclear palsy (PSP) and Wolfram syndrome (WS), AMX0114 for ALS; statements regarding the timing of clinical trials for PBH, PSP, WS and/or ALS; and expectations regarding our longer-term strategy and expected cash runway. Any forward-looking statements in this presentation are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: the success, cost, and timing of Amylyx’ program development activities, including ongoing and planned clinical trials, Amylyx’ ability to execute on its development and regulatory strategy, regulatory developments, Amylyx’ cash runway and ability to fund operations, as well as the risks and uncertainties set forth in Amylyx’ United States Securities and Exchange Commission (SEC) filings, including Amylyx’ Annual Report on Form 10-K for the year ended December 31, 2024, and subsequent filings with the SEC. All forward-looking statements contained in this presentation speak only as of the date on which they were made. Amylyx undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.
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3 PRECLINICAL IND PHASE 1 PHASE 2 PHASE 3 COMMERCIAL PBH and other rare diseases A Growing Pipeline of Therapies to Serve Communities with High Unmet Needs Led by an experienced team with a proven track record of commercialization in rare diseases GLP-1 receptor antagonist Sodium phenylbutyrate and taurursodiol (also known as ursodoxicoltaurine) ASO targeting calpain-2, a protein involved in axonal degeneration Wolfram Syndrome Progressive Supranuclear Palsy (PSP) Post-Bariatric Hypoglycemia (PBH) Amyotrophic Lateral Sclerosis (ALS) Congenital Hyperinsulinism (HI) • Engaging physician and community experts around next steps for clinical development • Phase 3 LUCIDITY trial underway. Began dosing in April 2025 and data readout anticipated in 1H 2026 • FDA-agreed upon primary outcome of reduction in hypoglycemic events • Positive Phase 2 HELIOS data showed improvement or stabilization across all disease measures at Week 24 (N=11) and sustained improvement or stabilization at Week 48 (N=10) • Phase 2b/3 ORION trial in PSP underway – Phase 2b data anticipated in Q3 2025 • Preclinical data showed improved neuronal survival and reductions in neurofilament light chain • Phase 1 LUMINA trial underway. Began dosing in April 2025 and early cohort data expected in 2025 • Granted FDA Fast Track designation to AMX0114 in May 2025 LUCIDITY PHASE 3 CLINICAL TRIAL HELIOS PHASE 2 CLINICAL TRIAL ORION PHASE 2b/3 CLINICAL TRIAL LUMINA PHASE 1 CLINICAL TRIAL AVEXITIDE AMX0035 AMX0114 • Entered into a collaboration with Gubra to develop a novel long- acting GLP-1 receptor antagonist to enter IND-enabling studies ASO=antisense oligonucleotide; FDA=U.S. Food and Drug Administration; GLP-1=glucagon-like peptide-1; IND=investigational new drug. 3 LONG-ACTING GLP-1 RECEPTOR ANTAGONIST FDA Breakthrough Therapy and Orphan Drug Designations
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Pancreatic islet cells First-in-class, Phase 3 GLP-1 Receptor Antagonist with FDA Breakthrough Therapy Designation AVEXITIDE
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5 • FDA Breakthrough Therapy Designation and Orphan Drug Designation in hyperinsulinemic hypoglycemia • Phase 3 LUCIDITY trial designed to evaluate FDA-agreed upon primary outcome of reduction in hypoglycemic events in PBH • Prior clinical studies generated highly statistically significant reductions in hypoglycemic events > Same outcome to be used in planned Phase 3 • PBH is an orphan condition that is often life-altering; ~160,000 prevalent patients • Strong IP position with patent rights through 2037 and potential for patent term extension • Collaboration with Gubra underway to develop potential novel long-acting GLP-1 receptor antagonist APRIL 2025 (Complete) 2025 1H 2026 Began Dosing in Avexitide Phase 3 Trial in PBH Complete Enrollment of Avexitide Phase 3 Trial in PBH Topline Data from Avexitide Phase 3 Trial in PBH EXPECTED MILESTONES Avexitide: Investigational, First-in-Class GLP-1 Receptor Antagonist FDA=U.S. Food and Drug Administration; GLP-1=glucagon-like peptide-1; IP=intellectual property; PBH=post-bariatric hypoglycemia
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6 Inhibiting Effects of Excessive GLP-1 in PBH to Mitigate Hypoglycemia • The GLP-1 receptor is a key regulator of glucose-insulin response • Endogenous GLP-1 secreted in response to a meal causes insulin secretion and glucose uptake • Avexitide inhibits endogenous GLP-1 from binding to the GLP-1 receptor, decreasing insulin secretion and thereby stabilizing blood glucose levels 16.7 G +/- 3 GLP-1 +/- Avexitide Glucose Glucose + GLP-1 Glucose + GLP-1 + Avexitide Time (min) Insulin (ng) / DNA (µg) Glucose + GLP-1 + Avexitide GLP-1 receptor antagonism blocks GLP-1 and decreases insulin response to glucose in rat pancreatic islet cells1,2 GLP-1=glucagon-like peptide-1; GSIS=glucose-stimulated insulin secretion; PBH=post-bariatric hypoglycemia; 1. Cabrera O. et al. The Journal of Biological Chemistry. 2022;298(2):101484. doi:10.1016/j.jbc.2021.101484; 2. Averaged data from five independent experiments; 3. Step-wise increase of glucose concentration from 2.8 to 16.7 mM (2.8G and 16.7G).
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7 Post-Bariatric Hypoglycemia (PBH) is Believed to be Caused by Excessive GLP-1 Response that Leads to Hyperinsulinemic Hypoglycemia Post-Meal GLP-1=glucagon-like peptide-1; 1. Craig, C. M. et al. Diabetes, Obesity & Metabolism. 2018;20:352–361. doi.org/10.1111/dom.13078. 2. Jalleh, R. J. et al. Reviews in Endocrine and Metabolic Disorders. 2023;24:1075-1088. doi.org/10.1007/s11154-023-09823-3. 3. van den Broek, M. et al. International Journal of Obesity. 2021;45(3):619-630. doi.org/10.1038/s41366-020-00726-w. 4. Larraufie et al., 2019, Cell Reports 26, 1399–1408. doi.org/10.1016/j.celrep.2019.01.047. Altered Stomach AvexitidePancreas Insulin GLP-1 Islet Beta Cells Glucose GLP-1 Receptor Insulin Evidence supports that PBH results from an up to 10x increase in post-meal GLP-1 levels, leading to hypersecretion of insulin1-4 Avexitide is designed to bind to the GLP-1 receptor and inhibit the effect of excessive GLP-1, leading to decreased insulin secretion and stabilized glucose levels1
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8 0 50,000 100,000 150,000 200,000 250,000 300,000 350,000 2013 '14 '15 '16 '17 '18 '19 '20 '21 22 2023 Rate of Gastric Bypass by Type Sleeve RYGB Total Currently living with PBH in the U.S.1-3 No approved treatment options ~160,000 people Post-Bariatric Hypoglycemia (PBH) is Believed to be Caused by Excessive GLP-1 Response that Leads to Hyperinsulinemic Hypoglycemia Post-Meal Hypoglycemia from PBH is Often Dangerous and Life-Altering • General fatigue, confusion, difficulty speaking, blurred vision • Risk of falls, seizures, vehicle accidents • Job and income loss “It affected my ability to work and take care of my family.” “I pass out multiple times a week. My lows are averaging 4-5 times a day.” “I lost my driver’s license since I am unaware of my lows.” LIVING WITH PBH BETWEEN 2013-2023 Sleeve.....~1.4 million RYGB......~0.6 Million Total………~2.5 Million >200K new procedures occur annually1 PBH develops on average 1-3 years post surgery PBH=post-bariatric hypoglycemia; RYGB=Roux-en-Y gastric bypass; 1. Estimate of Bariatric Surgery Numbers, 2013-2023. American Society for Metabolic and Bariatric Surgery (ASMBS). Accessed May 8, 2025. 2. Raverdy V. et al. Annals of Surgery. 2016;264(5):878-885. doi:10.1097/SLA.0000000000001768. 3. de Heide, L. J. M. et al. Diabetes, Obesity, & Metabolism. 2023;25:735-747. doi.org/10.1111/dom.14920.
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9Confidential. For internal purposes only. aThe ASMBS total bariatric procedure numbers are based on the best estimation from available data (BOLD,ACS/MBSAQIP, National Inpatient Sample Data and outpatient estimations) b Assumes 20-40% post-surgical hypoglycemic symptom prevalence; cSevere symptoms defined as glucose <40 mg/dL or emergency room/hospital visit Preliminary data from two industry-leading medical claims providers align with current literature understanding of ~160K prevalent population10 ~160K People Live With PBH in U.S. Based on representative sample of available studies ASMBS Registry of Bariatric Surgery1a 2.5M bariatric surgeries of which 2M were either sleeve gastrectomy [SG] or Roux-en-Y gastric bypass [RYGB]) 8-Study Meta-Analysis (N=280)2 56.1% prevalence of hypoglycemia in studies specifically examining RYGB and 54.3% in those examining SG Prospective, Longitudinal Cohort (N=1,448)3 43.2% prevalence of post-RYGB hypoglycemia symptoms Prospective 1-Year Study (N=186)4 32.8% of participants had at least one OGTT-related hypoglycemia after laparoscopic sleeve gastrectomy Prospective 2-Year Study (N=281)5 32.6% showed post-challenge hypoglycemia after RYGB; 22.6% after SG Retrospective Survey (N=341)6 29% with new-onset hypoglycemia symptoms post-RYGB or SG Source ~8% Finding Retrospective Study (N=120)7 Of 107 individuals with PBH treated with acarbose, 39% had persistent/unacceptable frequency of hypoglycemic events [Note: Equates to ~8-16% of total bariatric surgery populationb] Retrospective Study (N=1,206)8 13.1% met criteria for PBH 5 years post-op and 5% of those with PBH had severe symptomsc Prospective, Longitudinal Cohort (N=177)9 7.9% met criteria for PBH 5-years post-RYGB Prospective, Longitudinal Cohort (N=1,448)3 Symptoms of PBH requiring hospitalization or ER visit occurred in 2.6-3.6% of people who underwent RYGB at 5 years of follow-up ~20- 50% 1. Estimate of Bariatric Surgery Numbers, 2013-2023. American Society for Metabolic and Bariatric Surgery (ASMBS). Accessed May 8, 2025. 2. Lupoli R, et al. Nutr Metab Cardiovasc Dis. 2022;32(1):32-39. 3. Fischer LE, et al. Surg Obes Relat Dis.2021;17(10):1787-1798. 4. Belilgoli A, et al. Obes Surg. 2017;27:3179-3186 797-802.5. Brix JM, et al. Obes Facts. 2019;12:397-406. 6. Lee CJ, et al. Surg Obes and Relat Dis. 2018;14(6):797-802. 7. de Heide LJM, et al. Diabetes Obes Metab.2023;25:735-747.8. Lee CJ, et al. Obesity.2016.24(6):1342-1348. 9. Raverdy V, et al. Annals Surg. 2016.264(5):878-885.10. Data on file. 11. Hazelhurst J, et al. Endocr Connect. 2024;13(5):e230285. Total U.S. Bariatric Surgeries ~2 Million from 2013-2023 Prevalence of Hypoglycemia Following Bariatric Surgery ~400K – 1M PBH Prevalence ~160,000
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10 Phase 3 LUCIDITY Trial Designed to be Consistent with Phase 2 PREVENT and Phase 2b Trials Evaluating Avexitide for the Treatment of PBH 1:1 Randomization Avexitide 60 mg QD Avexitide 30 mg BID 14-day Treatment Period 14-day Treatment Period 14-day Treatment Period 14-day Treatment Period Avexitide 45 mg BID Avexitide 90 mg QD Participants enrolled had Roux-en-Y gastric bypass (RYGB) Participants enrolled had RYGB, vertical sleeve gastrectomy, esophagectomy, Nissen fundoplication, or gastrectomy 1:1 Randomization PHASE 2 PREVENT TRIAL DESIGN - 28-day, randomized, placebo-controlled crossover trial (N=18) PHASE 2B TRIAL DESIGN - 28-day, open-label, investigator-initiated, crossover trial (N=16) PHASE 3 LUCIDITY TRIAL DESIGN - Multicenter, randomized, double-blind, placebo-controlled trial (N=~75) Participants to be enrolled will have had RYGB 3:2 Randomization 16-week Double-blind Treatment Period 32-week Treatment Period At least 2 hypoglycemic events during 14-day run-in period despite adhering to consistent dietary management 2-day washout MMTT MMTT MMTT BID=twice daily; MMTT=mixed meal tolerance testing; PBH=post-bariatric hypoglycemia; QD=once daily. 14-day Eligibility Run-in Period 14-day Eligibility Run-in Period 21-day Eligibility Run-in Period Avexitide 30 mg BID Avexitide 60 mg QD Avexitide 90 mg QD Avexitide 45 mg BID Avexitide 90 mg QD Placebo Open-label Extension (OLE) At least 2 hypoglycemic events during 14-day run-in period despite adhering to consistent dietary management At least 3 hypoglycemic events during 21 -day run-in period despite adhering to consistent dietary management Placebo 14-day Treatment Period Placebo
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11 MAD=multiple ascending dose; PBH=post-bariatric hypoglycemia; QD=once daily; SAD=single ascending dose; Tmax=time to peak drug concentration; 1. Craig, C. M. et al. The Journal of Clinical Endocrinology & Metabolism. 2021;106(8):e3235-e3248. doi.org/10.1210/jendso/bvac150.725. 2. Tan, M. (2022). Efficacy and Safety of Avexitide for Treatment of Hypoglycemia after Gastrointestinal Surgery: Assessment of Novel Dosing Regimens in an Expanded Indication [Conference presentation]. ENDO Annual Symposium. Avexitide Significantly Reduced Rates of Hypoglycemia in Two Phase 2 Clinical Trials in PBH Treatment effect supported by consistent, dose-dependent effects across Phase 1, SAD, and MAD trials in PBH 0 10 20 30 40 50 60 70 80 90 100 Level 2 Level 3 Avexitide 30 mg twice daily Avexitide 60 mg once a day Avexitide 45 mg twice daily Avexitide 90 mg once a day PHASE 2 PREVENT STUDY PHASE 2B STUDY % Improvement in Rate of Hypoglycemia 40% p=0.04 23% p=0.2 60% p=0.004 57% p=0.003 68% p=0.0003 53% p=0.004 66% p=0.0003 % Improvement in Rate of Hypoglycemia by Avexitide Dose 56% p=0.01 Avexitide 90 mg QD demonstrated a half-life of ~3 hours, a Tmax ranging from 6-9 hours, and therapeutic exposure through 24 hours. Avexitide cut rates of hypoglycemic events by >50%
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12 FDA=U.S. Food and Drug Administration; PBH=post-bariatric hypoglycemia; 1. Craig, C. M. et al. The Journal of Clinical Endocrinology & Metabolism. 2021;106(8):e3235-e3248. doi.org/10.1210/jendso/bvac150.725. 2. Tan, M. (2022). Efficacy and Safety of Avexitide for Treatment of Hypoglycemia after Gastrointestinal Surgery: Assessment of Novel Dosing Regimens in an Expanded Indication [Conference presentation]. ENDO Annual Symposium. Phase 3 Endpoint Met in Phase 2 and Phase 2b Phase 3 program will evaluate 90 mg once daily in people living with PBH FDA-agreed upon primary endpoint: composite of Level 2 and Level 3 hypoglycemic events FDA Breakthrough Therapy Designation 0 10 20 30 40 50 60 70 80 90 100 Level 2 Level 3 Avexitide 30 mg twice daily Avexitide 60 mg once a day Avexitide 45 mg twice daily Avexitide 90 mg once a day PHASE 2 PREVENT STUDY % Improvement in Rate of Hypoglycemia 40% p=0.04 23% p=0.2 60% p=0.004 57% p=0.003 68% p=0.0003 53% p=0.004 66% p=0.0003 % Improvement in Rate of Hypoglycemia by Avexitide Dose 56% p=0.01 PHASE 2B STUDY
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13 Avexitide Reproducibly Improved Insulin and Glucose Responses During Standardized Meal Tests in People with PBH CONSISTENT RESULTS IN PBH CLINICAL TRIALS BID=twice daily; IV=intravenous; MAD=multiple ascending dose; MMTT=mixed meal tolerance testing; PBH=post-bariatric hypoglycemia; QD=once daily; SAD=single ascending dose; SC=subcutaneous; 1. Craig, C. M. et al. Diabetologia. 2017;60(3):531-540. doi:10.1007/s00125-016-4179-x; 2. Craig, C. M. et al. Diabetes, Obesity & Metabolism. 2018;20:352–361. doi.org/10.1111/dom.13078; 3. Tan, M. et al. Diabetes, Obesity & Metabolism. 2020;22(8):1406-1416. doi:10.1111/dom.14048; 4. Craig, C. M. et al. The Journal of Clinical Endocrinology & Metabolism. 2021;106(8):e3235-e3248. doi:10.1210/clinem/dgab103; 5. 18 participants were randomized and completed the trial with 17 included in the efficacy analysis due to a major protocol deviation (glycemic rescue was not administered as indicated per protocol during the Period 1 placebo MMTT). Phase 11 SAD2 MAD3 Phase 2 PREVENT4 Avexitide IV infusion (n=8) Avexitide SC injection (N=8) Avexitide 30 mg BID SC injection (n=5) Avexitide 30 mg BID SC injection (N=17)5 Avexitide 60 mg QD SC injection (N=17)5 Improvement vs. Placebo Postprandial Glucose Nadir Increase (p<0.001) Increase (p<0.001) Increase (p<0.05) Increase (p=0.001) Increase (p=0.0002)
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14 AE=adverse event; 1. Craig, C. M. et al. The Journal of Clinical Endocrinology & Metabolism. 2021;106(8):e3235-e3248. doi.org/10.1210/jendso/bvac150.725. 2. Tan, M. (2022). Efficacy and Safety of Avexitide for Treatment of Hypoglycemia after Gastrointestinal Surgery: Assessment of Novel Dosing Regimens in an Expanded Indication [Conference presentation]. ENDO Annual Symposium. Avexitide was Generally Well-Tolerated with a Favorable Safety Profile Across Both Phase 2 Trials Phase 2 PREVENT Study1 Phase 2b Study2 AEs generally mild to moderate and transient AEs generally mild to moderate and transient No treatment-related serious AEs • 1 serious adverse event (presyncope during avexitide 60 mg once daily) occurred; reported as unrelated to study drug and self-limited No serious AEs Most common AEs were injection* site bruising, headache, and nausea Most common AEs were diarrhea, headache, bloating, and injection* site reaction/bruising No participant discontinuations No participant discontinuations No clinically meaningful increases were observed in fasting or peak postprandial plasma glucose levels (i.e., no hyperglycemia observed) *Injection site reactions generally mild and transient with no grade 3 events or resulting discontinuations
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15 IP=intellectual property; NCE=new chemical entities. Phase 3 LUCIDITY Trial Underway, Readout in First Half of 2026 2025 1H 2026 2027 Began dosing in April 2025 Expected Phase 3 Recruitment Completion 2025 Planned Pivotal Study Readout First Half of 2026 Anticipated Commercial Launch, if approved, 2027 Strong IP position with patent rights through 2037, potential for additional term through Patent Term Extensions Granted Orphan Drug Designation and positioned for NCE exclusivity 15 April 2025
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AMX0035 Fixed-dose combination of sodium phenylbutyrate and taurursodiol designed to slow or mitigate neurodegeneration
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17 May 2025 (Complete) Q3 2025 Presented Week 48 data from Phase 2 HELIOS Trial in Wolfram syndrome Data from interim analysis of Phase 2b portion of Phase 2b/3 ORION trial in PSP EXPECTED MILESTONES • AMX0035 is designed to mitigate neurodegeneration by targeting ER stress and mitochondrial dysfunction, two cellular processes central to neuronal cell death and neurodegeneration • Focused on diseases in which ER stress and mitochondrial dysfunction are known contributors, including Wolfram syndrome and PSP > Primary efficacy outcome of improvement in pancreatic function at Week 24 met in Phase 2 HELIOS trial; treatment with AMX0035 from Week 24 to Week 48 showed continued stabilization or improvement in multiple outcomes related to disease progression, including pancreatic function, glycemic control, vision, and overall symptom burden > Phase 2b/3 ORION trial in PSP underway AMX0035: Fixed-dose Combination of Sodium Phenylbutyrate and Taurursodiol Designed to Slow or Mitigate Neurodegeneration ER=endoplasmic reticulum; PB=sodium phenylbutyrate; PSP=progressive supranuclear palsy; TURSO=taurursodiol.
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Retinal ganglion cells Raquel, living with Wolfram Syndrome Wolfram Syndrome Program
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19 Death occurs at a median age of 30 years (range 25-49 years), mainly from respiratory failure WFS1=Wolfram syndrome type 1 gene; 1. Urano, F. Diabetes. 2014;63(3):844-846. 2. Pallotta MT, et al. J Transl Med. 2019;17:238. 3. Lee, E., et al. Front Genet. 2023;14:1198171. 4. Leslie, M. Science. 2021;371(6530):663-665. 5. Matsunage et al. Plos One. 2014;9(9):106906. 6. Urano, F. Curr Diab Rep. 2016;16(1):6. Wolfram Syndrome is a Rare, Fatal, Monogenic, Progressive Disorder1-5 No approved therapies for Wolfram syndrome6 PROGRESSIVELY IMPACTS MULTIPLE ORGANS AND SYSTEMS1-5WFS1 GENE MUTATION Difficulty Breathing From brain stem damage Hearing Loss From cranial nerve damage Gradual Loss of Vision Leading to Blindness Optic nerve cell death Diabetes Insipidus Kidneys produce too much urine from a faulty pituitary gland Balance and Coordination Difficulty Ataxia from cerebellum damage Childhood-onset Diabetes Mellitus Elevated blood sugar levels from insulin- producing beta cell death Living with Wolfram Syndrome in the U.S.1,2 ~3,000 people
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20 WFS1=Wolfram syndrome type 1 gene; * Results for AMX0035 are synergistic relative to PB or TURSO alone. Supported by data on file with Amylyx & Cohen. J., et al. Clinical trial design for a phase II, randomized, placebo-controlled trial of AMX0035 in amyotrophic lateral sclerosis (CENTAUR). Poster presented at: 28th International Symposium for ALS/MND; December 4–10, 2017; Boston, MA 1. Urano, F. Diabetes. 2014;63(3):844-846. 2. Sarmara A, et al. Orphanet J Rare Dis. 2019; 14(1):279. 3. Pallotta MT, et al. J Transl Med. 2019;7(1):238-249. 4. Shang L, et al. Diabetes. 2014;63(3):923-933. 5. Zhou W. J Biol Chem. 2011;286(17):14941-14951. 6. Rodrigues CM, Steer CJ. Expert Opin Investig Drugs. 2001;10(7):1243-1253. 7. Mishra R, et al. Ther Adv Rare Dis. 2021:2:26330040211039518. Wolfram Syndrome is a Prototypical Endoplasmic Reticulum Stress Disorder1 AMX0035 targets endoplasmic reticulum stress and related mitochondrial dysfunction pathways Endoplasmic Reticulum Stress2-7 Impaired Mitochondrial Dynamics2-7 Mutations (Pathogenic Variants) in WFS12,3 Dysfunction, death of pancreatic beta cells and neurons2,3 AMX0035* SODIUM PHENYLBUTYRATE (PB) Stabilizes protein conformation during folding3,4 TAURURSODIOL (TURSO) Targets Bax, reduces mitochondrial driven cell death5,6 Clear Link of Mechanism of Disease and Mechanism of AMX0035 AMX0035 has been extensively studied in Wolfram models including patient- derived cells and mouse model
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21 Safety Follow-up GLP-1=glucagon-like peptide-1; WFS1=Wolfram syndrome type 1 gene; *Documented functionally relevant recessive mutations on both alleles of the WFS1 gene based on historical test results (if a vailable) or from a qualified laboratory at screening; 1. ClinicalTrials.gov identifier: NCT05676034. Updated November 21, 2023. Accessed April 9, 2024. https://www.clinicaltrials.gov/ct2/show/NCT05676034. 2. Urano, F. et al. (2025, May 10-13). 48-Week Results from the HELIOS Trial: A Phase 2, Open-Label Study Evaluating an Oral, Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Wolfram Syndrome [Poster presentation]. Joint Congress of ESPE and ESE 2025. HELIOS Study Design Open-label, single-arm clinical trial of AMX0035 in people with Wolfram syndrome, enrolling up to 12 participants OPEN-LABEL TREATMENT PERIODScreening Period EXTENSION TREATMENT PERIOD (48 weeks) (96 weeks) 4 weeks Week 24 Results showed improvement in pancreatic function, the study’s primary efficacy endpoint, and similar overall improvements or stabilization across all secondary endpoints 4 weeksWeek 48 Results showed continued improvement or stabilization across multiple outcomes consistent with Week 24 data PRIMARY OBJECTIVES: KEY TRIAL ENTRY CRITERIA1,2 • To assess the safety and tolerability of AMX0035 administered orally for up to 144 weeks • To evaluate the effect of AMX0035 on residual beta cell function over 24 weeks by monitoring C-peptide levels • Aged ≥17 years • Definite diagnosis of Wolfram syndrome defined by documented pathogenic mutations in WFS1 gene* • Stimulated C-peptide level of ≥0.2 ng/mL at screening • Insulin-dependent diabetes mellitus due to Wolfram syndrome • No current GLP-1 agonist use
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22 AUC=area under the curve; CGI-C=clinician-reported global impression of change ; HbA1c=glycated hemoglobin A1c; PGI-C=patient-reported global impression of change; Urano, F. et al. (2025, May 10-13). 48-Week Results from the HELIOS Trial: A Phase 2, Open-Label Study Evaluating an Oral, Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Wolfram Syndrome [Poster presentation]. Joint Congress of ESPE and ESE 2025. 1. Recent natural history study demonstrated C-peptide levels progressively decline in people with Wolfram syndrome. 2. Recent natural history study demonstrated that average HbA1c increases and time in target glucose range declines in people with Wolfram syndrome. 3. Recent natural history study demonstrated visual acuity progressively worsens in people with Wolfram syndrome. 4. AMX0035 was generally well-tolerated. All adverse events (AEs) were mild or moderate, and there were no serious AEs related to AMX0035 treatment. Long-Term Data Suggest Potential Benefit of AMX0035 in Wolfram Syndrome Across Multiple Outcomes Related to Disease Progression C-Peptide Response AUC ∆ C-Peptide HbA1c Time in Target Glucose Range (70-180 mg/dL) Visual Acuity CGI-C and PGI-C Partial Reversal in C-Peptide PhenotypeProgressive Decline Increase in Beta Cell ResponsivenessProgressive Decline1 Improved Glycemic Control Progressively More Difficult to Maintain2 Improved Glycemic Control Progressively More Difficult to Maintain Improved or Stable AcuityProgressive Decline3 Participant and Clinician Reported Improvement or Stabilization Progressive Decline Diabetic Measures Symptom Burden Visual Measure Safety profile was consistent with prior safety data4 Trend Baseline to Week 24 Expected Progression of Wolfram Syndrome Partial Reversal in C-Peptide Phenotype Increase in Beta Cell Responsiveness Improved Glycemic Control Improved Glycemic Control Improved or Stable Acuity Participant and Clinician Reported Improvement or Stabilization Safety profile was consistent with prior safety data4 Trend Baseline to Week 48
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23 Primary Endpoint: Improvement in C-Peptide Response Observed Overall increase in mean C-peptide production from 0-120 minutes during MMTT* C-Peptide Response to Mixed Meal Tolerance Test AUC change from baseline at 120 Minutes 20.2 (SE: 11.2) 34.5 (SE: 13.0; p=0.0263) -30 -20 -10 0 10 20 30 40 50 60 C-Peptide AUC (min*ng/mL) Change from Baseline Direction of Expected Change with Wolfram Syndrome Progression Week 24 (N=11) Week 48 (N=10) Per Protocol Population Improvement in C-Peptide Response Observed Compared to Screening WS NATURAL HISTORY EXPECTATIONS: C-peptide progressively decreases & JOINT CONGRESS OF 48-Week Results from the HELIOS Trial: A Phase 2, Open-Label Study Evaluating an Oral, Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Wolfram Syndrome *In non-diabetic individuals, C-peptide peaks after a meal at approximately ~30 minutes; in Wolfram syndrome, peak is slower but generally was at or before 120 minutes in HELIOS. AUC over 120 minutes after meal challenge reflects beta cell response to a meal. Amylyx is currently planning to focus on 120-min AUC as the C-peptide measure for future studies. AUC=Area under the curve; ITT=Intent to Treat; Min=Minute; ng/mL=Nanograms per milliliter; SE=Standard error; WS=Wolfram syndrome; Urano, F. et al. (2025, May 10-13). 48-Week Results from the HELIOS Trial: A Phase 2, Open-Label Study Evaluating an Oral, Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Wolfram Syndrome [Poster presentation]. Joint Congress of ESPE and ESE 2025. 23
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24 Positive Changes in Wolfram Syndrome-Related Symptoms by Participant Report in On-Study Interviews Qualitative on-study interview results support potential positive impact of AMX0035 on symptom burden AMX0035 Reduced Overall Symptom Burden at Week 24 and Week 48 0% 10% 20% 30% 40% 50% 60% 70% 80% Headaches/Migraine (n=4) Problems Swallowing (n=5) Fatigue (n=6) Insulin-Requiring Diabetes (n=10) Bladder Issues (n=11) Vision Problems (n=11) Important/Meaningful Positive Change Positive Change Data on File. Urano, F. et al. (2025, May 10-13). 48-Week Results from the HELIOS Trial: A Phase 2, Open-Label Study Evaluating an Oral, Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Wolfram Syndrome [Poster presentation]. Joint Congress of ESPE and ESE 2025. In on-study interviews after at least 24 weeks of treatment, 9 of 11 reported improvements in ≥1 Wolfram syndrome-related symptom with all noting the change being meaningful in at least one symptom n = the number of participants who reported experiencing the symptom pretrial
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25 Urano, F. et al. (2025, May 10-13). 48-Week Results from the HELIOS Trial: A Phase 2, Open-Label Study Evaluating an Oral, Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Wolfram Syndrome [Poster presentation]. Joint Congress of ESPE and ESE 2025. AMX0035 Safety and Tolerability in HELIOS • AMX0035 was generally well tolerated > Diarrhea was the most common TEAE (58.3%); all cases were of mild severity > All TEAEs were graded mild or moderate • No new safety signals were identified • Nearly all participants reported ≥1 TEAE during the trial > Most did not lead to modification or interruption of AMX0035 dosing and none led to drug discontinuation AMX0035 (N=12)* n (%) Participants with ≥1 TEAE 11 (91.7) TEAE related to study drug** 10 (83.3) Serious adverse events 0 (0) Drug interrupted owing to TEAE 3 (25.0) Dose reduced owing to TEAE 3 (25.0) Drug discontinued owing to TEAE 0 (0) Summary of Treatment Emergent Adverse Events (TEAEs) *All available safety data as of January 10, 2025 included **Includes those with TEAEs considered at least possibly related to treatment
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26 EU=European Union; FDA=U.S. Food and Drug Administration. AMX0035 Wolfram Syndrome Program Next Steps Orphan drug designation granted to AMX0035 for the treatment of Wolfram syndrome by U.S. FDA Positive preclinical data on AMX0035 published in Journal of Clinical Investigation Insight Phase 2 HELIOS study of AMX0035 in Wolfram syndrome initiated in April 2023 and completed enrollment in Feb 2024 Presented positive data from interim analysis of HELIOS study EU Orphan Drug Designation granted for AMX0035 in Wolfram syndrome Presented positive topline results from HELIOS study Presented positive Week 48 results from HELIOS study Week 48 data and ongoing discussions with the FDA will inform the design of a Phase 3 trial
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Tau Protein Progressive Supranuclear Palsy (PSP) Program
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28 MRI=magnetic resonance imaging; PET=positron emission tomography; PSP=progressive supranuclear palsy; 1. Swallow, D. M. A., et al. Mov Disord Clin Pract. 2022 Jun 28;9(5):604-613. doi: 10.1002/mdc3.13489. 2. Lyons, S., et al. J Neurol. 2023; June 8. epub ahead of print. 3. Stamelou, M., et al. Nat Rev Neurol. 2021;17(10):601-620. 4. Viscidi, E., et al. Front Neurol. 2021;12:571800. 5. Golbe and Ohman-Strickland. Brain. 2007;130(6):1552-65. 6. Swallow and Counsell. J Neurol. 2023;270(7):3464-3474 PSP is a Rare, Progressive, and Fatal Tauopathy • PSP affects body movements, including balance and eye movements • No disease-modifying therapies approved • PSP is considered a tauopathy based on the strong genetic link between tau variants and disease development and the presence of abnormal tau protein deposits in the brain • Biomarker data from Phase 2 trial of AMX0035 in Alzheimer’s disease demonstrated a significant reduction in tau HEALTHY CONTROL PSP (PSP Rating Scale Score < 31) vs. 18F-PI-2620 Tau PET Midbrain MRI vs. vs. Within 6-8 years from symptom onset3-6 PSP is typically fatal 7 ESTIMATED PREVALENCE 100,000in Worldwide1,2 U.S. PREVALENCE 23,000 Approximately
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29 Arnold SE, Hendrix S,Nicodemus-Johnson J, et al. Biological effects of sodiumphenylbutyrate and taurursodiol in Alzheimer’s disease. Alzheimer’s Dement. 2024;10:e12487.https://doi.org/10.1002/trc2.12487. AMX0035 Significantly Lowered CSF Tau and p-Tau in Randomized Placebo Controlled Phase 2 PEGASUS Trial in People with Alzheimer's Disease t-Tau = total tau p-Tau181 = phosphorylated tau at site threonine 181 Week 24 Mean CSF p-tau 181 (n=67) Week 24 Mean CSF t-tau (n=67) -20% -15% -10% -5% 0% 5% 10% Between-group Comparisona p <.0001 AMX0035Placebo -12.5% +1.7% Percent Change from Baseline -20% -15% -10% -5% 0% 5% 10% AMX0035Placebo Percent Change from Baseline -12.7%-0.6% Between-group Comparisona p =.0002
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30 ORION: Operationally Seamless Phase 2b/3 Clinical Trial Underway PHASE 2B DATA EXPECTED IN Q3 2025 Key Eligibility Criteria • Adults 40-80 years old • Possible or Probable PSP (Steele-Richardson-Olszewski Syndrome) according to MDS 2017 criteria1,2 • Presence of PSP symptoms <5 years • Able to walk independently or with minimal assistance3 • PSPRS total score <40 • MMSE score ≥24 • Study partner required • No feeding tube use Primary Endpoint • PSPRS score* Secondary Endpoints • PSPRS score* • MDS-UPDRS Part II score Additional Endpoints • Brain volume (MRI) • Participant QoL and caregiver burden • CSF and plasma biomarkers of neuronal injury and neuro-inflammation • Overall survival PRIMARY OBJECTIVE: To assess the impact of AMX0035 compared to placebo on disease progression rate as measured by PSPRS Randomized 3:2 (N=139) AMX0035 Placebo AMX0035 PHASE 2B STUDY PORTION DESIGN Screening Double-blind Treatment Open Label Extension WEEK -6 WEEK 24 WEEK 52WEEK 1 Randomized 3:2 AMX0035 Placebo AMX0035 PHASE 3 STUDY PORTION DESIGN Screening Double-blind Treatment Open Label Extension WEEK -6 WEEK 52WEEK 1 Unblinded Analysis expected in Q3 2025 Proceed to Phase 3 if Data are Strong *Given regional evidentiary requirements, the 10-item PSPRS is the primary endpoint in the U.S. and the 28-item PSPRS is the primary endpoint outside of the U.S.; for each region, the other form of the PSPRS is considered a secondary endpoint. MDS, Movement Disorders Society; MMSE, mini-mental status exam; PSPRS, Progressive Supranuclear Palsy Rating Scale; MRI, magnetic resonance imaging; QoL, quality of life; CSF, cerebrospinal fluid 1. Gradually progressive disorder, with age at disease onset ≥ 40 years 2. Either or both of the following two items are met: i. Vertical supranuclear gaze palsy OR slow velocity of vertical saccades AND postural instability with repeated unprovoked falls within 3 years OR tendency to fall on the pull-test within 3 years ii. Slow velocity of vertical saccades AND postural instability with more than two steps backward on the pull-test within 3 years. 1,2. Höglinger et al. Movement Disorders 2017. 3. Ability to walk 5 steps with minimal assistance (stabilization of one arm).
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In memory of Mick, a husband and father, who was a gifted tattoo artist and musician. Nerve cells in the brain AMX0114 PROGRAM Potent antisense oligonucleotide (ASO) targeting calpain-2
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32 APRIL 2025 (Complete) 2025 Began dosing in Phase 1 LUMINA trial of AMX0114 in people living with ALS Early cohort data for the Phase 1 LUMINA trial expected EXPECTED MILESTONES • ALS leads to deteriorating muscle function, inability to move and speak, respiratory paralysis, and death1,2 • ALS affects as many as 30,000 adults in the U.S.3 o >90% of people have no family history of disease • Calpain-2, a protein involved in neurofilament biology, plays an essential role in axonal degeneration, a critical effector in the progression of ALS • In preclinical studies, treatment with AMX0114 resulted in potent, dose-dependent, and durable reduction in CAPN2 mRNA and calpain-2 protein levels in disease-relevant cell models of axonal degeneration • Phase 1 LUMINA trial will evaluate the safety and biological activity of AMX0114 in people living with ALS • The FDA granted Fast Track designation to AMX0114 in May 2025 providing eligibility for Priority Review if relevant criteria continue to be met AMX0114: Antisense Oligonucleotide (ASO) Targeting CAPN2 for the Potential Treatment of ALS ALS=amyotrophic lateral sclerosis; ER=endoplasmic reticulum; PB=sodium phenylbutyrate; mRNA=messenger ribonucleic acid; PSP=progressive supranuclear palsy; TURSO=taurursodiol. ; 1. Brown, R. H., Al-Chalabi A. N Engl J Med. 2017;377(2):162-172; 2. Al-Chalabi, A., et al. Lancet Neurol. 2016;15(11):1182-1194; 3. Mehta, P., et al. Amyotroph Lateral Scler Frontotemporal Degener. 2023:1-7. doi: 10.1080/21678421.2023.2245858.
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33 ALS=amyotrophic lateral sclerosis; 1. Ueyama H et al. J Neurol Sci. 1998;155(2):163-169. 2. Yamashita T et al. Nat Commun. 2012;3:1307. 3. Rao MV, et al. J Neurochem. 2016;137(2):253-65. 4. Ma M, et al. Neurobiol Dis. 2013;56:34-46. 5. Asakawa, K., Handa, H., Kawakami, K. Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS. Cell Mol Life Sci. 2021;78(10):4453-4465. doi:10.1007/s00018-021-03792-z Calpain-2 Plays a Critical Role in Axonal Degeneration, a Key Mechanism Underlying ALS Pathophysiology Full Length Neurofilament (68 kDa) is not observed in ALS or Healthy Control Mechanisms of Axonal Degeneration5 Muscle denervation observed in ALS Multiple injury paradigms and hypotheses of axonal degeneration converge on calpain-2 Evidence for Targeting Calpain-2 in ALS1-4 AMX0114 has shown efficacy in pre-clinical ALS models Calpain-2 substrates include neurofilament and TDP-43 Inhibition of calpain-2 has shown benefit in ALS mouse model Calpain-2 levels are elevated in people with ALS
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34 ALS=amyotrophic lateral sclerosis; NfL=neurofilament light chain; Data on File. Amylyx Pharmaceuticals Inc. 2024; Survival analyses performed in the lab of Dr. Sami Barmada at the University of Michigan Medical School by Dr. Michael Bekier. AMX0114 Reduces Extracellular NfL Levels in Multiple Models of Trigger-Induced Neuronal Injury and Improves Survival in Relevant Models Presented at Similar NfL Reduction in Rotenone and Colchicine models AMX0114 Control Pre (0h) Post (144h) Representative Images of Motor Neurons Pre- and Post-Exposure to H2O2 TDP-43 ALS Model ALS model neurons (with AMX0114) Healthy neurons (no AMX0114) ALS model neurons (no AMX0114)
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35 ALS=amyotrophic lateral sclerosis; SBDP-145=spectrin breakdown product-145. 1. The open-label extension may be implemented if safety and efficacy data support a positive benefit-risk profile. LUMINA: Phase 1 Clinical Trial of AMX0114 in ALS PRIMARY OBJECTIVE: To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMX0114 in people living with ALS • Will assess ALS biomarkers, including change from baseline in neurofilament light (NfL) levels DOSING AND ADMINISTRATION Intrathecal administration every 4 weeks for a total of up to 4 doses per cohort (N=48) Screening Period (up to 4 wk) Treatment Period (up to 13 wk) Safety Follow-Up Period (up to 8 wk) Cohort 3 (Planned dose level 3) AMX0114 (n=9) Placebo (n=3) Open-Label Extension1 Cohort 4 (Planned dose level 4) AMX0114 (n=9) Placebo (n=3) Cohort 1 (12.5 mg) AMX0114 (n=9) Placebo (n=3) (Recruiting) Cohort 2 (Planned dose level 2) AMX0114 (n=9) Placebo (n=3) EARLY COHORT DATA EXPECTED IN 2025 LUMINA UNDERWAY; EARLY COHORT DATA EXPECTED IN 2025
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Key Corporate Highlights
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37 Focus on diseases with well-defined mechanistic rationale, clear clinical outcomes and biomarkers, and rigorous preclinical data Advancing Three Therapies Across Four Indications • Began dosing in the pivotal Phase 3 LUCIDITY trial in PBH in April 2025, data readout anticipated in first half of 2026 • Shared positive Week 48 results from ongoing Phase 2 HELIOS trial in Wolfram syndrome in May 2025; Week 48 data and discussions with FDA will inform the design of a Phase 3 trial of AMX0035 in Wolfram syndrome • Phase 2b/3 ORION trial in PSP underway, unblinded analysis of the Phase 2b portion of ORION in Q3 2025 • Began dosing in the Phase 1 LUMINA trial in ALS in April 2025, early cohort data expected in 2025 • Granted FDA Fast Track designation in May 2025 AVEXITIDE First-in-class, GLP-1 receptor antagonist with Breakthrough Therapy and Orphan Drug designations AMX0035 Oral, fixed-dose combination of two small molecules, sodium phenylbutyrate and taurursodiol AMX0114 Antisense oligonucleotide designed to target calpain-2, a protein involved in axonal degeneration & neurofilament biology ALS=amyotrophic lateral sclerosis; ER=endoplasmic reticulum; GLP-1=glucagon-like peptide-1; PBH=post-bariatric hypoglycemia; PSP=progressive supranuclear palsy;
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38 NCE=new chemical entities. Avexitide, AMX0035, and AM0114 are Protected by Robust Global IP Portfolio * Includes in-licensed patents ** Additional patent term potentially available through patent term extension >190 Pending composition of matter patent provides potential patent term through 2043 if granted granted patents and over 40 pending applications worldwide* >70 granted patents and over 50 pending applications worldwide AVEXITIDE AMX0035 AMX0114 • Granted US patent rights through 2037** • Positioned for NCE exclusivity • Granted Orphan Drug Designation for the treatment of hyperinsulinemic hypoglycemia • Granted US patent rights through 2040 • Granted Orphan Drug Designation for the treatment of Wolfram syndrome • Positioned for NCE exclusivity
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39 Public Offering Closed on January 13, 2025 EXPECTED CASH THROUGH THE END OF 2026 . As of March 31, 2025 $204.1M in cash, cash equivalents, and marketable securities 19.7MM ~$65.5MM SHARES ISSUED NET PROCEEDS
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40 Team Leadership Team Tenured in Rare Disease with Commercial and Clinical Development Capabilities Joshua Cohen, BSE Co-CEO and Director Co-Founded Amylyx, Co-CEO since 2013, led preclinical, clinical and commercial development of RELYVRIO as well as IPO and ~$1B in financing Justin Klee, ScB Co-CEO and Director Co-Founded Amylyx, Co-CEO since 2013, led preclinical, clinical and commercial development of RELYVRIO as well as IPO and ~$1B in financing Linda Arsenault Chief Human Resources Officer 25+ years of global HR experience at multibillion-dollar life sciences and technology companies, including at Sumitomo Pharma America Holdings (SMPA) Camille L. Bedrosian, MD Chief Medical Officer Nearly 30 years of experience within the biotech industry; Former CMO at Ultragenyx, Alexion, and ARIAD Tom Holmes Chief Technical Operations Officer More than 25 years of biotech experience. Former Head of Global External Manufacturing at Biogen Gina M. Mazzariello Chief Legal Officer and General Counsel 20+ years of corporate and commercial legal experience within the healthcare industry, including at Boehringer Ingelheim Jim Frates Chief Financial Officer 22-year CFO at Alkermes; grew to >$1B in annual revenue and >2,000 employees worldwide Dan Monahan Chief Commercial Officer 20+ years of commercial leadership experience. Former commercial lead for multiple industry-leading medicines at Otsuka, Novartis, and Sanofi
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Ushering in a new era for treating diseases with high unmet needs