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Maggie, living with post-bariatric hypoglycemia (PBH) Pancreatic islet cells SEPTEMBER 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 Wolfram syndrome, and AMX0114 for ALS; statements regarding the timing of clinical trials for PBH, Wolfram syndrome 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 Wolfram Syndrome Amyotrophic Lateral Sclerosis (ALS) 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 Post-Bariatric Hypoglycemia (PBH) 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) • 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 FDA Breakthrough Therapy and Orphan Drug Designations • 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 LUCIDITY PHASE 3 CLINICAL TRIAL HELIOS PHASE 2 CLINICAL TRIAL LUMINA PHASE 1 CLINICAL TRIAL
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Pancreatic islet cells First-in-class 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 following RYGB surgery • Prior clinical studies generated highly statistically significant reductions in hypoglycemic events • 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 Avexitide, a First-in-Class GLP-1 Receptor Antagonist, Targets a Central Pathway of PBH Pathophysiology 1 Altered Stomach Pancreas Altered Nutrient Transit due to anatomical changes associated with bariatric surgery (e.g., Roux-en-Y gastric bypass) leads to exaggerated GLP-1 secretion in people with PBH GLP-1=glucagon-like peptide-1; PBH=post-bariatric hypoglycemia; 1. Sheehan A, Patti ME. Diabetes Metab Syndr Obes. 2020;13:4469-4482; 2. Craig CM, et al. Diabetes Obes Metab. 2017; 1-10. 3. Thorens B,. et al. Diabetes.1993;42(11):1678-1682. 4. Craig CM, et al. Diabetes Obes Metab. 2018;20(2):352-361. 5. Smith NK, et al. Neurochem Int. 2019;128:94-105. 6. Meloni AR, et al. Diabetes Obes Metab. 2013;15(1):15-27. 7. Craig CM, et al. Diabetologia. 2017;60(3):531-540. 8. Craig C, et al. J Endocr Soc. 2022;6(Suppl 1):A349. Hyper-secretion of Insulin Results in Recurrent, Rapid Drops in Blood Glucose 2 This exaggerated GLP-1 secretion leads to abnormally high insulin levels in the bloodstream, and subsequent hypoglycemia Avexitide Binds to GLP-1 Receptor 3 Avexitide Islet Beta Cells GLP-1 Receptor Avexitide binds to the GLP-1 receptor on pancreatic islet beta cells to inhibit the effect of exaggerated GLP-1 4 Decreased insulin secretion and stabilized glucose levels resulting from inhibition of the effect of exaggerated GLP-1 Insulin Mitigates Insulin Hypersecretion and Promotes Glucose Stabilization GLP-1 Receptor Antagonism Insulin +10x increase in GLP-1 levels Intestine GLP-1 Meal Rapid Drop in Blood Glucose BLOOD SUGAR LEVEL TIME Meal Stable Blood Glucose Response BLOOD SUGAR LEVEL TIME
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7 Avexitide, a GLP-1 receptor antagonist, inhibits GLP-1 receptor activity and decreases the insulin response to glucose in rat pancreatic islet cells1,2, 3 120 100 Time (min) 300 GLP-1; pmol/L Gastric Bypass + PBH (GB + PBH) Gastric Bypass (GB) Overweight (OW) Morbidly Overweight (Mob) 0 20 40 60 80 100 0 200 GLP-1 levels observed to be more than 10-fold higher in PBH than in Nonsurgical Controls, resulting in dysregulated secretion of insulin and subsequent hypoglycemia Targeted Approach to Inhibit Effects of Excessive GLP-1 in PBH to Mitigate Hypoglycemia 16.7 G +/- 4 GLP-1 +/- Avexitide Glucose Glucose + GLP-1 Glucose + GLP-1 + Avexitide Time (min) Insulin (ng) / DNA (µg) Glucose + GLP-1 + Avexitide GLP-1=glucagon-like peptide-1; GSIS=glucose-stimulated insulin secretion; PBH=post-bariatric hypoglycemia; 1. Goldfine A. B. et al. J Clin Endocrinol Metab. 2007; 92(12):4678–4685. doi.org/10.1210/jc.2007- 0918. 2. Cabrera O. et al. The Journal of Biological Chemistry. 2022;298(2):101484. doi:10.1016/j.jbc.2021.101484; 3. Averaged data from five independent experiments; 4. Step-wise increase of glucose concentration from 2.8 to 16.7 mM (2.8G and 16.7G).
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8 Time (min) Time (min) (mg/dL, mean ± SEM)(μU/mL, mean ± SEM) Placebo Avexitide NS-Controls Glycemic Rescue Below 50 mg/dL Proof of Concept in People with PBH (N=8) Demonstrated: • 100% prevention of hypoglycemia • Increased the plasma glucose nadir by 70%, matching NS controls • Ameliorated hyperinsulinemia Insulin Glucose Placebo Avexitide NS-Controls GLP-1=Glucagon-like peptide-1; NS-Controls=Non-surgical controls; PBH=post-bariatric hypoglycemia; SEM=standard error of the mean; Craig et al. Diabetologia 2017 Clinical Data Underscores the Critical Role of GLP-1 in PBH and Supports the Potential of GLP-1 Receptor Antagonism as a Targeted Approach
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9 MAD=multiple ascending dose; PBH=post-bariatric hypoglycemia; 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 % Reduction in Rate of Hypoglycemia (Least Squared Mean) 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 % Reduction in Rate of Hypoglycemia by Avexitide Dose 56% p=0.01 Avexitide cut rates of hypoglycemic events by >50%
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10 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. aRate defined the weekly number of discrete events during respective treatment periods; bLevel 2 hypoglycemia: self-monitoring of blood glucose <54 mg/dLcLevel 3 hypoglycemia: a severe event characterized by altered mental and/or physical functioning that requires assistance from another person for recovery whether an individual receives external assistance or not. Avexitide Significantly Reduced Rates of Composite Level 2 and 3 Hypoglycemia in New Exploratory Analysis 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 40% p=0.04 23% p=0.2 60% p=0.004 57% p=0.003 68% p=0.0003 53% p=0.004 % Reduction in Rate of Hypoglycemia by Avexitide Dose 56% p=0.01 PHASE 2B STUDY 0 10 20 30 40 50 60 70 80 90 100 Level 2 Level 3 Phase 3 program will evaluate 90 mg once daily in people with PBH FDA-agreed upon primary endpoint: Reduction in the composite of Level 2 and Level 3 hypoglycemic events All dose regimens demonstrated consistent reductions in composite rate of Level 2 and Level 3 hypoglycemic events Avexitide 90 mg once a day 64% p=0.0031 EXPLORATORY ANALYSIS FROM PHASE 2B STUDY % Reduction in Composite Ratea of Level 2b and 3c Hypoglycemia FDA Breakthrough Therapy Designation 66% p=0.0003 ENDO 2025 PRESENTATION % Reduction in Rate of Hypoglycemia (Least Squared Mean)
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11 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; 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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12 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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13 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 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 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 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 Placebo 14-day Treatment Period Placebo 3:2 Randomization 14-day Eligibility Run-in Period 1:1 Randomization 21-day Eligibility Run-in Period At least 3 hypoglycemic events during 21-day run-in period despite adhering to consistent dietary management
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14 Phase 3 LUCIDITY Trial Designed to be Consistent with Phase 2 PREVENT and Phase 2b Trials Evaluating Avexitide for the Treatment of PBH BID=twice daily; PBH=post-bariatric hypoglycemia; QD=once daily; RYGB=Roux-en-Y gastric bypass; OLE=open-label extension. Study Population: Surgery RYGB RYGB Sleeve gastrectomy, Esophagectomy, Nissen fundoplication, Gastrectomy RYGB Study Population: Diet Hypoglycemic events despite dietary management Hypoglycemic events despite dietary management Hypoglycemic events despite dietary management Run-In Hypoglycemic Event Rate At least one per week At least one per week At least one per week Avexitide Dose 30 mg BID/60 mg QD 45 mg BID/90 mg QD (90 mg QD administered as 2 sequential injections) 90 mg QD (90 mg QD administered as 2 sequential injections during double blind treatment period and OLE Part A and as 1 injection during OLE Part B) Endpoints Exploratory: Level 2 hypoglycemic events Level 3 hypoglycemic events Secondary: Level 2 hypoglycemic events Level 3 hypoglycemic events Primary: Composite of Level 2 and Level 3 hypoglycemic events STUDY DESIGN ELEMENTS PHASE 2 PREVENT PHASE 2B PHASE 3 LUCIDITY
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15 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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16Confidential. For internal purposes only. Incidence Prevalence RYGB SG RYGB SG Total Any PBH • >3 hypoglycemia symptoms • Neuroglycopenia • Need for assistance or • Glucose ≤54 mg/Dl 27.3% 10.3% 275,717 111,370 387,087 Medically-Important PBH Visit to inpatient or outpatient facility 11.8% 4.4% 118,843 48,026 166,869 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. 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. 12. McLaughlin, T et al. (2025, July 12-15). Prevalence of Post-bariatric Hypoglycemia in the United States, [Poster presentation]. ENDO 2025. 1 2 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 Finding Retrospective Study (N=120)7 Of 107 individuals with PBH treated with acarbose, 37% 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 after 5 years Data from a Recent Academic Review12d: 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; dAnalysis incorporated historical census data dating back to 1993, life expectancy estimates, and disease-state modeling to inform projections
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17 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 in 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 17 April 2025
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Retinal ganglion cells Raquel, living with Wolfram syndrome Fixed-dose combination of sodium phenylbutyrate and taurursodiol designed to slow or mitigate neurodegeneration AMX0035
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19 May 2025 (Complete) 2H 2025 Presented Week 48 data from Phase 2 HELIOS Trial in Wolfram syndrome Week 48 data and discussions with FDA will inform design of Phase 3 trial 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 studying AMX0035 in Wolfram syndrome, a prototypical ER stress disorder • 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 AMX0035: Fixed-dose Combination of Sodium Phenylbutyrate and Taurursodiol Designed to Slow or Mitigate Neurodegeneration ER=endoplasmic reticulum
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20 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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21 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 (ER) Stress Disorder1 AMX0035 targets ER stress and related mitochondrial dysfunction pathways ER 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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22 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 available) 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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23 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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24 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. 24 MMTT=mixed meal tolerance testing
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25 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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26 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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27 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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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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29 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 Knockdown of Calpain-2 for the Potential Treatment of ALS ALS=amyotrophic lateral sclerosis; mRNA=messenger ribonucleic acid; 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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30 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 6. Lombardi, V., Carassiti, D., Giovannoni, G. et al. The potential of neurofilaments analysis using dry-blood and plasma spots. Sci Rep 10, 97 (2020). https://doi.org/10.1038/s41598-019-54310-y 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 Control6 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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31 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 atSimilar NfL Reduction in Rotenone and Colchicine iPSC 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) Induced pluripotent stem cell (iPSC)-derived motor neurons were exposed to varying concentrations of the neurotoxic compounds vincristine (and rotenone and colchicine) after pretreatment with AMX0114. Bars represent mean (SD) Nfl concentrations relative to vehicle. Overlying symbols represent individuaI repIicate values. NS= P>.05. * = P<.05. ** = P<.01, *** = P<.001, **** = P<.0001. NfL, neurofilament light chain; NS, not significant; TE, tris ethylenediaminetetraacetic acid.
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32 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 week) Treatment Period (up to 13 week) Safety Follow-Up Period (up to 8 week) 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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34 Advancing Three Novel Therapies for Diseases with High Unmet Needs Focus on diseases with well-defined mechanistic rationale, clear clinical outcomes and biomarkers, and rigorous preclinical data ALS=amyotrophic lateral sclerosis; GLP-1=glucagon-like peptide-1; PBH=post-bariatric hypoglycemia 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 with FDA Fast Track designation 2025 Avexitide PBH Clinical Phase 3 LUCIDITY recruitment anticipated completion in 2025 1H26 Avexitide PBH Clinical Phase 3 LUCIDITY topline data anticipated in 1H 2026 2027 Avexitide PBH Regulatory Commercial launch, if approved, anticipated in 2027 2025 AMX0035 Wolfram syndrome Update Week 48 data and discussions with FDA will inform design of Phase 3 trial 2025 AMX0114 ALS Clinical LUMINA early cohort data expected in 2025 Expected Upcoming Milestones
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35 NCE=new chemical entities. Avexitide, AMX0035, and AMX0114 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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36 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