#1AMYLYX Investor Presentation June 2023 photo in memory of Mick, a husband and father, who was a gifted tattoo artist and musician#2Disclaimer 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, statements regarding the potential approval of AMX0035 for the treatment of ALS in countries other than Canada and the United States; statements regarding the timing of any regulatory re-examination process in Europe; the potential of AMX0035 as a treatment for ALS and the Company's plans to explore the use of AMX0035 for other neurodegenerative diseases, including progressive surpranuclear palsy and Wolfram syndrome; the potential market acceptance and market opportunity for RELYVRIO®; as well as access to and coverage for RELYVRIO; and expectations regarding our longer-term strategy. 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 successfully market RELYVRIO in the United States, Amylyx' ability to execute on its commercial and regulatory strategy, regulatory developments, expectations regarding the timing of EMA review of AMX0035 for the treatment of ALS, Amylyx' ability to fund operations, and the impact that the ongoing COVID- 19 pandemic will have on Amylyx' 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, 2022, 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. 2#3Amylyx Highlights 1st RELYVRIO®Ⓡ and ALBRIOZATM RELYVRIO (sodium phenylbutyrate and taurursodiol) and ALBRIOZA (sodium phenylbutyrate and ursodoxicoltaurine) are the first drug to show statistically significant functional benefit and observed survival benefit in ALS Approved in the United States and Canada Pending CHMP re-examination process in Europe following negative CHMP Opinion in June 2023 - supported by robust clinical data published in The New England Journal of Medicine Jun. 2022 Sep. 2022 Fall 2023 Strong Global IP Position Composition of matter patents issued; NCE exclusivity received; orphan drug exclusivity received I+I ALBRIOZA approved for use with conditions RELYVRIO approved * Amylyx intends to seek re-examination of the negative CHMP opinion as announced on June 23, 2023. Final CHMP Opinion post re-examination* AMYLYX 3 3#4Why ALS GE We need to work on the ALS clock... I lost the privilege of working on the human clock on January 6, 2018. My clock is a lot faster. Sandy Morris, 51-year-old mother of three, person who lived with ALS AMYLYX 4#5photo in memory of Eric, a husband and father, who was a courageous skydiver and Army veteran ALS is Relentlessly Progressive and Universally Fatal Significant unmet need for new treatment options ALS leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis, and death 1,2 >90% of people living with ALS have no family history of the disease ~50% of people with ALS will pass away in about 2 years from diagnosis³ References: 1. Brown RH, 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. Knibb JA, Keren N, Kulka A, et al. J Neurol Neurosurg Psychiatry. 2016;87(12):1361-1367. AMYLYX | 5 LO#6CENTAUR Trial Results Statistically Significant Functional Benefit as Measured by the ALSFRS-R, the Gold Standard Clinical Scale in ALS ALSFRS-R Estimate 35.0- 32.5 30.5 HHH 1A for T H+ H HA H Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis Published in The New England Journal of Medicine Sabrina Paganoni, M.D., Ph.D., Eric A. Macklin, Ph.D., Suzanne Hendrix, Ph.D., James D. Berry, M.D., Michael A. Elliott, M.D., Samuel Maiser, M.D., Chafic Karam, M.D., James B. Caress, M.D., Margaret A. Owegi, D.O., Adam Quick, M.D., James Wymer, M.D., Ph.D., Stephen A. Goutman, M.D., Daragh Heitzman, M.D., Terry Heiman- Patterson, M.D., Carlayne E. Jackson, M.D., Colin Quinn, M.D., Jeffrey D. Rothstein, M.D., Ph.D., Edward J. Kasarskis, M.D., Ph.D., Jonathan Katz, M.D., Liberty Jenkins, M.D., Shafeeq Ladha, M.D., Timothy M. Miller, M.D., Ph.D., Stephen N. Scelsa, M.D., Tuan H. Vu, M.D., Christina N. Fournier, M.D., Jonathan D. Glass, M.D., Kristin M. Johnson, D.O., Andrea Swenson, M.D., Namita A. Goyal, M.D., Gary L. Pattee, M.D., Patricia L. Andres, M.S., D.P.T., Suma Babu, M.B., B.S., M.P.H., Marianne Chase, B.A., Derek Dagostino, B.A., Samuel P. Dickson, Ph.D., Noel Ellison, M.S., Meghan Hall, M.S., Kent Hendrix, B.S., Gale Kittle, R.N., M.P.H., Michelle McGovern, B.S., Joseph Ostrow, B.S., Lindsay Pothier, B.A., Rebecca Randall, M.S., R.D., Jeremy M. Shefner, M.D., Ph.D., Alexander V. Sherman, M.Sc., Eric Tustison, B.A., Prasha Vigneswaran, M.S., Jason Walker, B.S., Hong Yu, M.S., James Chan, M.A., Janet Wittes, Ph.D., Joshua Cohen, B.S.E., Justin Klee, Sc. B., Kent Leslie, M.S., Rudolph E. Tanzi, Ph.D., Walter Gilbert, Ph.D., Patrick D. Yeramian, M.D., David Schoenfeld, Ph.D., and Merit E. Cudkowicz, M.D. 27.5 No. of Participants¹ 0 AMX0035 87 CO 6 12 Week - 84 79 79 75 70 70 Placebo 48 48 48 18 72 67 24 68 88 Ho 64 44 44 44 43 39 38 38 2 AMX0035 Placebo 37 37 2.32 point difference, p=0.03 “Each category in the ALSFRS-R seems clinically important, and because each domain includes only five levels that span O (cannot do) to 4 (normal), prevention of even 1 unit of worsening in a single domain seems meaningful and desirable for individuals with ALS".3 References: 1. Two participants did not have follow-up efficacy assessments and were not included in the efficacy population (modified intention to treat n=135). 2. 77% of participants were on Riluzole or edaravone at or prior to study entry. 3. FDA Center for Drug Evaluation and Research, Application Number 2091760rig1s000, Office Director Memo, Ellis F. Unger, MD, May 4, 2017. Paganoni S, et al. New Eng J Med. 2020. AMYLYX | 6#7CENTAUR Trial Results Participants Randomized to RELYVRIO Were Observed to Survive Longer Than Those Randomized to Placebo 1 0.8 0.6 Survival 18.7 mo Probability 0.4 0.2 23.5 mo wwwwwwwww AMX0035 + SOC Placebo + SOC In a post hoc exploratory, long- term Intention-to-treat (ITT) survival analysis using data from the last participant last visit in the open-label phase (March 2021), median survival duration was 23.5 months in the group originally randomized to RELYVRIO and 18.7 months in the group originally randomized to placebo (4.8-month difference, HR=0.64, 95% CI=0.416-0.995)* 0 T 0 6 12 18 24 30 36 42 HR (95% CI) # of events Cox Regression Model 0.64 (0.416, 0.995) 94 Note: This is an ITT (all 137 patients) analysis Survival defined as All Cause Mortality (True Overall Survival) SOC standard of care; CI = confidence interval; HR = hazard ratio. *This exploratory analysis should be interpreted cautiously given the limitations of data collected outside of a controlled study, which may be subject to confounding. AMYLYX | 7#8CENTAUR Adverse Events (AEs) The most common adverse events occurring with RELYVRIO (at least 15% and at least 5% greater than placebo) were diarrhea, abdominal pain, nausea, and upper respiratory tract infection. Gastrointestinal-related adverse reactions occurred throughout the study but were more frequent during the first three weeks. of treatment. Adverse Reactions Reported in More than 5% of RELYVRIO-Treated Patients with ALS and at least 5% Greater than Placebo Adverse Reaction Diarrhea* Abdominal pain* RELYVRIO (n=89) % Placebo (n=48) % 25 19 21 13 Nausea 18 13 Upper respiratory tract infection* Fatigue* 18 10 12 6 11 2 10 4 Salivary hypersecretion Dizziness 30 Incidence of Gastrointestinal Adverse Events by Study Week Proportion of Participants, % 10 20 20 30 RELYVRIO + SOC Placebo + SOC Weeks ≤3 3< Weeks 6< Weeks <6 ≤9 9 Weeks 12< Weeks 15< Weeks 18< Weeks 21< Weeks ≤12 ≤15 ≤18 ≤21 ≤24 * Adverse reaction is composed of several similar terms. Paganoni S, et al. N Engl J Med. 2020;383:919-930. Missing AMYLYX | 8#9Rx only NDC 73063-035-04 relyvrio TM (sodium phenylbutyrate and taurursodiol) for oral suspension 3 g/1 g per packet Each packet contains 3 g sodium phenylbutyrate (equivalent to 2630 mg phenylbutyrate) and 1 g taurursodiol. Each packet contains 464 mg of sodium. Recommended Dosage: See prescribing information. Keep out of sight and reach of children. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature). Protect from moisture. Overview of Prescribing Information Indication Statement Dosing and Administration RELYVRIO is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults. Administered orally or via a feeding tube. The recommended dosage for the first 3 weeks of treatment is 1 packet daily, increasing to 2 packets daily starting at the beginning of week 4. Diarrhea Abdominal pain Most common adverse events occurring with RELYVRIO • • Nausea • Upper respiratory infection Preparation: Empty contents of one packet in a cup containing 8 ounces of water. Stir well and take (or administer) within 1 hour of preparation. Contains 7 single-dose packets Please see full Prescribing Information at RELYVRIO.com AMYLYX | 9#10Significant Unmet Need in the U.S. and Globally ALS is a global disease that affects at least 200,000 people worldwide United States Canada ~29,000 People¹ living with ALS ~3,000 People² living with ALS Affects people globally regardless of ethnic, geographic, or racial background Europe >30,000 People³ living with ALS (European Union and United Kingdom) References: 1. Nelson LM, et al. Neuroepidemiology. 2021 Dec 20. DOI: 10.1159/000521591 2. Shoesmith C, et al. CMAJ Nov 2020, 192 (46) E1453-E1468; DOI: 10.1503/cmaj. 191721 3. Brown CA, et al. Neuroepidemiology. 2021;55(5):342-353. AMYLYX 10#11Helping People with ALS Gain Access to RELYVRIO AMYLYX 11#12Experienced Commercial Team Educating the Market Focused on three key priorities to support a successful launch Driving awareness and 1 education of RELYVRIO 2 Engaging payors on access 3 Ensuring people living with ALS have positive interactions through their treatment journey with RELYVRIO and ALS clinics have positive interactions with Amylyx AMYLYX 12#13Targeted Approach Covering The Vast Majority of the U.S. Market ~2,700 potential ALS prescribers in the U.S.1 Physicians Treating ALS by Patient Volume2 shington North Dakota Montana Minnesota South Oregon Idaho Dakota . Wyoming California Nevada Utah United States • west Kansas Misurl rginia O Arizona Nein Mexico References: 1. Amylyx Internal Data; Mar. '23 2. Amylyx Internal Data; Sep '22. Texas Louisi Mississ insidy Maine Patient Volume 336-570 171-336 77-171 27-77 0-27 AMYLYX 13#14Amylyx Care Team (ACT) Support Program Ready to provide personalized support to adults living with ALS that have been prescribed to RELYVRIO and healthcare professionals Compassionate support from a caring team You'll get to know the ACT™ team as people who are deeply dedicated to your well-being, providing personalized support throughout your treatment journey. Team of actual Amylyx employees ACT Care Support Specialists ACT Care Support Specialists • Committed to answering your questions by phone before you are enrolled in ACT •Help you get enrolled in the program ACT Care Coordinators Your ACT Care Coordinator • Will be paired with you throughout your treatment journey • Available by phone or email, once you are enrolled in ACT • An experienced, full-time Amylyx employee • Dedicated to providing the highest levels of customer service + ACT Care Educators ACT Care Educators • Registered nurses who can provide additional education about ALS and RELYVRIOTM (sodium phenylbutyrate and taurursodiol)* *Your doctor is always your best source for treatment information. A wide range of support Through your dedicated ACT Care Coordinator, you will be connected with the following support and resources. Reimbursement & Insurance Support We can help you understand your insurance coverage and benefits for RELYVRIO. Financial Assistance, if Eligible We can provide resources for access support through our $0 Co-Pay Program,* Interim Access Program, and Patient Assistance Program. Talk to your ACT Care Coordinator or visit Amylyx CareTeam.com to learn more. ALS Education Our team is here to support you with learning more about ALS and your treatment. Your doctor is always your best source for treatment information. Partnership With Specialty Pharmacies Because RELYVRIO is a specialty medication, it is only available through specialty pharmacies. We'll partner with these facilities to coordinate delivery to your home. To learn more, visit AmylyxCareTeam.com. Continuous Support We'll help you get started on RELYVRIO treatment and keep supporting you as you continue on it. Call ACT Today 866-318-2989 Monday-Friday, 8 AM to 8 PM ET *Out-of-pocket costs related to medication, appointments, evaluations, testing, or other related services are not covered by the RELYVRIO Co-Pay Program. The RELYVRIO Co-Pay Program is not available for prescriptions purchased under Medicare, Medicaid, TRICARE, or other federal and state-funded programs. Amylyx reserves the right to amend or terminate the Program at any time without notice. Co-pay amounts after applying co-pay assistance may depend on the individual's insurance plan and may vary The RELYVRIO Co-Pay Program is intended to help individuals afford RELYVRIO TM ACT Amylyx Care Team Your ACT Care Coordinator is your primary source for one-on-one support For more information about RELYVRIO, please see additional Important Safety Information throughout and the full Prescribing Information and Medication Guide. IMPORTANT SAFETY INFORMATION (continued) Before you receive RELYVRIO, tell your doctor about all of your medical conditions, including if you: -Have high blood pressure - Have kidney problems relyvrio™ (sodium phenylbutyrate and taurursodial) in for oral Tyrone Living with ALS AMYLYX 14#15Canada ALBRIOZA™ Commercial Launch Underway in Canada 1st First Regulatory Approval for Amylyx Worldwide ALBRIOZA commercial launch in Canada underway; moving with urgency to make ALBRIOZA available to Canadians living with ALS. Approximately 1,000 people die from ALS in Canada every year, with a similar number of diagnoses annually. New Treatment Option Available for Canadians ALBRIOZA is only the third product candidate to be approved for the treatment of ALS in Canada in the past 30 years. Unmet need remains high, with ~3,000 Canadians living with ALS. Navigating Complex Reimbursement System ~40% of Canadians are covered by private insurance. Negotiated agreements with all of the largest private insurers to cover ALBRIOZA, represents ~80% of privately insured population ~60% of Canadians rely on public insurance. By the end of 2023, Amylyx expects to finalize and sign product listing agreements with the majority of federal, provincial, and territorial public drug plans. Experienced Team Driving Dalbrioza sodium phenylbutyrate and ursodoxicoltaurine powder for suspension TM Successful Launch in Canada Staffed by a team with considerable experience with new therapy launches in Canada Chris Aiello Head of Canada and General Manager Julie Girodat Head of Patient Services & Distribution sanofi Bioverativ Biogen AMGEN Bristol Myers Squibb™ Celgene Tracey Jason, PhD abbvie Celgene Pfizer Head of Medical Affairs Jason Lee Head of Market Access Blaine MacNeil Head of Sales, Marketing and Commercial Operations BAYER Biogen Lilly BAYER sanofi AMYLYX 15#16Europe Path to commercialization TOD Significant Unmet Need in Europe 30,000+ people are living with ALS in the EU and U.K.1 There is a crucial need for new, effective treatments for ALS in Europe, which only has one approved therapy (Riluzole), and no new therapies in over 25 years Riluzole is prescribed to 75-90% of people living with ALS across Germany, France, Spain, Italy, and the U.K.2 Targeted, Local Commercial Approach Actively preparing launch in the EU and engaging with key stakeholders in each member state. Expect to launch in Germany first, followed by expansion in additional countries; reimbursement process and timelines differ by country Working with ALS community and reimbursement bodies to facilitate access to ALBRIOZAⓇ, if approved Experienced, Established Local Leadership Team Accomplished cross functional leadership team in place developing commercialization strategy for ALBRIOZA in EMEA and ensuring its implementation, including Regional Head of EMEA, Head of EMEA Market Access, Head of EMEA Regulatory, Head of EMEA Medical, and GMs for major European markets, including Germany Continuing to build a highly targeted and lean team References: 1. Chiò /Logroscino/Traynor/Collins / Simeone/Goldstein/Nelson LM, et al. Neuroepidemiology. 2021 Dec 20. doi: 10.1159/000521591. 2. Source: IQVIA MIDAS data. AMYLYX 16#17Germany Case Study High Unmet Need ~7,000 people living with ALS in Germany1, majority of patients diagnosed and initially treated in ~25 ALS centers of expertise • Focused Outreach to Key Physicians • • Engagement with top national KOLs, including KOLs at five participating PHOENIX trial sites Dividing country into six territories to target ~25 ALS centers of expertise and ~200 community-based neurologists that are responsible for the majority of Riluzole prescriptions Local team hired in Germany Commercial Launch Followed by Reimbursement Negotiations Preparing to commercialize in Germany after EU approval; free pricing at launch; reimbursement negotiations then typically take ~12 months following pricing and reimbursement dossier filing Husum Rostock Greifswaldy Itzehoe Neubrandenburg Bremerhaven Hamburg Schwerin Emden Bremen 2 Velzen Neuruppin Schwedt Meppen Vechta ♡ Hannover Rheine Bielefeld Stendal Berlin Frankfurt Luckenwalde Gosla Magdeburg Cottbus Bocholt Do trund Hoyerswerda Nordhausen Brilon Leipzig Kassel Vierse Dresden Erfurt Καλη Aachen Siegen ☆ +Chemnitz Bonn Fulda Frankfurt. Bayreuth Trier Würzburg Mannheim Nürnberg Saarbrücken Heilbronn Regensburg Stutgart Aalen Passau Pfaffenhofen Offenburg München- Traunreut Freiburg Lörrach Kempten 1. Rosenbohm et al, J Neurol (2017) 264:749-757, Epidemiology of amyotrophic lateral sclerosis in Southern Germany, 'ALS registry Swabia pts diagnosed 10/2008 - 12/2014', N=648 prospective patients were analyzed AMYLYX 17#18EMEA Leadership Highly Experienced, Local Team to Lead Commercialization in Europe Stéphanie Hoffmann-Gendebien Head, General Manager, EMEA Secoya clementia FLUIDIFY ALEXION genzyme Lugdivine Le Dez Head of Patient Advocacy and Government Affairs, EMEA Alcon Chiara Troncatti Head of Commercial Operations, EMEA Qral Group AKCEA THERAPEUTICS Boehringer Ingelheim IZS Brid Carberry Head of Supply Chain, EMEA ALEXION Celgene Susanne Digel General Manager, Germany ①Koncopeptides Spark. bluebirdbio ALEXION NOVARTIS BIOMARIN Eric Litjens 2Pfizer Head of Marketing & Corporate Communications, EMEA } HORIZON ON Orphan Now HANSA BIOPHARMA Consulting Leo Stričan Head of Market Access, EMEA bluebirdbio Biogen NOVARTIS Thomas Biet Head of Finance, EMEA Bernd-Jan Sanson, M.D. Head of Medical Affairs, EMEA O Cell Point AstraZeneca SANOFI GENZYME Kiadispo Jan van Emous Head of Regulatory Affairs, Europe pharma Biogen Pfizer agios NOVARTIS SANOFI GENZYME ☑ I Bristol Myers Squibb Schering-Plough ✓ AMYLYX 18#19photo in memory of Mick, a husband and father, who was a gifted tattoo artist and musician PHOENIX Phase 3 Trial Designed to provide additional safety and efficacy data on RELYVRIO for the treatment of ALS to further support our global regulatory efforts Nov 2021 First participants dosed Feb 2023 Mid- 2024 Trial completed enrollment with 664 participants Topline data anticipated AMYLYX 19#20PHOENIX is a Large, Global Phase 3 Clinical Trial in ALS Designed to Support Global Regulatory Efforts and Continue to Provide Data on RELYVRIO TRICALS The highway towards a cure W UNIVERSITY of WASHINGTON SWEDISH Sutter Health CPMC UC Irvine Health Keck School of Medicine of USC BARROW Neurological Institute Hennepin Health UMASS 3811 M Northwestern MedicinePenn COLUMBIA UNIVERSITY MEDICAL CENTER RUTGERS When we Medicine School of Medicine Feinberg School of Medicine THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER Health. TEMPLE UNIVERSITY JOHNS HOPKINS MEDICINE University of Colorado Anschutz Medical Campus Washington University in St Louis SCHOOL OF MEDICINE TEXAS NEUROLOGY ☑ AUSTIN NEUROMUSCULAR CENTER UNIVERSITY NEUROSCIENCE EMORY UNIVERSITY SCHOOL OF MEDICINE UFHealth USF MORSANI THE UNIVERSITY of NORTH CAROLINA at CHAPEL HILL Wake Forest" School of Medicine NEALS Northeast Amyotrophic Lateral Sclerosis Consortium Note: 26 of the 28 PHOENIX sites in the U.S. are NEALS member sites. ✓ AMYLYX 20#21• . PHOENIX Trial Design for RELYVRIO Slightly broader inclusion-exclusion criteria than CENTAUR; substantially greater statistical power Stratified PHOENIX based on whether people meet CENTAUR inclusion criteria or not Plan to analyze subset of participants who meet CENTAUR criteria as well as the broader population RELYVRIO Screen for eligibility Key inclusion criteria: • Clinically definite or clinically probable ALS by El Escorial criteria (2-4 body areas with clinical signs consistent with ALS) • <24 months from symptom onset • Slow vital capacity (SVC) >55% • Riluzole/edaravone use permitted Randomization 3:2 (n = 664) Placebo Randomized Phase 48 weeks *40 item assessment questionnaire which provides a subjective health measure to specifically assess quality of life for patients with ALS. Primary Efficacy Outcomes • ALSFRS-R Safety and tolerability Secondary Efficacy Outcomes • ALSAQ-40* • Overall Survival Slow vital capacity (SVC) AMYLYX 21#22AMX0035 Potential to Treat Several Diseases of Neurodegeneration 22 222#23Neurodegenerative Diseases are the Biological Opposite of Cancer Cancer is Characterized by Abnormal Cellular Growth; Neurodegenerative Diseases are Characterized by Abnormal Cellular Death B C WHO grade III (top row) and grade IV (bottom row) astrocytomas. R Mild Cognitive Impairment Healthy controls Typical AD Limbic- predominant Hippocampal- sparing Minimal atrophy Subtypes of brain atrophy patterns in MCI from visual rating scales Update on Brain Tumor Imaging: From Anatomy to Physiology S. Cha American Journal of Neuroradiology Mar 2006, 27 (3) 475-487 Ekman, U., Ferreira, D. & Westman, E. The A/T/N biomarker scheme and patterns of brain atrophy assessed in mild cognitive impairment. Sci Rep 8, 8431 (2018). https://doi.org/10.1038/s41598-018-26151-8 AMYLYX 23#24The 2002 Nobel Prize in Physiology or Medicine was for Discoveries in the Field of Programmed Cell Death Cancer is Characterized by Abnormal Cellular Growth; Neurodegenerative Diseases are Characterized by Abnormal Cellular Death The Nobel Prize in Physiology or Medicine 2002 RSG Proc. Natl. Acad. Sci. USA Vol. 95, pp. 4997-5002, April 1998 Cell Biology Bax directly induces release of cytochrome c from isolated mitochondria JULIANE M. JÜRGENSMEIER, ZHIHUA XIE, QUINN DEVERAUX, LISA ELLERBY, DALE BREDESEN, AND JOHN C. REED* Program on Apoptosis and Cell Death Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 Edited by Lewis T. Williams, Chiron Technologies, Emeryville, CA, and approved February 23, 1998 (received for review October 10, 1997) nature reviews molecular cell biology JCI The Journal of Clinical Investigation About Editors Consulting Editors For authors Publication ethics Alerts Advertising Current Issue Past issues By specialty Videos Reviews ▾ Viewpoint Collections Review Series Free access | 10.1172/JC126373 Job board Subscribe Clinical Medicine Contact JCI This Mor Endoplasmic reticulum stress: cell life and death decisions Chunyan Xu, Beatrice Bailly-Maitre, and John C. Reed nature reviews drug discovery Explore content About the journal Publish with us ▾ Subscribe Explore content About the journal ✓ Publish with us ▾ Subscribe The Nobel Prize in Physiology or Medicine 2002 was awarded jointly to Sydney Brenner, H. Robert Horvitz and John E. Sulston "for their discoveries concerning genetic regulation of organ development and programmed cell death." nature > nature reviews molecular cell biology > review articles article Review Article Published: 21 October 2019 Mitochondria as multifaceted regulators of cell death Florian J. Bock & Stephen W. G. Tait Nature Reviews Molecular Cell Biology 21, 85-100 (2020) | Cite this article 21k Accesses 256 Citations 131 Altmetric Metrics nature > nature reviews drug discovery > review articles > article Published: December 2008 Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities Inki Kim, Wenjie Xu & John C. Reed The Nobel Prize in Physiology or Medicine 2002 - Nobel Prize.org AMYLYX 24#25In ALS, Multiple Pathways May Converge on ER and Mitochondrial Dysfunction to Cause Neuronal Death Multiple pathways are implicated in ALS with many thought to cause and exacerbate ER stress and mitochondrial dysfunction, two pathways central to neuronal death Mitochondrial death proteins, including BAX, are upregulated in post-mortem ALS spinal cord samples, as are unfolded protein response (UPR) related proteins Genetic causes of ALS, including the most well-known genes SOD1, C9orf72 and TDP43, are mechanistically linked to mitochondrial and ER dysfunction Upper motor neuron Motor cortex Astrocyte TDP43 FUS aggregates Ca Na O-Glutamate Glutamate excitotoxicity lonotropic glutamate receptors Microglia Release of pro-inflammatory cytokines Mitochondrial dysfunction Ca-dependent enzymatic pathways -TCa Na-K pump dysfunction Neuronal death 2K 3Na TNa C9orf72, TARDBP. FUS and SOD1 Oxidative stress lon channel dysfunction Na ER stress Defects in nucleo- cytoplasmic trafficking K 10 EAAT2- Glutamate excitotoxicity Lower motor Schwann cells neuron Mu, X Annals of Neurology 1996, Israelson A et al., 2010; Pickles S and Van de Velde C., 2012; Nishitoh H et al., 2008; Kiskinis E et al., 2014; Farg et al., 2012 Archana P et al., 2019; Huang C et al., 2020; Tan W et al., 2014; Choi SY et al., 2019; Mehta AR et al., 2021; Tsai Y-L et al., 2020; Nakaya T et al., 2018, Montibeller, L. Cell Stress Chaperones. 2018; Manfredi G, Kawamata H. Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis. Neurobiol Dis. 2016;90:35-42. doi:10.1016/j.nbd.2015.08.004; Smith EF, Shaw PJ, De Vos KJ. The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. 2019;710:132933. doi:10.1016/j.neulet.2017.06.052. mutations Defects in RNA Na processing and Schwann cell defects Defects in protein folding and degradation protein synthesis SOD1 aggregates Neuromuscular Muscle junction Dysfunction of axonal transport systems -Accumulated neurofilament Adapted from Kiernan, M.C., Vucic, S., Talbot, K. et al. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Reviews Neurology 17, 104-118 (2021). https://doi.org/10.1038/s41582-020-00434-z Ca Reversal of Na-Ca exchanger AMYLYX 25#26AMX0035 - Designed to Reduce Neuronal Cell Death AMX0035: Dual UPR, mitochondrial apoptosis targeting Reduces ER dependent death Reduces Mito MOTOR NEURON dependent death MICROGLIAL CELL Neuroinflammation (inflammatory cytokine release, immune cell infiltration) Glutamate excitotoxicity Oxidative stress Impaired crosstalk and calcium dysregulation ER stress Mitochondrial dysfunction N Unfolded protein Apoptosis response Misfolded and aggregated protein (SOD1, FUS, TDP-43) Cell injury and death NUCLEUS Aberrant transcription, mRNA processing, and transport CYTOPLASM MOA of AMX0035 in ALS is unknown Zhou W. J Biol Chem. 2011;286(17):14941-14951.; Rodrigues CM, Steer CJ. Expert Opin Investig Drugs. 2001;10(7):1243-1253.; Rodrigues CM, et al. Biochemistry. 2003;42(10):3070- 3080.; Fels JA, et al. Ann Clin Transl Neurol. 2022. doi.org/10.1002/acn3.51648. The mechanism of action is unknown ✓ AMYLYX 26#27AMX0035 Targets Both Pathways Simultaneously to Prevent or Slow Cell Death AMX0035 Effect in Relevant Preclinical Models Glutamate excitotoxicity model showing favorable effects on neuronal survival1 Models of primary mitochondrial disease showing restoration of mitochondrial functions1 Protection against neuronal death in model of primary cortical neuron damage2 AMX0035 demonstrates synergistic protection of cortical neurons against peroxide-mediated neuronal death in a range of ratios² Cell Viability (%) → 60 150 Taurursodiol µM → 900 700 600 500 400 300 200 100 Sodium Phenylbutyrate μM Figure from 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. MOA of AMX0035 in ALS is unknown 1. Data on File. Amylyx Pharmaceuticals. 1. 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. AMYLYX 27#28Framework to Select Future Indications Rigorous process in place to determine next indication for AMX0035 Clear unmet need Strong scientific rationale Biomarker evidence Existing and robust understanding of the natural history of the disease Potential to move directly into a Phase 3 pivotal trial Adjacencies and synergies with ALS Interest and support from KOLS and advocacy groups AMYLYX 28#29Progressive Supranuclear Palsy (PSP) Selected as Next Indication for AMX0035 Clear unmet need Typically fatal within just 5 to 8 years; no disease-modifying treatments for PSP Strong scientific rationale PSP leads to rapid & significant neurodegeneration and is characterized by tau protein deposition in affected regions of brain; AMX0035 shown preclinically to protect neurons against degeneration and clinically to lower tau Biomarker evidence AMX0035 demonstrated a statistically significant lowering of phosphotau181 & total tau in the CSF of people with Alzheimer's disease Existing and robust understanding of the natural history of the disease PSP progression is predictable and well understood Potential to move directly into a Phase 3 pivotal trial Preparing for Phase 3 study with ~600 adults in a randomized, placebo-controlled study Adjacencies and synergies with ALS Shares mechanistic characteristics with ALS - unfolded protein response, mitochondrial dysfunction and related cell death Interest and support from KOLS and advocacy groups Collaborated with key global academic leaders, people living with PSP, and advocacy groups AMYLYX 29#30Upcoming Pivotal Phase 3 Study in Progressive Supranuclear Palsy (PSP) PSP is Associated with Tau Protein Rare neurological disorder that affects body movements, walking and balance, and eye movement. Pathology characterized by widespread neurodegeneration associated with tau protein deposition in subcortical regions of the brain. AMX0035 Demonstrates Potent Impact on Tau4,5 Data from Phase 2 PEGASUS study in Alzheimer's disease demonstrated that AMX0035 lowered total tau by 64.9 pg/mL and lowered phosphorylated tau by 14.6 pg/mL at week 24. Select CSF Biomarkers Change from Baseline to Week 24 LS Mean Week 24 (95% CI) p-value (nominal) Linear mixed effect AMX0035 Placebo Difference between AMX0035 and Placebo Estimated prevalence of * 5-7 in 100,000 worldwide¹ model estimation PSP is typically fatal within 5 to 8 years2,3 Total Tau (pg/mL) -64.9 8.8 -73.7 (-106.8, -40.7) <0.0001 Phosphorylated Tau (pTau181) (pg/mL) -14.6 -0.3 -14.4 (-21.5, -7.2) 0.0002 1. Shoeibi A., Olfati N., Litvan I. Frontrunner in translation: Progressive supranuclear palsy. Front. Neurol. 2019;10:1125. doi: 10.3389/fneur.2019.01125. Swallow D.M., Zheng C.S., Counsell C.E. Systematic review of prevalence studies of progressive supranuclear palsy and corticobasal syndrome. Mov. Disord. Clin. Pract. 2022;9:604-613. doi: 10.1002/mdc3.13489. 2. Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009;8(3):270-279. 3. Guasp M., Molina-Porcel L., Painous C., Caballol N., Camara A., Perez-Soriano A., Sánchez-Gómez A., Garrido A., Muñoz E., Marti M.J. Association of PSP phenotypes with survival: A brain-bank study. Parkinsonism Relat. Disord. 2021;84:77-81. doi: 10.1016/j.parkreldis.2021.01.015. 4. Analysis conducted with biomarker core lab of the Mass General Institute for Neurodegenerative Disease (MIND) on CSF samples. Data from Phase 2 PEGASUS trial of AMX0035 for the treatment of Alzheimer's disease. Arnold et al. CTAD 2022. 5. Marie K. Bondulich, Tong Guo, Christopher Meehan, John Manion, Teresa Rodriguez Martin, Jacqueline C. Mitchell, Tibor Hortobagyi, Natalia Yankova, Virginie Stygelbout, Jean-Pierre Brion, Wendy Noble, Diane P. Hanger, Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate, Brain, Volume 139, Issue 8, August 2016, Pages 2290-2306, https://doi.org/10.1093/brain/aww137 AMYLYX 30#31Potential of AMX0035 in Wolfram syndrome Wolfram syndrome Ultra-rare disease, affecting ~5,000 people in U.S.,¹ with an estimated prevalence of 1 in 500,000 people worldwide. 2 Causes multi-system failure resulting in blindness, deafness, diabetes, ataxia, neurodegeneration, and typically death by early adulthood. Characterized as a prototypical disease of ER stress. Dysfunction of the WFS1 gene causes the accumulation of unfolded/misfolded proteins in the ER (referred to as ER stress); terminal ER stress and cell death in pancreatic B-cells and neuronal cells thought to be the mechanism of Wolfram syndrome development.³ Effect of AMX0035 in Preclinical Studies³ Improved WFS1 protein expression and increased insulin secretion in ẞ cells with the WFS1 variant (Figure) Inhibited cell death in ẞ cells with the WFS1 variant (Figure), ameliorated organelle dysfunction, mitophagy, ER stress JCI insIGHT Delayed onset of the diabetic phenotype in Wolfram syndrome mouse model KO, Ctrl: Baseline 500 800- 1000- 400- 2000- ## 800- 800- 0000 600- 300- 600- 1500- 600- 400- 200- KO, P+T: Baseline WT: Baseline KO, Ctrl: 1 month KO, P+T: 1 month WT: 1 month 400- 400- 1000- 100 **** 200- *** 200- 200- 500- 0- 20mM 2mM 2mM 20mM Ctrl P+T 0 2mM 20mM 2mM 0 30 20mM Ctrl P+T Ctrl P+T 1. U.S. Department of Health and Human Services. (n.d.). Wolfram syndrome. Genetic and Rare Diseases Information Center. Retrieved April 28, 2023, from https://rarediseases.info.nih.gov/diseases/7898/wolfram-syndrome. 2. U.S. National Library of Medicine. (n.d.). Wolfram syndrome. MedlinePlus. Retrieved April 28, 2023, from https://medlineplus.gov/genetics/condition/wolfram-syndrome/. 3. Morikawa et al. Front. Endocrinol., 25 March 2022, Sec. Diabetes: Molecular Mechanisms, Volume 13 - 2022, https://doi.org/10.3389/fendo.2022.849204 4. Kitamura RA, et al. JCI Insight. 2022;7(18):e156549. AMYLYX 31 60 min 90 120#32HELIOS Phase 2 Study of AMX0035 in Wolfram syndrome 12 adult participants 24 weeks B Open-label study at the Washington University School of Medicine in St. Louis Primary Efficacy Outcomes Secondary Efficacy Outcomes First participant dosed in • C-peptide response • Visual acuity • • Safety and tolerability Exogenous insulin dose • Glucose range April 2023 Topline results anticipated in 2024 • HbA1c levels Orphan drug designation granted to AMX0035 for the treatment of Wolfram syndrome by U.S. FDA ✓ AMYLYX 32#33Strong Global IP Position Portfolio Provides Robust Protection of RELYVRIO and Related Combinations 59 issued patents worldwide Patents and patent applications cover: Composition of matter of the combination of PB and TURSO, including in the U.S. - through 2033* 47 additional patents pending + many additional filings planned FISH FISH & RICHARDSON • - And in some territories, the combination of related compounds Method of use of the combination and related combinations for treating neurodegenerative disease • Formulation of the combination and manufacturing process • Methods of treating ALS based on clinical trial results - through 2040 Five orange book listed patents directed to RELYVRIO and/or its method of use NCE exclusivity and Orphan exclusivity granted; protects against generics (7 years in US, 10 in EU, 8 in Canada) * Once approved in a jurisdiction, we plan to seek any applicable patent term extensions (PTE). PTE applications have been filed in the U.S. AMYLYX 33#34Team Deeply Experienced Executive Team to Oversee Global Growth, Clinical Development, Approvals, and Commercial Execution Joshua Cohen BSE Co-CEO and Director Co-invented AMX0035, dedicated to ALS/neurodegenerative research since 2013, co-designed CENTAUR study, co-led development of AMX0035 as 3-person company for 6 years, then built Amylyx team Tammy Sarnelli Global Head of Regulatory Affairs 30+ years in Regulatory, including at Biogen leading approvals of Tysabri and Tecfidera Former Head of Global Regulatory Affairs, Neurology & Immunology at EMD Serono Keith White Head of Global Market Access 20+ years in Market Access, including at Genentech, Intermune, and Intercept Justin Klee ScB Co-CEO and Director Co-invented AMX0035, dedicated to ALS/neurodegenerative research since 2013, co-designed CENTAUR study, co-led development of AMX0035 as 3-person company for 6 years, then built Amylyx team Debra Canner Chief HR Officer Former CHRO at Akamai, Juniper, several others; VP HR at Genzyme Timothy Lee Head of US Commercial Development and Global Commercial Training 20+ years of sales, marketing and product commercialization experience, including at Alexion Pharmaceuticals, Novartis, and Pfizer Jim Frates Chief Financial Officer 22-year CFO at Alkermes; grew to >$1B in annual revenue and >2,000 employees worldwide Tom Holmes Global Head of Supply Chain Former Head of Global External Manufacturing at Biogen Maryellen Garrett Head of Global Accounting and Finance Operations CPA with 20+ years of finance and accounting experience, including at Entasis Therapeutics, Cubist Pharmaceuticals and PWC Shauna Horvath Head of Global Marketing 15+ years of marketing experience, including at Cambridge BioMarketing Margaret Olinger, MBA Chief Commercial Officer 2nd commercial employee at Alexion; helped oversee launch of Soliris and Strensiq at Alexion. 30+ years in commercial John Landry Head of Commercial Operations 25+ years of sales and operations experience, including at Akcea Therapeutics, Alexion Pharmaceuticals and Novartis Gina M. Mazzariello Chief Legal Officer and General Counsel 20+ years of corporate and commercial legal experience within the healthcare industry, including at Boehringer Ingelheim Patrick Yeramian, MD, MSC, MBA Chief Medical Officer Over 25 years as clinical trialist, CMO, and clinical consultant including as CMO of Viragen Machelle Manuel, PhD Head of Global Medical Affairs Former Head of Global Medical Scientific Affairs at Ironwood 20+ years in medical affairs AMYLYX 34#35Financial Overview#36Amylyx Select Financial Data Statement of Operations ($ thousands except per share data) Product revenue, net Cost of sales Research and development Selling, general and administrative 1Q23 4Q22 71,428 $ 21,885 5,283 2,821 24,192 22,813 44,006 40,844 Total operating expenses $ 73,481 $ 66,478 Net income (loss) $ 1,573 $ (42,704) Net income (loss) per share - diluted $ 0.02 $ (0.65) Balance Sheet ($ thousands) 1Q23 4Q22 Cash, cash equivalents and short- $ 345,674 $ 346,945 term investments AMYLYX 36#37Focused Priorities Helping people gain access to RELYVRIOⓇ in the U.S. and ALBRIOZATM in Canada, bringing a much-needed new treatment option to people with ALS I+I ALBRIOZA Launch in Canada Commercial RELYVRIO Commercial Launch in U.S. * Amylyx intends to seek re-examination of the negative CHMP opinion as announced on June 23, 2023. Final CHMP Opinion expected Fall 2023 with decision in late Q4'23 at the earliest* AMYLYX 37#38AMYLYX Thank you. Our mission is to one day end the suffering caused by neurodegenerative diseases. Every day, we strive for better therapies.