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CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Amylyx Pharmaceuticals, Inc. (Nasdaq: AMLX) (“Amylyx” or the “Company”) today reported financial results for the second quarter ended June 30, 2024. “We recently expanded our late-stage pipeline with our acquisition of avexitide and now have three assets targeting orphan indications. Avexitide is Phase 3-ready with FDA Breakthrough Therapy Designation in post-bariatric hypoglycemia (PBH) and congenital hyperinsulinism, highly statistically significant data from two Phase 2 studies, and an FDA-agreed upon primary outcome for the pivotal study in PBH,” said Joshua Cohen, Co-CEO of Amylyx. “PBH represents a major unmet need with an estimated 160,000 individuals in the U.S. impacted by symptomatic PBH, which can cause brain glucose starvation, known as neuroglycopenia. We are focused on progressing avexitide into Phase 3 development, which is on track to occur in Q1 2025, with topline data anticipated in 2026.” “Our recent restructuring and our focus on efficient and targeted clinical development is expected to help advance all four programs efficiently to potentially bring new treatments to communities with high unmet needs. We continue to make important progress in neurodegenerative diseases and are excited to share updated data from our Wolfram syndrome program in the months ahead,” added Justin Klee, Co-CEO of Amylyx. “We also look forward to initiating a multiple ascending dose clinical trial of AMX0114 in ALS before the end of the year and reporting interim data from our AMX0035 progressive supranuclear palsy program in mid-2025.” Second Quarter and Recent Corporate Updates: Acquired avexitide, a Phase 3-ready GLP-1 receptor antagonist with U.S. Food and Drug Administration (FDA) Breakthrough Therapy Designation and Orphan Drug Designation in hyperinsulinemic hypoglycemia. Avexitide has been evaluated in five clinical trials for post-bariatric hypoglycemia (PBH) and has also been studied in three clinical trials for congenital hyperinsulinism (HI), two indications characterized by hyperinsulinemic hypoglycemia. In previous Phase 2 and Phase 2b studies in PBH, avexitide showed statistically significant reductions in hypoglycemic events. FDA guidance for industry combined with initial FDA feedback specific to the pivotal Phase 3 program of avexitide for PBH suggest that reduction in hypoglycemic events could be an endpoint to support approval following positive results from a pivotal Phase 3 clinical trial. Announced interim data from the ongoing Phase 2 HELIOS clinical trial of AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) in eight adults living with Wolfram syndrome which demonstrated encouraging improvement in glycemic control, pancreatic beta cell function, and vision. Wolfram syndrome is a prototypical disease of endoplasmic reticulum stress that is rare, progressive, and monogenic and is characterized by childhood-onset diabetes mellitus, optic nerve atrophy, deafness, diabetes insipidus, and neurodegeneration. In April, the Company hosted a virtual webcast to discuss these data with Dr. Fumihiko Urano, a leading expert in Wolfram syndrome, the Principal Investigator of the Phase 2 HELIOS clinical trial in Wolfram syndrome, and the Samuel E. Schechter Professor of Medicine in the Division of Endocrinology, Metabolism & Lipid Research at Washington University School of Medicine in St. Louis. A replay is available here . Received Orphan Drug Designation from the European Commission (EC) for AMX0035 for the treatment of Wolfram syndrome. The designation was based on a positive opinion issued by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA). The FDA previously granted AMX0035 Orphan Drug Designation for the treatment of Wolfram syndrome in 2020. Upcoming Expected Milestones: The Company plans to initiate a multiple ascending dose clinical trial of AMX0114 in people living with ALS in the second half of 2024 . Amylyx has completed IND-enabling studies of AMX0114, a potent antisense oligonucleotide targeting inhibition of calpain-2, a well-established target in a number of neurological diseases and a protease known to cleave many substrates including neurofilament, tau, and TDP43 proteins. Amylyx has observed rescue of cellular degeneration and neurofilament biology in multiple cellular experiments with AMX0114. Amylyx plans to present updated Phase 2 HELIOS topline data at the International Society for Pediatric and Adolescent Diabetes (ISPAD) Conference in Lisbon, Portugal, October 16-19, 2024, including data for all 12 participants at Week 24 and additional longer-term data for any participant that completed their Week 36 or 48 visit prior to the data cutoff. The Company is engaging with stakeholders, including the FDA, and planning for a single Phase 3 clinical trial. Amylyx will share additional details on the clinical trial design once finalized. Amylyx expects to initiate its Phase 3 program for avexitide in PBH in Q1 2025. Topline data are anticipated in 2026. Data from an interim analysis of the ORION study of AMX0035 in progressive supranuclear palsy (PSP) continue to be expected in mid-2025. The Company introduced an operationally seamless Phase 2b/3 study design into ORION. The first part will include approximately 100 people living with PSP. Amylyx plans to conduct an interim analysis in these participants and evaluate topline outcomes through Week 24. PSP is considered a tauopathy based on the strong genetic linkage of tau variants to the disease and presence of tau pathology in post-mortem brain samples. AMX0035 has been shown to significantly reduce tau in cerebrospinal fluid (CSF) in a Phase 2, randomized, placebo-controlled trial in Alzheimer’s disease. Financial Results for the Second Quarter Ended June 30, 2024 Net product revenue: Net product revenue was $(1.0) million for the three months ended June 30, 2024, as a result of adjustments to gross-to-net revenue reserve estimates. This is compared to net product revenue of $98.2 million for the same period in 2023. On April 4, 2024, the Company announced that it had started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO ® and ALBRIOZA™ and remove the product from the market based on topline results from the global Phase 3 PHOENIX trial, which failed to meet its prespecified primary and secondary endpoints. For the three months ended June 30, 2023, net product revenue was primarily related to units of RELYVRIO and ALBRIOZA sold in the U.S. and Canada. Cost of Sales: Cost of sales were $7.4 million in the three months ended June 30, 2024, compared to cost of sales of $5.6 million for the same period in 2023. Cost of sales in the three months ended June 30, 2024 primarily relate to losses on firm purchase commitments under Amylyx’ commercial manufacturing supply agreements for AMX0035 that were established prior to the results from the Phase 3 PHOENIX trial. R&D Expenses: Research and development expenses were $23.3 million for the three months ended June 30, 2024, compared to $29.0 million for the same period in 2023. The decrease was primarily due to a decrease in payroll and personnel-related costs and a decrease in clinical expenses. The decrease in payroll and personnel-related costs was primarily related to a decrease in the number of employees as a result of the restructuring plan announced on April 4, 2024. The decrease in clinical expenses is primarily due to a decrease in spending on AMX0035 for the treatment of ALS due to the completion of the Phase 3 PHOENIX trial. SG&A Expenses: Selling, general and administrative expenses were $21.6 million for the three months ended June 30, 2024, compared to $43.4 million for the same period in 2023. The decrease was primarily due to a decrease in payroll and personnel-related costs and a decrease in consulting and professional services. The decrease in payroll and personnel-related costs was primarily related to a decrease in the number of employees as a result of the restructuring plan announced on April 4, 2024. The decrease in consulting and professional services is primarily due to a decrease in commercial sales and marketing activity as a result of removing RELYVRIO/ALBRIOZA from the market in the U.S. and Canada based on topline results from the Phase 3 PHOENIX trial. Restructuring Expenses: Restructuring expenses were $22.9 million for the three months ended June 30, 2024, compared to zero for the same period in 2023. Restructuring expenses included employee severance and termination benefits of approximately $21.8 million, contract termination costs, impairment of long-lived assets and other costs. The Company substantially completed its restructuring plan during the second quarter of 2024. Net Loss: Net loss for the three months ended June 30, 2024 was $72.7 million, or $1.07 per share, compared to net income of $22.1 million, or $0.31 per diluted share for the same period in 2023. Cash Position: Cash, cash equivalents, and short-term investments were $309.8 million at June 30, 2024, compared to $373.3 million at March 31, 2024. The Company expects cash runway into 2026. Investor Conference Call Information Amylyx’ management team will host a conference call and webcast today, August 8, 2024, at 8:00 a.m. ET to discuss financial results and provide an update on the business. To access the conference call, please dial +1 (800)-836-8184 (U.S. & Canada) or +1 (646)-357-8785 (international) at least 10 minutes prior to the start time and ask to be joined into the Amylyx Pharmaceuticals call. A live audio webcast of the call will be available under “Events and Presentations” in the Investor section of the Company’s website, https://investors.amylyx.com/news-events/events . The webcast will be archived and available for replay for 90 days following the event. Available Information We periodically provide other information for investors on our corporate website, https://amylyx.com , and our investor relations website, https://investors.amylyx.com . This includes press releases and other information about financial performance, information on corporate governance, and details related to our annual meeting of stockholders. We intend to use our website as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD. Accordingly, investors should monitor our website, in addition to following the Company’s press releases, SEC filings, and public conference calls and webcasts. About Avexitide Avexitide is an investigational, first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist with the potential to treat hyperinsulinemic hypoglycemia that has been evaluated in five Phase 2 clinical studies for post-bariatric hypoglycemia (PBH) and has also been studied in congenital hyperinsulinism (HI). The U.S. Food and Drug Administration (FDA) has granted avexitide Breakthrough Therapy Designation for both indications, Rare Pediatric Disease Designation in congenital HI, and Orphan Drug Designation for the treatment of hyperinsulinemic hypoglycemia (which includes PBH and congenital HI). Avexitide is designed to bind to the GLP-1 receptor on pancreatic islet beta cells and block the effect of excessive GLP-1 to mitigate hypoglycemia by decreasing insulin secretion and stabilizing glucose levels. In PBH, excessive GLP-1 can lead to the hypersecretion of insulin and subsequent serious hypoglycemic events. In two Phase 2 PBH trials, avexitide demonstrated highly statistically significant reductions in hypoglycemic events. These events can lead to autonomic and neuroglycopenic symptoms that can have a devastating impact on daily living. About AMX0035 AMX0035 is an investigational, oral, fixed-dose combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine outside of the U.S.). AMX0035 is designed to slow or mitigate neurodegeneration by targeting endoplasmic reticulum (ER) stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration. Preclinical studies have provided evidence that AMX0035 may reduce cell death and improve cellular function, also supporting the synergistic effect of AMX0035 compared to individual compounds. AMX0035 is being studied as a potential treatment in neurodegenerative diseases, including Wolfram syndrome and progressive supranuclear palsy (PSP). About AMX0114 AMX0114 is an investigational, antisense oligonucleotide designed to target the gene encoding calpain-2, a key contributor to the axonal (Wallerian) degeneration pathway. Axonal degeneration has been recognized as an important early contributor to the clinical presentation and pathogenesis of ALS and other neurodegenerative diseases. Calpain-2 has been implicated in the pathogenesis of ALS based on findings of elevated levels of calpain-2 and its cleavage products in postmortem ALS tissue, therapeutic benefit of calpain-2 modulation in animal models of ALS, and the role of calpain-2 in cleaving neurofilament, a broadly researched biomarker in ALS. Preclinical studies completed to date have shown that AMX0114 achieves potent, dose-dependent, and durable knockdown of CAPN2 mRNA expression and calpain-2 protein levels in human motor neurons. Moreover, in preclinical efficacy studies, treatment with AMX0114 reduced extracellular neurofilament light chain levels following neurotoxic insult in induced pluripotent stem cell (iPSC)-derived human motor neurons, and improved survival of iPSC-derived human motor neurons harboring ALS-linked, pathogenic TDP-43 mutations. About Post-Bariatric Hypoglycemia (PBH) Symptomatic post-bariatric hypoglycemia (PBH) is a condition that affects approximately 8% of people who have undergone bariatric surgery. It is characterized by exaggerated secretion of glucagon-like peptide-1 (GLP-1), dysregulated secretion of insulin, and a rapid drop in blood sugar. PBH can cause serious hypoglycemic events associated with brain glucose starvation, known as neuroglycopenia, including impaired cognition, cardiac arrhythmias, loss of consciousness, and seizures. PBH is associated with a high degree of disability and can result in major disruptions to life, including falls, motor vehicle accidents, and job and income loss. It is estimated that ~160,000 people are currently living with symptomatic PBH in the U.S., classifying it as an orphan condition. About Congenital Hyperinsulinism (HI) Congenital hyperinsulinism (HI) is a rare disease characterized by hypersecretion of insulin leading to severe, persistent hypoglycemia in infants and young children with limited therapeutic options. Common symptoms of congenital HI include lack of energy, irritability, lethargy, and excessive hunger. Repeated episodes of low blood glucose increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma. About the HELIOS Trial The HELIOS trial ( NCT05676034 ) is a 12-participant, open-label Phase 2 trial designed to study the effect of AMX0035 on safety and tolerability, and various measures of endocrinological, neurological, and ophthalmologic function in adult participants living with Wolfram syndrome. About Wolfram Syndrome Wolfram syndrome is a rare, progressive, monogenic disease characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration. Common manifestations of Wolfram syndrome include diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties. The prognosis of Wolfram syndrome is poor, and many people with the disease die prematurely with severe neurological disabilities. Literature suggests approximately 3,000 people are living with Wolfram syndrome in the U.S. Wolfram syndrome is often characterized as a prototypical disease of endoplasmic reticulum (ER) stress. ER stress and mitochondrial dysfunction are believed to drive the underlying disease pathophysiology in Wolfram syndrome. Individuals with Wolfram syndrome generally have mutations in the WFS1 gene, which encodes wolframin, a protein spanning the membrane of the ER. Wolframin is thought to play a role in protein folding and aid in the maintenance of ER function by regulating calcium levels. Loss of wolframin function leads to ER stress and impaired mitochondrial dynamics. About the ORION Trial The ORION trial ( NCT06122662 ) is a global, randomized, double-blind, placebo-controlled Phase 2b/3 clinical trial designed to assess the efficacy, safety, and tolerability of AMX0035 compared to placebo in people living with progressive supranuclear palsy (PSP). ORION was designed and planned in collaboration with key global academic leaders, people living with PSP and their caregivers, and industry advocacy organizations. About PSP Progressive supranuclear palsy (PSP) is a sporadic, rare, and adult-onset neurodegenerative disorder that affects walking and balance, eye movement, swallowing, and speech. People living with PSP have a life expectancy of six to eight years after initial diagnosis, and its epidemiology is similar to that of amyotrophic lateral sclerosis (ALS). PSP typically begins in late-middle age and rapidly progresses over time. The disease affects approximately seven in 100,000 people worldwide, and there are currently no disease-modifying therapies approved for the treatment of PSP. PSP is characterized by abnormal tau inclusions and is consequently also known as a tauopathy. Similar to other neurodegenerative diseases, pathophysiologic changes underlying PSP are multifactorial, with several genetic and environmental factors likely contributing to tau dysfunction and aggregation. Multiple pathways, including genetic mutations, endoplasmic reticulum (ER) stress, and the activation of unfolded protein response, mitochondrial dysfunction, and neuroinflammation have been implicated as contributors to tau dysfunction and aggregation. About ALS Amyotrophic lateral sclerosis (ALS, also known as motor neuron disease) is a relentlessly progressive and fatal neurodegenerative disorder caused by motor neuron death in the brain and spinal cord. Motor neuron loss in ALS leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis, and eventually, death. More than 90% of people with ALS have sporadic disease, showing no clear family history. ALS affects around 30,000 people in the U.S., and more than 30,000 people are estimated to be living with ALS in Europe (European Union and the United Kingdom). People living with ALS have a median survival of approximately two years from diagnosis. About Amylyx Pharmaceuticals Amylyx is committed to the discovery and development of new treatment options for communities with high unmet needs, including people living with serious and fatal diseases. The Company has preclinical or clinical development programs underway in neurodegenerative, neuroendocrine, and endocrine diseases. Since its founding, Amylyx has been guided by science to address unanswered questions, keeping communities at the heart and center of all decisions. Amylyx is headquartered in Cambridge, Massachusetts. For more information, visit amylyx.com and follow us on LinkedIn and X . For investors, please visit investors.amylyx.com . Forward-Looking Statements Statements contained in this press release and related comments in our earnings conference call 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 potential of AMX0035 (sodium phenylbutyrate and taurursodiol) as a treatment for Wolfram syndrome and PSP or other neurodegenerative diseases; expectations regarding the timing of the announcement of results from the Company’s Phase 3 ORION trial of AMX0035 for the treatment of PSP, and additional results from the Company’s Phase 2 HELIOS trial of AMX0035 for the treatment of Wolfram syndrome and plans to possibly initiate a phase 3 trial, including planned discussions with regulatory authorities related thereto; the potential for AMX0114 as a treatment for ALS and the planned initiation of a trial evaluating AMX0114 in ALS; expectations regarding the Company’s ability to develop, manufacture and commercialize avexitide, if approved; the potential for avexitide as a treatment for PBH; expectations regarding the timing for initiation and readout of the Phase 3 avexitide program in PBH; and expectations regarding the Company’s cash runway and longer-term strategy. Any forward-looking statements in this press release and related comments in the Company's earnings conference call 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; Amylyx’ ability to execute on its regulatory development plans and expectations regarding the timing of results from its planned data announcements and initiation of clinical studies; the risk that early-stage results may not reflect later-stage results; Amylyx’ ability to fund operations, and the impact that global macroeconomic uncertainty, geopolitical instability, and public health events 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, 2023, and subsequent filings with the SEC. All forward-looking statements contained in this press release and related comments in our earnings conference call 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, except as required by law. AMYLYX PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED BALANCE SHEETS UNAUDITED (in thousands) June 30, 2024 December 31, 2023 Assets Cash, cash equivalents and short-term investments $ 309,812 $ 371,362 Accounts receivable, net 4,091 40,050 Inventories — 83,280 Prepaid expenses and other current assets 12,819 14,931 Other assets 5,440 7,831 Total assets $ 332,162 $ 517,454 Liabilities and Stockholders’ Equity Accounts payable and accrued expenses $ 67,712 $ 79,785 Other liabilities 3,141 4,237 Total liabilities 70,853 84,022 Stockholders’ equity 261,309 433,432 Total liabilities and stockholders' equity $ 332,162 $ 517,454 AMYLYX PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS UNAUDITED (in thousands, except share and per share data) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Product revenue, net $ (1,023 ) $ 98,216 $ 87,620 $ 169,644 Operating expenses: Cost of sales 8 5,580 5,953 10,863 Cost of sales - inventory impairment and loss on firm purchase commitments 7,410 — 117,871 — Research and development 23,347 29,044 59,955 53,236 Selling, general and administrative 21,647 43,391 79,406 87,397 Restructuring expenses 22,851 — 22,851 — Total operating expenses 75,263 78,015 286,036 151,496 (Loss) income from operations (76,286 ) 20,201 (198,416 ) 18,148 Other income, net 3,586 3,806 7,165 7,262 (Loss) income before income taxes (72,700 ) 24,007 (191,251 ) 25,410 Provision for income taxes — 1,933 242 1,763 Net (loss) income $ (72,700 ) $ 22,074 $ (191,493 ) $ 23,647 Net (loss) income per share Basic $ (1.07 ) $ 0.33 $ (2.82 ) $ 0.35 Diluted $ (1.07 ) $ 0.31 $ (2.82 ) $ 0.34 Weighted-average shares used in computing net (loss) income per share Basic 68,024,929 67,233,617 67,939,642 66,976,871 Diluted 68,024,929 70,132,040 67,939,642 70,471,821

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX) (“Amylyx” or the “Company”) today announced the European Commission (EC), based on a positive opinion issued by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA), has granted Orphan Drug Designation for AMX0035, Amylyx’ proprietary, fixed-dose combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine outside of the U.S.) for the treatment of Wolfram syndrome. Wolfram syndrome is a prototypical disease of endoplasmic reticulum (ER) stress that is rare, progressive, and monogenic and is characterized by childhood-onset diabetes mellitus, optic nerve atrophy, deafness, diabetes insipidus, and neurodegeneration. There are currently no drugs approved for Wolfram syndrome, and many people with the disease die prematurely with severe neurological disabilities. The FDA previously granted AMX0035 Orphan Drug Designation for the treatment of Wolfram syndrome in 2020. The EMA grants Orphan Drug Designation status for products intended for the treatment, prevention, or diagnosis of rare, life-threatening, or chronically debilitating conditions where the product may represent a significant benefit over existing treatments. Amylyx recently presented positive data from an interim analysis of its Phase 2 HELIOS study, including eight participants with Wolfram syndrome assessed at Week 24, which demonstrated that AMX0035 improved pancreatic function and glycemic control, as measured by C-peptide, HbA1c, and other markers of glucose metabolism. All eight participants met prespecified responder criteria showing either improvement or stabilization of disease according to both the Patient Reported Global Impression of Change (PGIC) and the Clinical Reported Global Impression of Change (CGIC) scales. The majority of participants reported some improvement in vision. In Wolfram syndrome, progressive decline and worsening of outcomes would have been expected on all measures, so disease improvement or stabilization alone is clinically meaningful. AMX0035 was generally well tolerated in all participants. The Company anticipates reporting topline data from all 12 participants at Week 24 this fall. “Wolfram syndrome is a disease where there are well-defined measurable biomarkers, rigorous supporting preclinical data, and clear rationale for our potential therapy based on its mechanism of action. Specifically, Wolfram syndrome is considered a prototypical endoplasmic reticulum (ER) stress disorder because of the clear link between WFS1 mutations and ER stress. AMX0035 is believed to target ER stress and mitochondrial dysfunction,” said Camille L. Bedrosian, MD, Chief Medical Officer at Amylyx. “The interim data from HELIOS showed stabilization or even improvement across key outcomes at Week 24. HELIOS follows strong preclinical research with data showing clear effects in cellular and animal models. We look forward to reporting topline data from all participants at Week 24 this fall. We aim to address an urgent unmet medical need, given there are no approved treatment options for Wolfram syndrome.” About Wolfram Syndrome Wolfram syndrome is rare, progressive, monogenic disease characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration. Common manifestations of Wolfram syndrome include diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties. The prognosis of Wolfram syndrome is poor, and many people with the disease die prematurely with severe neurological disabilities. Literature suggests approximately 3,000 people are living with Wolfram syndrome in the United States. Wolfram syndrome is often characterized as a prototypical disease of endoplasmic reticulum (ER) stress. ER stress and mitochondrial dysfunction are believed to drive the underlying disease pathophysiology in Wolfram syndrome. Individuals with Wolfram syndrome generally have mutations in the WFS1 gene, which encodes wolframin, a protein spanning the membrane of the ER. Wolframin is thought to play a role in protein folding and aid in the maintenance of ER function by regulating calcium levels. Loss of wolframin function leads to ER stress and impaired mitochondrial dynamics. About AMX0035 AMX0035 is an oral, fixed-dose combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine outside of the U.S.). AMX0035 was designed to slow or mitigate neurodegeneration by simultaneously targeting endoplasmic reticulum (ER) stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration. Preclinical studies have provided evidence that the proprietary combination of PB and TURSO and their complementary mechanisms of action targets cell death and better prevents neurodegeneration than targeting either mechanism of action alone. AMX0035 is being studied as a potential treatment in neurodegenerative diseases, including Wolfram syndrome and progressive supranuclear palsy (PSP). About the HELIOS Trial The HELIOS trial (NCT05676034) is a 12-participant, open-label Phase 2 trial designed to study the effect of AMX0035 on safety and tolerability, and various measures of endocrinological, neurological, and ophthalmologic function in adult participants living with Wolfram syndrome. About Amylyx Pharmaceuticals Amylyx is committed to the discovery and development of new treatment options for communities with high unmet needs, including people living with serious and fatal diseases. The Company has preclinical or clinical development programs underway in neurodegenerative, neuroendocrine, and endocrine diseases. Since its founding, Amylyx has been guided by science to address unanswered questions, keeping communities at the heart and center of all decisions. Amylyx is headquartered in Cambridge, Massachusetts. For more information, visit amylyx.com and follow us on LinkedIn and X . For investors, please visit investors.amylyx.com . Forward-Looking Statements Statements contained in this press release 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, Amylyx’ expectations regarding: interactions with regulatory authorities; the ongoing evaluation of AMX0035 in Wolfram syndrome, including that early-stage results may not reflect later-stage results and the timing for expected topline data in the HELIOS study; and the potential for AMX0035 to help people living with Wolfram syndrome. Any forward-looking statements in this press release 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 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, 2023, and subsequent filings with the SEC. All forward-looking statements contained in this press release 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.

Pictured: A brain hovers over a hand against a yellow-striped background/Taylor Tieden for BioSpace The first half of 2024 was filled with ups and downs for patients and researchers in the neurological disease space. The amyotrophic lateral sclerosis community took a hit when Amylyx’s Relyvrio failed its confirmatory Phase III trial and was subsequently withdrawn from the market. Huntington’s disease patients saw new hope in the form of positive mid-stage data from Wave Life Sciences. The second half of the year kicked off with the approval of a novel disease-modifying treatment for Alzheimer’s disease, only the second such option now available to patients. The next six months are shaping up to be just as eventful in clinical research, with key data readouts expected in Alzheimer’s, schizophrenia, depression and a couple of rare diseases. Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, noted several key upcoming data readouts in both the neuropsychiatric and neurodegenerative spaces. Here are five BioSpace is keeping a close eye on. Athira Pharma’s Fosgonimeton Alzheimer’s disease Recently approved medicines Leqembi and Kisunla command the most attention in the Alzheimer’s disease treatment space as the first anti-amyloid antibodies on the market, but the experimental Alzheimer’s pipeline is still robust. One candidate with a different mechanism of action is fosgonimeton, currently in a Phase II/III trial. Topline data from the trial, which includes around 550 patients, are expected in the second half of this year. Developed by Athira Pharma, fosgonimeton is designed to modulate the HGF/MET system to activate neuroprotective and anti-inflammatory pathways in the central nervous system. Athira presented data from the Phase II SHAPE trial in Parkinson’s disease dementia and dementia with Lewy bodies at the AD/PD 2024 International Conference in March, showing “encouraging safety and pro-cognitive measures.” These results “underscore confidence” in the Phase II/III LIFT-AD trial in Alzheimer’s disease, according to the company’s press release. In 2022, fosgonimeton combined with standard-of-care acetylcholinesterase inhibitors missed the primary endpoint in Athira’s Phase II ACT-AD study, failing to best placebo in ERP P300 latency, a measure of working memory processing speed. However, a planned analysis of subgroup data showed cognitive and functional improvements through the drug’s modulation of the HGF/MET system, and Athira moved forward investigating fosgonimeton as a monotherapy for Alzheimer’s. AbbVie/Cerevel’s Emraclidine Schizophrenia In December 2023, AbbVie invested nearly $9 billion in the schizophrenia space with the acquisition of Cerevel Therapeutics and its late-stage asset emraclidine. (This deal has not yet closed.) Later this year, the company will learn whether its investment has paid off. Two Phase II trials, EMPOWER-1 and EMPOWER-2, comprise approximately 750 individuals in total and are projected to read out by the end of 2024. In these trials, AbbVie is seeking the rapid improvement of schizophrenia symptoms. The trials’ primary endpoint is change from baseline after six weeks on the Positive and Negative Syndrome Scale (PANSS) scale. The studies are also evaluating the safety and tolerability of emraclidine, a positive allosteric modulator of the muscarinic M4 receptor. AbbVie will need strong data from the EMPOWER trials to keep pace with Bristol Myers Squibb, which is expecting an FDA decision in September on its own novel schizophrenia treatment, KarXT, which also targets the M4 as well as M1 muscarinic receptors. BMS obtained KarXT in its December acquisition of Karuna Therapeutics. “[Emraclidine] is behind,” Suvannevejh said. “Cerevel knew that they needed to play catch-up versus Karuna,” so they tried to design the Phase II studies to be large enough and robust enough to be considered by the FDA as Phase III studies. “We don't know if FDA is going to agree to that, [but] that’s what their hope is going to be.” Neumora Therapeutics’ Navacaprant Major depressive disorder Also in the neuropsychiatric space, Watertown, Mass.–based Neumora Therapeutics is expecting the first Phase III data for its lead asset navacaprant, a Kappa-opioid receptor (KOR) antagonist in development for major depressive disorder (MDD), in the fourth quarter of this year. The KOR system is a “well-characterized pathway known to mediate depressive-like states, and modulating this system represents a novel approach to treating MDD and other major neuropsychiatric disorders,” according to Neumora’s website. Mizuho is “bullish” on navacaprant’s prospects, due to “de-risking” Phase II data, validation from a competitor program, a positive reception from key opinion leaders on the KOR class and a large, addressable MDD market, Suvannevejh wrote in a July 8 investor note. “This represents a brand-new class for depression,” Suvannevejh said, adding that there is a “fair amount of industry excitement” around KOR antagonists due to the less-than-ideal side effects associated with currently marketed antidepressants. Neumora launched the Phase III trial in July 2023 after navacaprant monotherapy demonstrated “statistically significant and clinically meaningful reductions in symptoms of depression and anhedonia” in Phase II trial participants with moderate-to-severe MDD. If these studies are successful, Neumora intends to New Drug Application with the FDA for navacaprant in 2025. Amylyx’s AMX003 Wolfram syndrome A week after announcing the voluntary withdrawal of recently approved ALS treatment Relyvrio (AMX0035) from the U.S. and Canadian markets, Amylyx received a glimmer of hope for the drug—a combination of sodium phenylbutyrate and taurursodiol—in another neurodegenerative condition: Wolfram syndrome. Wolfram syndrome is characterized by childhood-onset insulin-dependent diabetes mellitus and progressive optic atrophy, with many patients also developing diabetes insipidus, sensorineural hearing loss and autonomic nervous system degeneration. The multi-organ disease is caused by mutations in the WFS1 gene that lead to endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which causes “lack of function across many different cell types, and ultimately, cell death across multiple cell types, starting with beta cells in the pancreas and then moving to parts of the nervous system,” explained Justin Klee, co-CEO of Amylyx. “AMX0035 targets ER stress and mitochondrial dysfunction.” Interim results from the ongoing Phase II HELIOS trial showed AMX0035 improved pancreatic function and glycemic control in adult patients with the rare, inherited disease. Treatment with Amylyx’s drug led to an increase in total C-peptide response, an established marker of pancreatic beta cell function and glycemic control and the trial’s primary efficacy measure. With these data, from eight patients who had completed 24 weeks of treatment, Amylyx co-CEO Josh Cohen told BioSpace that the company plans to engage with regulators on a possible development path for AMX0035 in Wolfram syndrome. Amylyx expects topline data from all 12 trial participants after 24 weeks of treatment during the second half of 2024. Vigil Neuroscience’s Iluzanebart ALSP Another company anticipating mid-stage data for a rare disease candidate is Vigil Neuroscience. Vigil is developing iluzanebart for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), an inherited, autosomal dominant neurological disease affecting approximately 10,000 people in the U.S. Phase II data are expected in the third quarter of 2024. ALSP is caused by loss-of-function mutations in the CSF1R gene, leading to microglial dysfunction. Iluzanebart is designed to increase signaling through DAP12/SYK to mitigate microglial dysfunction, according to Vigil. In preclinical studies, iluzanebart has “demonstrated sub-nanomolar potency and selective target engagement with TREM2,” which activates the cascade of downstream signals to mediate neuroprotective and homeostatic functions of the microglia. “It's important for Vigil and it's important for patients with this disease because there are no FDA-approved treatments . . . and Vigil is the only game in town for this disease,” Suvannevejh said. “It’s a very novel agent targeting this TREM2 mechanism of action,” and for investors, the jury is still out on whether this is an effective approach, he said. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.