TDP43

AC Immune Reports Full Year 2023 Financial Results and Provides a Corporate Update ACI-24.060 ABATE Phase 2 trial to report Abeta-PET imaging results in Q2 and H2ACI-7104.056 VacSYn Phase 2 trial in Parkinson’s disease on track for interim data in H2ACI-24.060 for Alzheimer’s disease (AD) received FDA Fast Track designationACI-35.030 ReTain Phase 2b program in preclinical (pre-symptomatic) AD patients, initiated by collaboration partnerCash of CHF 103 million at year end, plus the CHF 15 million milestone payment received on February 1, 2024 and the next CHF 25 million ACI-35.030-related milestone, provides funding into 2026 Lausanne, Switzerland, March 14, 2024 – AC Immune SA (NASDAQ: ACIU), a clinical-stage biopharmaceutical company pioneering the development of precision medicine approaches for the diagnosis, treatment, and prevention of neurodegenerative diseases, today reported results for the year ended December 31, 2023, and provided a corporate update. Dr. Andrea Pfeifer, CEO of AC Immune SA, commented: “We made significant progress in 2023 advancing our three innovative active immunotherapy programs in Phase 2 clinical trials in Alzheimer’s and Parkinson’s diseases. This sets the stage for a number of important milestones in 2024, which have the potential to further enhance our understanding of how best to prevent neurodegeneration and to generate significant value for AC Immune. In the second quarter and second half of 2024, we will be reporting Phase 2 ACI-24.060 data on amyloid plaque reduction after 6- and 12-months treatment, respectively. Amyloid plaque is a clinically validated biomarker of efficacy, making these data announcements potentially de-risking and providing an opportunity to accelerate ACI-24.060 into a registrational program. “We are also delighted that ACI-35.030 (JNJ-64042056), our anti-phospho-Tau active immunotherapy, has now entered the Phase 2b trial, conducted by our partner in pre-symptomatic AD patients. In addition, our ACI-7104.056 anti-alpha-synuclein active immunotherapy is advancing through Phase 2 testing for Parkinson’s disease (PD) with initial safety and immunogenicity data expected in the second half of 2024. “AC Immune’s primary focus remains on these three active immunotherapy programs, each of which has the potential to transform how neurodegenerative diseases are treated and ultimately, to enable precision prevention of these diseases. Thanks to our strengthened leadership team and reinforced balance sheet, we are well-positioned to deliver de-risking clinical milestones, working towards our mission to shift the paradigm from disease treatment to disease prevention.” 2023 and Subsequent Highlights Active Immunotherapy Programs ACI-24.060 anti-Abeta active immunotherapy Received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of ADThe enrolment in the ABATE Phase 2 AD trial continues with cohort 3 now being expanded. Following data safety monitoring board (DSMB) review, no safety concerns have been raised to date, consistent with the previously observed safety profile.Initial interim ABATE safety and immunogenicity data from the first, low dose AD cohort were promising, with clear evidence of anti-Abeta antibody responses against toxic Abeta species observed in the blinded data.The first participant with Down syndrome (DS) was dosed in the Phase 2 ABATE trial.Six-month Abeta positron emission tomography (PET) imaging results are expected in Q2 2024, and 12-month Abeta-PET data are expected in H2 2024. ACI-35.030 (JNJ-64042056) anti-phospho-Tau (anti-pTau) active immunotherapy Phase 2b ReTain clinical trial in participants with preclinical AD preparations are ongoing to initiate the study by H1 2024 by Janssen Pharmaceuticals, Inc., a Johnson & Johnson company (Janssen).ReTain will evaluate the effect of ACI-35.030 on cognition and Tau pathology in approximately 500 participants with preclinical AD. These will be randomized in a 1:1 ratio to a single dose level of ACI-35.030 or placebo, administered as intramuscular injections for a maximum of 4 years.Under the terms of the licensing agreement, AC Immune received a milestone payment of CHF 15 million on February 1, 2024 and expects to receive another milestone payment of CHF 25 million related to achieving an undisclosed enrolment target in 2025. ACI-7104.056 anti-a-syn active immunotherapy Completed enrolment of cohort 1 in the VacSYn Phase 2 trial in Parkinson’s disease (PD), with 16 patients randomized. Enrolment and randomization of cohort 2 is ongoing as planned.No safety concerns have been reported to date with no reports of moderate or severe adverse events. Safety and immunogenicity updates from the trial are expected in H2 2024. Diagnostic Programs A peer-reviewed paper published in Nature Communications (Smith et al., Nat. Comm., 2023) showed that AC Immune’s wholly-owned a-syn-PET tracer ACI-12589 can detect a-syn pathology in multiple system atrophy (MSA) and differentiate MSA from other a-synucleinopathies.The TDP-43-PET tracer program has progressed as planned and a clinical candidate has been selected. Further IND-enabling studies will be completed over the coming months to permit the initiation of a Phase 1 clinical trial in H2 2024.In the pivotal Phase 3 ADvance trial evaluating the Morphomer® derived Tau-PET tracer, PI-2620 in AD, the first participant was imaged and the study is progressing well. PI-2620 was discovered and developed using the Morphomer® platform as part of a research collaboration between AC Immune and Life Molecular Imaging. Corporate Updates Completed USD 50 million equity financing in December 2023, extending cash runway into Q1 2026. (This assumes the second ACI-35-related milestone payment of CHF 25 million is received in 2025)New grants that collectively provide more than USD 500,000 in additional non-dilutive capital to support the advancement of diagnostic programs targeting TDP-43 (TAR DNA-binding protein 43) were awarded to AC Immune by The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Target ALS Foundation.Strengthened leadership team with appointments of Dr. Nuno Mendonça as Chief Medical Officer, Dr. Madiha Derouazi as Chief Scientific Officer, and Mr. Christopher Roberts as Chief Financial Officer. Thought Leadership and Collaborations Initiated a research collaboration with Prof. Michael Heneka, director of the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, to evaluate the therapeutic potential of AC Immune’s SupraAntigen®- and Morphomer®-derived inhibitors of the NLRP3-ASC inflammasome pathway in preclinical disease models.Hosted webinar on PET imaging in AD featuring key opinion leader (KOL) Victor Villemagne, M.D. (University of Pittsburg). To view a replay of the event, click HERE.Hosted KOL webinar on early diagnosis and prevention of AD featuring presentations by Kaj Blennow, MD, PhD, of University of Gothenburg and Sahlgrenska University Hospital, and Giovanni Frisoni, MD, of University of Geneva and the Memory Clinic at Geneva University Hospital. To view a replay of the webinar, click HERE. Anticipated 2024 Milestones ACI-24.060anti-Abeta active immunotherapy 6-month and 12-month Abeta-PET data in AD expected in Q2 2024 and H2 2024, respectivelyInitial safety and immunogenicity data in DS cohort expected in H2 2024 ACI-7104.056anti-a-syn active immunotherapy Interim safety and immunogenicity update from the Phase 2 VacSYn study in Parkinson’s disease expected in H2 2024 ACI-35.030anti-pTau active immunotherapy First-patient in ReTain Phase 2b clinical trial expected in H1 2024 Anti-TDP-43 antibody Completion of regulatory tox studies expected in H1 2024 TDP-43-PET tracer Phase 1 initiation expected in H2 2024 ACI-15916 a-syn-PET tracer IND-enabling studies in PD expected to be completed in H2 2024 Analysis of Financial Statements for the Year Ended December 31, 2023 Cash Position: The Company had a total cash balance of CHF 103.1 million as of December 31, 2023, compared to a total cash balance of CHF 122.6 million as of December 31, 2022. On February 1, 2024, the Company received the milestone payment of CHF 14.8 million from Janssen for the commencement of ReTain, the ACI-35.030 Phase 2b clinical study. The Company’s cash balance provides sufficient capital resources to progress into at least Q1 2026, assuming potential milestone payment of CHF 24.6 million related to achieving an undisclosed enrolment target for our ACI-35.030 and no other milestones.Contract Revenues: The Company recorded CHF 14.8 million in contract revenues for the year end December 31, 2023 compared with CHF 3.9 million in contract revenues in the prior year. For the year ended December 31, 2023, our contract revenues of CHF 14.8 million were related to the commencement of the first Phase 2b clinical study of ACI-35.030 per our agreement with Janssen.R&D Expenditures: R&D expenses decreased by CHF 5.7 million for the year ended December 31, 2023 to CHF 54.6 million, predominantly due to: Discovery and preclinical expenses (- CHF 5.8 million): The Company decreased expenditures across a variety of its discovery and preclinical programs.Clinical expenses (- CHF 2.0 million): The Company had a net decrease in clinical expenditures largely due the completion of the Phase 1b/2a and the advancement into Phase 2b for our ACI-35.030 active immunotherapy. We increased expenditures for the continued clinical development of our Phase 1b/2 ABATE study for ACI-24.060.Salary- and benefit-related costs (+ CHF 2.2 million): While the staffing position remained stable in 2023, personnel expenses increased due to the annualization of 2022 hires. G&A Expenditures: G&A expenses decreased by CHF 0.5 million for the year ended December 31, 2023 to CHF 15.3 million. This decrease is related to a decrease in operating expenses across various cost centers. This is partially offset by an increase in salaries and related costs.Other Operating Income: The Company recorded CHF 1.4 million in grant income for R&D activities performed under our grants for the year ended December 31, 2023.IFRS Loss for the Period: The Company reported a net loss after taxes of CHF 54.2 million for the year ended December 31, 2023, compared with a net loss of CHF 70.8 million for the prior period. About AC Immune SA AC Immune SA is a clinical-stage biopharmaceutical company and a global leader in precision prevention for neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and NeuroOrphan indications driven by misfolded proteins. The Company’s two clinically validated technology platforms, SupraAntigen® and Morphomer®, fuel its broad and diversified pipeline of first- and best-in-class assets, which currently features sixteen therapeutic and diagnostic programs, five of which are currently in Phase 2 clinical trials and one of which is in Phase 3. AC Immune has a strong track record of securing strategic partnerships with leading global pharmaceutical companies, resulting in substantial non-dilutive funding in potential milestone payments plus royalties. SupraAntigen® is a registered trademark of AC Immune SA in the following territories: AU, EU, CH, GB, JP, RU, SG and USA. Morphomer® is a registered trademark of AC Immune SA in CN, CH, GB, JP, KR, NO and RU. The information on our website and any other websites referenced herein is expressly not incorporated by reference into, and does not constitute a part of, this press release. For further information, please contact: SVP, Investor Relations & Corporate CommunicationsGary Waanders, Ph.D., MBAAC ImmunePhone: +41 21 345 91 91Email: gary.waanders@acimmune.comU.S. InvestorsCorey Davis, Ph.D.LifeSci AdvisorsPhone: +1 212 915 2577 Email: cdavis@lifesciadvisors.comInternational MediaChris MaggosCohesion BureauPhone: +41 79 367 6254Email: chris.maggos@cohesionbureau.com Forward looking statementsThis press release contains statements that constitute “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements are statements other than historical fact and may include statements that address future operating, financial or business performance or AC Immune’s strategies or expectations. In some cases, you can identify these statements by forward-looking words such as “may,” “might,” “will,” “should,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “predicts,” “projects,” “potential,” “outlook” or “continue,” and other comparable terminology. Forward-looking statements are based on management’s current expectations and beliefs and involve significant risks and uncertainties that could cause actual results, developments and business decisions to differ materially from those contemplated by these statements. These risks and uncertainties include those described under the captions “Item 3. Key Information – Risk Factors” and “Item 5. Operating and Financial Review and Prospects” in AC Immune’s Annual Report on Form 20-F and other filings with the Securities and Exchange Commission. Forward-looking statements speak only as of the date they are made, and AC Immune does not undertake any obligation to update them in light of new information, future developments or otherwise, except as may be required under applicable law. All forward-looking statements are qualified in their entirety by this cautionary statement. Consolidated Balance Sheets(In CHF thousands) As of December 31, 2023 2022Assets Non-current assets Property, plant and equipment 3,376 4,259Right-of-use assets 3,508 2,808Intangible asset 50,416 50,416Long-term financial assets 361 361Total non-current assets 57,661 57,844 Current assets Prepaid expenses 6,437 4,708Accrued income 246 408Other current receivables 622 392Accounts receivable 14,800 —Short-term financial assets 24,554 91,000Cash and cash equivalents 78,494 31,586Total current assets 125,153 128,094Total assets 182,814 185,938 Shareholders' equity and liabilities Shareholders’ equity Share capital 2,089 1,797Share premium 474,907 431,323Treasury shares (105) (124)Currency translation differences (51) 10Accumulated losses (316,197) (264,015)Total shareholders’ equity 160,643 168,991 Non-current liabilities Long-term lease liabilities 2,825 2,253Net employee defined benefit liabilities 5,770 3,213Total non-current liabilities 8,595 5,466 Current liabilities Trade and other payables 1,679 929Accrued expenses 11,087 9,417Deferred income 138 587Short-term lease liabilities 672 548Total current liabilities 13,576 11,481Total liabilities 22,171 16,947Total shareholders’ equity and liabilities 182,814 185,938 Consolidated Statements of Income/(Loss)(In CHF thousands, except for per-share data) For the Year Ended December 31, 2023 2022 2021Revenue Contract revenue 14,801 3,935 —Total revenue 14,801 3,935 — Operating expenses Research & development expenses (54,606) (60,336) (62,282)General & administrative expenses (15,305) (15,789) (17,910)Other operating income/(expense), net 1,486 1,343 1,182Total operating expenses (68,425) (74,782) (79,010)Operating loss (53,624) (70,847) (79,010) Financial income 1,044 69 6,485Financial expense (176) (355) (581)Exchange differences (1,467) 393 113Finance result, net (599) 107 6,017 Loss before tax (54,223) (70,740) (72,993)Income tax expense (10) (13) (3)Loss for the period (54,233) (70,753) (72,996) Loss per share: Basic and diluted loss for the period attributable to equity holders (0.64) (0.85) (0.97) Consolidated Statements of Comprehensive Income/(Loss)(In CHF thousands) For the Year Ended December 31, 2023 2022 2021Loss for the period (54,233) (70,753) (72,996)Items that may be reclassified to income or loss in subsequent periods (net of tax): Currency translation differences (61) 10 —Items that will not to be reclassified to income or loss in subsequent periods (net of tax): Remeasurement gains/(losses) on defined-benefit plans (net of tax) (1,669) 4,426 956Other comprehensive income/(loss) (1,730) 4,436 956Total comprehensive loss, net of tax (55,963) (66,317) (72,040) Attachment 20240314_ACIU_Q4_Earnings_FINAL-pg

Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients -- especially glucose and oxygen -- to activate all neuronal functions. A new study reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system. Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients -- especially glucose and oxygen -- to activate all neuronal functions. Now, a study led by the University of Barcelona and the Bellvitge Biomedical Research Institute (IBIDELL) reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system. According to the study, featured on the cover of the journal JCI Insight, the TDP-43 protein is also critical in maintaining the integrity of the blood-brain barrier, which prevents toxins and pathogens from reaching the central nervous system. The project is led by Professor Eloi Montañez, from the Faculty of Medicine and Health Sciences of the University of Barcelona and IDIBELL, and involves teams from the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB), the Josep Carreras Leukaemia Research Institute, and the National Centre for Genomic Analysis (CNAG-CRG). What is the role of the TDP-43 protein in the vascular system? The TDP-43 protein is a key factor in nervous system function and neuronal plasticity. It is a DNA- and RNA-binding protein that regulates gene expression, and its dysfunction has been associated with various neurodegenerative disorders. Although much progress has been made recently in understanding the functions of TDP-43 in neurons, its exact role in the endothelial cells that make up the circulatory system, the formation of new blood vessels (angiogenesis) and vascular function was not yet known. "The study reveals for the first time that TDP-43 is essential for the formation and stability of blood vessels in the central nervous system, and for the integrity of the blood-brain barrier," says Professor Montañez, from the UB's Department of Physiological Sciences. The vascularization of the central nervous system and the formation of the blood-brain barrier are regulated by different signalling pathways. For example, the integrin signalling pathway that regulates the interaction of cells with the extracellular matrix and the signalling carried out by the transcription factor β-catenin. "In the study, we found that TDP-43 deficiency alters the extracellular matrix that surrounds blood vessels and reduces β-catenin signalling in endothelial cells," says the researcher. "Thus, mice without endothelial TDP-43 protein show multiple haemorrhages and vascular degeneration in the brain and spinal cord." Vascular defects and inflammatory response in neurosciences The authors also identify TDP-43 in endothelial cells as a potential contributing factor to the vascular defects that trigger the inflammatory response observed in patients diagnosed with TDP-43-associated diseases. "Some alterations in the blood vessels of the central nervous system -- defects in the integrity of the blood-brain barrier or degeneration of endothelial cells -- are associated with inflammatory and immune responses that can cause neuronal loss. This process of neuronal degeneration underlies the origin or progression of various neurological disorders -- stroke, diabetic retinopathy -- and some neurodegenerative diseases such as Alzheimer's disease, ALS or LATE (Limbic-predominant age-related TDP- 43 encephalopathy). The study will help to better understand the molecular mechanisms linking vascular defects and neuroinflammation. "Our goal now is to analyse whether defects in TDP-43 protein function in the endothelium of mature vessels could be involved in ALS or other TDP-43-associated pathologies due to increased vascular permeability or inflammatory processes," Montañez concludes.

- PHOENIX Study Did Not Meet Prespecified Primary or Secondary Endpoints - Data From 664-Participant Study Reinforce That AMX0035 is Generally Safe and Well-Tolerated - Within the Next Eight Weeks, Amylyx Will Continue to Engage With Regulatory Authorities and the ALS Community to Share Topline Data; Amylyx Will Share Plans for RELYVRIO/ALBRIOZA in ALS Which May Include Voluntarily Withdrawing RELYVRIO/ALBRIOZA From the Market - At This Time, RELYVRIO/ALBRIOZA Will Continue to be Available for People Living With ALS; Amylyx Has Voluntarily Decided to Pause Promotion; Related Patient Support Services Will Remain in Place - Studies With AMX0035 in Wolfram Syndrome (WS) and Progressive Supranuclear Palsy (PSP) to Continue Based on Data Supporting its Potential in These Diseases - Amylyx to Host Investor Conference Call Today, March 8, at 8:00 a.m. ET CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX) (“Amylyx” or the “Company”) today announced topline results from PHOENIX, a global, 48-week, randomized, placebo-controlled Phase 3 clinical trial of AMX0035 (sodium phenylbutyrate and taurursodiol [also known as ursodoxicoltaurine]; RELYVRIO® in the U.S., ALBRIOZA™ in Canada) in people living with amyotrophic lateral sclerosis (ALS). PHOENIX did not meet its primary endpoint of reaching statistical significance (p=0.667) as measured by change from baseline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at Week 48, nor was there statistical significance seen in secondary endpoints. Amylyx plans to present the data from PHOENIX at an upcoming medical meeting and will publish the results in a medical journal later this year. Amylyx will continue to engage with regulatory authorities and the broader ALS community, including ALS specialists and other multidisciplinary experts, people living with ALS, and advocates, to discuss the results from PHOENIX within the next eight weeks and make informed decisions. Amylyx intends to share plans for RELYVRIO/ALBRIOZA in ALS, which may include voluntarily withdrawing RELYVRIO/ALBRIOZA from the market. At this time, RELYVRIO/ALBRIOZA and its related patient support program will continue to be available for people living with ALS. Amylyx has voluntarily decided to pause promotion of the medication during this time. “We are surprised and deeply disappointed by the PHOENIX results following the positive data from the CENTAUR trial. Our main priority at the moment is sharing the information with people living with ALS and their treating physicians; this is part of our continued commitment to them and our mission. Over the next eight weeks, our team will continue to engage with regulatory authorities and the ALS community to discuss the results from PHOENIX. We will be led in our decisions by two key principles: doing what is right for people living with ALS, informed by regulatory authorities and the ALS community, and by what the science tells us. On behalf of the entire Amylyx team, we are grateful to the ALS community and for the dedication of trial participants, investigators, and study site teams. With data collected from 664 participants in PHOENIX, we are certain there will be important learnings that will help inform future ALS research. We are steadfast in our commitment to the ALS community and our mission, including with AMX0035 where it has shown potential in neurodegenerative diseases such as Wolfram syndrome and progressive supranuclear palsy, and with AMX0114, our investigational antisense oligonucleotide targeting calpain-2, in ALS,” said Justin Klee and Joshua Cohen, Co-CEOs of Amylyx. PHOENIX Study Results: The Phase 3 PHOENIX study enrolled 664 adults living with ALS. Participants were randomized three-to-two to receive either AMX0035 or placebo, with both treatment groups receiving standard-of-care. Continuation of a stable dosing regimen of riluzole and/or edaravone was permitted. PHOENIX did not meet the primary endpoint: There was no significant difference observed between participants treated with AMX0035 and placebo in ALSFRS-R total score change from baseline at Week 48 (p=0.667). No significant difference was observed in the subset of participants who met the CENTAUR trial criteria. There were also no significant differences observed across secondary endpoints. Consistent safety and tolerability profile: AMX0035 was well-tolerated in PHOENIX. There were no new safety signals, reinforcing the favorable and manageable safety pro with AMX0035 to date. European participants who completed the 48-week randomized phase had the option to enroll in an open label extension of the trial of up to two years in duration, which remains ongoing. Science of AMX0035: AMX0035, a specially formulated oral fixed-dose combination of PB and TURSO, has been shown in numerous preclinical studies to have a robust, synergistic effect in targeting two different destructive neurodegenerative disease pathways by mitigating endoplasmic reticulum stress and the associated unfolded protein response and mitochondrial dysfunction thereby reducing neuronal cell death. Additionally, AMX0035 has been shown to also reduce markers associated with neurodegenerative diseases in clinical trials, including a reduction of tau, a key protein aggregate shared across several neurodegenerative diseases, and YKL-40, a marker of neuroinflammation. Update on Ongoing AMX0035 Studies: The global, randomized, double-blind, placebo-controlled Phase 3 ORION clinical study of AMX0035 in PSP remains ongoing. The first participant was dosed in December 2023, and the Company is planning for an interim analysis. Topline results continue to be anticipated in 2025 or 2026. Data from the ongoing 12-participant, single site, open-label Phase 2 HELIOS clinical study are demonstrating evidence of clinical activity of AMX0035 in Wolfram syndrome. This study is fully recruited, and the Company plans to present preliminary data in the second quarter of 2024. Investor Conference Call Information Amylyx’ management team will host a live conference call and webcast today, March 8, 2024, at 8:00 a.m. ET to discuss the results of the PHOENIX trial. To participate in the conference call, please dial +1 (877) 870-4263 (U.S.), +1 (855) 669-9657 (Canada), or +1 (412) 317-0790 (International) at least 10 minutes prior to the start time and ask to be joined into the Amylyx Pharmaceuticals call. All interested parties are invited to access a live broadcast of the call via a webcast, which will be available on the “Events and Presentations” page in the “Investors” section of the Company’s website at investors.amylyx.com/news-events/events. An archived webcast will be available on the Company's website approximately two hours after the conference call and will be available for replay for 90 days following the call. About the PHOENIX Trial PHOENIX was a 48-week, randomized, placebo-controlled, global Phase 3 clinical trial further evaluating the safety and efficacy of AMX0035 (sodium phenylbutyrate and taurursodiol) for the treatment of ALS. The primary efficacy outcome of the trial was change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 48 weeks. Secondary endpoints include quality of life patient-reported outcome assessments, overall survival, and respiratory function as measured by slow vital capacity (SVC). Safety and tolerability were also assessed. European participants who completed the 48-week trial had the option to enroll in an open-label extension (OLE) phase. During this phase, all participants receive AMX0035, and continued safety and efficacy measures will be assessed. About the CENTAUR Trial CENTAUR was a multicenter Phase 2 clinical trial in 137 participants with ALS encompassing a 6-month randomized, placebo-controlled phase and an open-label long-term follow-up phase. The trial met its primary efficacy endpoint of reducing functional decline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Overall, reported rates of adverse events and discontinuations were similar between AMX0035 and placebo groups during the 24-week randomized phase; however, gastrointestinal events occurred with greater frequency (≥2%) in the AMX0035 group. Detailed data from CENTAUR is published in the New England Journal of Medicine (NEJM) and Muscle & Nerve. The CENTAUR trial was funded, in part, by the ALS ACT grant and the ALS Ice Bucket Challenge, and was supported by The ALS Association, ALS Finding a Cure (a program of The Leandro P. Rizzuto Foundation), the Northeast ALS Consortium, and the Sean M. Healey & AMG Center for ALS at Mass General. About AMX0114 AMX0114 is an 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 iPSC-derived human motor neurons, and improved survival of iPSC-derived human motor neurons harboring ALS-linked, pathogenic TDP-43 mutations. 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 United Kingdom). People living with ALS have a median survival of approximately two years from diagnosis. About HELIOS The HELIOS trial (NCT05676034) is a 12-participant, open-label proof of biology, 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 (WS). About Wolfram Syndrome Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disease characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration. Common manifestations of WS include diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties. Genetic and experimental evidence suggest that endoplasmic reticulum (ER) dysfunction is a critical pathogenic component of WS. The prognosis of WS is poor, and many people with the disease die prematurely with severe neurological disabilities. About the ORION Trial The Phase 3 ORION trial (NCT06122662) is a global, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to assess the efficacy, safety, and tolerability of AMX0035 compared to placebo in people living with progressive supranuclear palsy (PSP). The ORION Phase 3 trial 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 AMX0035 / RELYVRIO® / ALBRIOZA™ AMX0035 is an oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol (known as ursodoxicoltaurine outside of the U.S.). It is approved as RELYVRIO® to treat amyotrophic lateral sclerosis (ALS) in adults in the U.S. and approved with conditions as ALBRIOZA™ for the treatment of ALS in Canada. AMX0035 is being studied for the potential treatment of other neurodegenerative diseases, and Amylyx is exploring its treatment in other populations and regions. The formulation of RELYVRIO, ALBRIOZA, and AMX0035 is identical. RELYVRIO® (sodium phenylbutyrate and taurursodiol) Safety Information for United States WARNINGS AND PRECAUTIONS Risk in Patients with Enterohepatic Circulation Disorders, Pancreatic Disorders, or Intestinal Disorders RELYVRIO contains taurursodiol, which is a bile acid. In patients with disorders that interfere with bile acid circulation, there may be an increased risk for worsening diarrhea, and patients should be monitored appropriately for this adverse reaction. Pancreatic insufficiency, intestinal malabsorption, or intestinal diseases that may alter the concentration of bile acids may also lead to decreased absorption of either of the components of RELYVRIO. Because different enterohepatic circulation, pancreatic, and intestinal disorders have varying degrees of severity, consider consulting with a specialist. Patients with disorders of enterohepatic circulation (e.g., biliary infection, active cholecystitis), severe pancreatic disorders (e.g., pancreatitis), and intestinal disorders that may alter concentrations of bile acids (e.g., ileal resection, regional ileitis) were excluded from the study; therefore, there is no clinical experience in these conditions. Use in Patients Sensitive to High Sodium Intake RELYVRIO has a high salt content. Each initial daily dosage of 1 packet contains 464 mg of sodium; each maintenance dosage of 2 packets daily contains 928 mg of sodium. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of RELYVRIO and monitor appropriately. ADVERSE REACTIONS The most common adverse reactions (at least 15% and at least 5% greater than placebo) with RELYVRIO 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 3 weeks of treatment. Please click here for RELYVRIO Full U.S. Prescribing Information. About Amylyx Pharmaceuticals Amylyx Pharmaceuticals, Inc. is committed to supporting and creating more moments for the neurodegenerative disease community through the discovery and development of innovative new treatments. Amylyx is headquartered in Cambridge, Massachusetts and has operations in Canada, EMEA, and Japan. For more information, visit amylyx.com and follow us on LinkedIn and X, (formerly Twitter). 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, Amylyx’ expectations regarding: interactions with regulatory authorities; the continued availability of RELYVRIO/ALBRIOZA for people living with ALS while such interactions are ongoing; the pausing of promotion of RELYVRIO/ALBRIOZA; pathways for continued access for patients if RELYVRIO/ALBRIOZA are withdrawn from the market; the possibility for Amylyx to voluntarily withdraw RELYVRIO/ALBRIOZA from the market; the continued evaluation of AMX0035 in other neurodegenerative diseases, including the timing for expected data readouts in the ORION and HELIOS studies; and the evidence of biological activity of AMX0035 in Wolfram syndrome. Any forward-looking statements in this press release and related comments in the Company's 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 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 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.