Optic Atrophy

- Dr. Zeiher brings more than 20 years of drug development experience in areas with serious unmet treatment needs at companies including Astellas Pharma, Pfizer, Eli Lilly and Company, and Merck CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX) (“Amylyx” or the “Company”) today announced the addition of Bernhardt G. Zeiher, MD, FCCP, FACP, to its Board of Directors (“Board”). Dr. Zeiher brings more than 20 years of drug development experience where, in his various roles, he oversaw the approval of 15 new treatments that addressed people’s unmet needs in serious diseases with few to no treatment options. Most recently, he served as Chief Medical Officer (“CMO”) of Astellas Pharma, where he led early- and late-stage drug development, medical and regulatory affairs, pharmacovigilance, and quality assurance. “This is a pivotal time for Amylyx, and we are thrilled to welcome Dr. Zeiher to our Board to share his perspectives and expertise as the company continues to build a pipeline supporting our collective mission to one day end the suffering of neurodegenerative diseases,” said George M. Milne, Jr., PhD, Chairman of Amylyx’ Board. “Dr. Zeiher's insights of the intricacies and complexities of drug development and innovation in diseases with clear unmet need will be valuable as we continue to serve neurodegenerative disease communities impacted by these devastating diseases.” Dr. Zeiher is a recognized industry leader who spent more than 10 years at Astellas Pharma, holding multiple roles of increasing responsibility in the drug development division, leading up to his role as CMO from 2018 to 2022. Prior to his time at Astellas, Dr. Zeiher held various roles leading drug development at other pharmaceutical companies including Pfizer, Eli Lilly and Company, and Merck. Dr. Zeiher also practiced medicine at a tertiary medical center in Indianapolis and has held a range of board appointments since 2014, including positions at PhRMA Biomedical Advisory Committee, TransCelerate Biopharma, Biotechnology Innovation Organization, Astellas Global Health Foundation, and most recently, Entrada Therapeutics, which he joined in 2023. “We are seeing a transformation in neurodegenerative diseases, both in potential new treatments and what we’re learning through research, and I believe Amylyx is a catalyst in that change,” said Dr. Zeiher. “The company’s community-centric values, steadfast commitment to following the science, and beyond-therapy approaches and support for the neurodegenerative disease community are a few examples of why I am excited for the future and what we can accomplish to support those living with these devastating diseases and their loved ones.” “Dr. Zeiher brings to the Board his distinguished drug development background in overseeing the approval of 15 medicines, and his first-hand experience as a physician. On behalf of the entire Amylyx team, we are delighted to welcome him onboard as we continue to advance our mission to one day end the suffering caused by neurodegenerative diseases,” said Joshua Cohen and Justin Klee, Co-CEOs of Amylyx. “We have several important milestones that we’re working toward this year where Dr. Zeiher’s expertise will be key, including our goal to bring our antisense oligonucleotide AMX0114, developed in-house, to the clinic for ALS, continuing to research the potential of AMX0035 in diseases like Wolfram syndrome and progressive supranuclear palsy, and sharing additional insights, learnings, and next steps from our Phase 3 PHOENIX trial in ALS.” Dr. Zeiher received a B.S. in biology from the University of Toledo and an MD from Case Western Reserve University School of Medicine. He completed his internal medicine residency and chief residency at University Hospitals of Cleveland and then finished his physician training as a Pulmonary and Critical Care Fellow at University of Iowa Hospitals and Clinics. 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 known as 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, the Company’s expectations of contributions from its board of directors; the Company’s beliefs regarding the benefits of AMX0035 in neurodegenerative diseases; expectations regarding the continued research of AMX0035 in progressive supranuclear palsy and Wolfram syndrome; the Company’s potential announcement of additional insights, learnings, and next steps from the Phase 3 PHOENIX trial; the Company’s expectations with respect to its progress through IND-enabling studies of AMX0114; the Company’s expectations with respect to its early-stage ALS diagnostic test; and expectations regarding the Company’s longer-term strategy. 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’ filings with the Securities and Exchange Commission (“SEC”), including its 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. Subject to any obligations under applicable law, 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.

Rate of visual improvement (Clinically Relevant Recovery, or CRR) among patients treated with LUMEVOQ® gene therapy is greater than that of idebenone-treated patients and untreated patients First set of meta-analyses to compare visual outcomes in Leber Hereditary Optic Neuropathy (LHON) patients with the ND4 mutation only PARIS--(BUSINESS WIRE)-- Regulatory News: This press release features multimedia. View the full release here: Figure 1. Visual Recovery (CRR from Nadir) Among ND4 LHON Patients – Results from Three New Meta-Analyses (Graphic: Business Wire) GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced initial results of new meta-analyses in Leber Hereditary Optic Neuropathy (LHON), which show those treated with LUMEVOQ® (GS010; lenadogene nolparvovec) gene therapy experienced a rate of visual recovery greater than that of idebenone-treated patients and untreated (natural history) patients. The meta-analyses are the first to focus solely on patients with the m.11778G>A ND4 mutation, which is the most common mutation and one with a poor visual prognosis1. Figure 1. Visual Recovery (CRR1 from Nadir2) Among ND4 LHON Patients – Results from Three New Meta-Analyses3,4 (See Figure 1) The meta-analyses depict a gradient of efficacy of visual recovery with LUMEVOQ® intravitreal gene therapy resulting in greater recovery rates than that of idebenone treatment, and both greater than that in the natural history of the disease. This gradient of recovery, based on the CRR measure of visual improvement, is observed at both eye level and patient level (response in one or both eyes). There is no overlap in confidence intervals when LUMEVOQ® is compared to idebenone and to natural history, indicating a positive difference in visual outcomes. The results were presented at the 2024 annual meeting of the North American Neuro-Ophthalmology Society (NANOS) and will also be presented at other major ophthalmology, neurology and neuro-ophthalmology medical conferences in Europe and the US later this year. Dr. Nancy J. Newman, LeoDelle Jolley Professor of Ophthalmology and Neurology at the Emory University School of Medicine in Atlanta, United-States, presented the findings at NANOS 2024. She noted, “This study is very important in order to compare these therapies’ abilities to achieve equivalent end-point metrics. It is clear that the degree of efficacy of the gene therapy was greater than the other currently available options of no treatment and idebenone use as previously administered in studies.” Based on the pre-defined statistical analysis plan, the three meta-analyses were performed on three groups of ND4-LHON patients according to therapy: LUMEVOQ® gene therapy one-time intravitreal injection, idebenone therapy and no treatment (natural history). To be included in the meta-analyses, studies had to satisfy a number of criteria that ensured comparability: for example, at least 3 data points per eye, information on the type of mutation with inclusion of ND4 patients only, and availability of visual outcomes data such as CRR. Clinically Relevant Recovery (CRR) is an accepted criterion of clinically meaningful visual improvement in LHON patients6 and could be extracted from all three patient samples. The final set of qualifying studies consisted of five natural history studies (173 patients), six idebenone studies (201 patients) and three LUMEVOQ® studies (174 patients). “The meta-analyses formalize the patient testimonies we have received that attest to the difference LUMEVOQ can make in patients’ lives: this treatment transforms the natural history of the disease,” said Laurence Rodriguez, Chief Executive Officer of GenSight. “The team is working hard to make sure that patients and clinicians facing the visual emergency that is LHON have access to an efficacious treatment.” The Company is currently engaging with authorities in the US, EU, and UK to align on the regulatory path for LUMEVOQ®. The Company aims to restart the Early Access Program (AAC) in France in Q3 2024. Follow-up of patients in the Phase III REFLECT study of LUMEVOQ® is ongoing, with topline results at Year 4 of follow-up expected this month. About GenSight Biologics GenSight Biologics S.A. is a clinical-stage biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics’ pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. GenSight Biologics’ lead product candidate, GS010, is in Phase III trials in Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease that leads to irreversible blindness in teens and young adults. Using its gene therapy-based approach, GenSight Biologics’ product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery. About Leber Hereditary Optic Neuropathy (LHON) Leber Hereditary Optic Neuropathy (LHON) is a rare maternally inherited mitochondrial genetic disease, characterized by the degeneration of retinal ganglion cells that results in brutal and irreversible vision loss that can lead to legal blindness, and mainly affects adolescents and young adults. LHON is associated with painless, sudden loss of central vision in the 1st eye, with the 2nd eye sequentially impaired. It is a symmetric disease with poor functional visual recovery. 97% of subjects have bilateral involvement at less than one year of onset of vision loss, and in 25% of cases, vision loss occurs in both eyes simultaneously. About LUMEVOQ® (GS010; lenadogene nolparvovec) LUMEVOQ® (GS010; lenadogene nolparvovec) targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a mitochondrial targeting sequence (MTS) proprietary technology platform, arising from research conducted at the Institut de la Vision in Paris, which, when associated with the gene of interest, allows the platform to specifically address defects inside the mitochondria using an AAV vector (Adeno-Associated Virus). The gene of interest is transferred into the cell to be expressed and produces the functional protein, which will then be shuttled to the mitochondria through specific nucleotidic sequences in order to restore the missing or deficient mitochondrial function. “LUMEVOQ” was accepted as the invented name for GS010 (lenadogene nolparvovec) by the European Medicines Agency (EMA) in October 2018. LUMEVOQ® (GS010; lenadogene nolparvovec) has not been registered in any country at this stage. _________________________ 1 Newman et al: J Neuro-Ophthalmol 2020 Dec;40(4):547-557. 2 “Clinically Relevant Recovery”, or CRR, denotes an improvement in Best-Corrected Visual Acuity (BCVA) that satisfies one of two conditions: (1) A 10-letter (≥0.2 LogMAR) improvement for an on-chart starting visual acuity. (2) Improvement from “off-chart” to “on-chart” (≤1.6 LogMAR). 3 Nadir = lowest observation of visual acuity between baseline and time point of interest. 4 Three meta-analyses pre-definedin a statistical analysis plan 5 Sources of data: For idebenone and natural history data, systematic review of the literature and available clinical/regulatory reports on ND4 LHON patients; for Lumevoq, all phase 3 studies (RESCUE/RESTORE, REVERSE/RESTORE and REFLECT). 6 Carelli et al: J Neuro-Ophthalmol 2017; 0: 1-11 View source version on businesswire.com: Contacts GenSight Biologics Chief Financial Officer Ivan Tortet itortet@GENSIGHT-BIOLOGICS.com LifeSci Advisors Investor Relations Guillaume van Renterghem gvanrenterghem@lifesciadvisors.com +41 (0)76 735 01 31 Source: GenSight Biologics S.A. Smart Multimedia Gallery Photo Figure 1. Visual Recovery (CRR from Nadir) Among ND4 LHON Patients – Results from Three New Meta-Analyses (Graphic: Business Wire) Logo View this news release and multimedia online at:

An Amylyx Pharmaceuticals amyotrophic lateral sclerosis drug that won a controversial FDA approval based on mid-stage clinical trial results has failed to meet all of the goals of a larger Phase 3 clinical trial, putting the future of the drug and the company in question. According to preliminary results announced Friday, the drug, Relyvrio, was not better than a placebo at slowing progression of the neuromuscular disorder. The study’s primary endpoint was to show a change in score according to a rating scale used to assess function in ALS patients. Cambridge, Massachusetts-based Amylyx said this result was not statistically significant. The drug also did not achieve statistical significance on secondary goals that include measures of breathing function and quality of life. Detailed results were not disclosed, but the company said data from the clinical trial will be presented at an upcoming medical meeting and published in a medical journal later this year. In the near term, the company has set an eight-week timeline to determine its next steps for Relyvrio. Those steps could include voluntarily withdrawing the drug from the market, co-CEO Justin Klee said, speaking during a Friday conference call. To inform this decision, Klee said the company will share the topline data with the FDA and Health Canada as well as the ALS community. “As we consider our plans, we will be led by two key principles: doing what is right for people living with ALS informed by regulatory authorities and the ALS community, and doing what the science tells us,” Klee said. Shares of Amylyx opened Friday at $2.99 apiece, down more than 82% from Thursday’s closing price. Relyvrio is a fixed-dose combination of two compounds, each targeting a different neurodegenerative disease pathway. Hitting both pathways is intended to reduce cellular stress that contributes to neuronal cell death. The drug achieved positive results in a 137-patient placebo-controlled Phase 2 study that was the basis for its 2022 approval. The FDA had initially asked Amylyx to conduct a larger Phase 3 study to support a regulatory submission. But in explaining its decision to approve Relyvrio based on a single Phase 2 trial, the FDA said it was exercising “regulatory flexibility” due to the life-threatening nature of the disease, which has few treatment options. Relyvrio’s approval was a traditional approval, not an accelerated one. Accelerated approvals require a post-marketing confirmatory clinical trial. But Amylyx remained committed to completing the Phase 3 study, expecting the additional data would be needed in other markets (ahead of the FDA decision, the Amylyx drug was approved in Canada, where it is marketed as Albrioza; European authorities last year issued a negative opinion on drug’s application). During the advisory committee preceding the FDA decision, Klee said Amylyx would withdraw Relyvrio from the market if it failed the larger clinical trial. The Phase 3 study had a design similar to the Phase 2 study and it used the same clinical trial goals. But with four times as many patients evaluated for twice as long, this study was better-powered to detect the drug’s effects. In addition to the measures of function, the study had the additional goal of measuring overall survival. Co-CEO Joshua Cohen said survival data are not yet mature. While detailed results for the primary and secondary endpoints remain undisclosed, Klee said they speak to the heterogeneity of ALS—a single disease can be driven by multiple causes. The results also speak to the challenges of neurodegenerative disorders broadly, he added. Amylyx has been evaluating whether Relyvrio’s approach to protecting neurons can also treat other neurodegenerative diseases. A Phase 3 test is ongoing in progressive supranuclear palsy; preliminary data are expected in 2025 or 2026. A Phase 2 study in Wolfram syndrome is expected to yield preliminary data in the second quarter of this year. The Amylyx pipeline also includes AMX0114, an antisense oligonucleotide targeting a gene that encodes an enzyme associated with neurodegeneration. Cohen said the company hopes to advance this program to the clinic in the second half of this year. In 2023, Relyvrio/Albrioza accounted for $380.7 million in revenue, according to Amylyx’s annual report. While the company evaluates its next steps. the product will continue to be available to patients in the U.S. and Canada, Klee said. Amylyx will no longer promote the drug, but the company’s patient support services will remain in place. Amylyx completed 2023 with $371 million in cash. Chief Financial Officer Jim Frates said Amylyx has the financial resources to focus on its earlier-stage programs, but that work may be under a different company structure. He declined to elaborate, saying “now is not right time to give clear plans.” Image: koto_feja, Getty Images