Wolfram Syndrome

Today, a brief rundown of news from PTC Therapeutics and Novartis, as well as updates from Amylyx Pharmaceuticals and Intercept Pharmaceuticals that you may have missed.Europes drug regulator is standing firm in its decision not to renew the marketing permit for Translarna, a treatment developed by PTC Therapeutics for a rare muscle-wasting disease. The European Medicines Agency initially authorized Translarna in 2014, with the condition PTC gather more data to show the drug is effective in certain cases of Duchenne muscular dystrophy. But after four reviews of the evidence now available, the EMA concluded Translarnas effectiveness still has yet to be confirmed. The agency will send its verdict to the European Commission, which will make the final decision on the drugs status for EU countries. Jacob BellNovartis is paying China-based Chengdu Baiyu Pharmaceutical $70 million for global licensing rights to a single small molecule cancer drug. The deal, which includes up to $1.1 billion in additional payments based on achievement of development and commercial milestones, doesnt specify any biological or disease targets for the drug. Chengdu Baiyu said it is has “focused research on the core pharmacological components of Ginkgo biloba including development of botanical drugs. It has six cancer-related experimental drugs in its pipeline. Jonathan GardnerShares of Amylyx Pharmaceuticals oscillated Thursday with the release of data for one the companys two main drugs. Amylyx said the drug, known as AMX0035, succeeded in a small study of patients with Wolfram Syndrome, a rare, inherited condition that damages organs like the eyes, brain and pancreas. The company now plans to meet with stakeholders, including the Food and Drug Administration, for input on Phase 3 testing, and expects to provide updates on that program next year. AMX0035 had been cleared as a treatment for ALS, but was pulled from the market in April after an important follow-on trial found it wasnt substantially better than a placebo at treating the nerve-destroying disorder. Jacob BellThe Food and Drug Administration has delayed a decision on full approval of Intercept Pharmaceuticals Ocaliva in primary biliary cholangitis, a condition for which the Alfasigma subsidiary won accelerated approval in 2016. The FDA delayed its Oct. 15 decision deadline, but didnt provide a new action date, Intercept said in a statement. The delay follows a negative vote by a panel of independent FDA advisers on Sept. 13. That committee concluded confirmatory trials intended to justify full approval didnt provide enough evidence Ocaliva prevented liver transplants and death in people with the rare disorder. Ocaliva is Intercepts only drug, and generated $286 million in sales in 2022, Intercepts last full year as an independent company. Jonathan GardnerThe Australian agency that regulates pharmaceuticals has decided not to clear for market Leqembi, the closely watched Alzheimers disease drug from Eisai and Biogen. In a statement Wednesday, the Therapeutic Goods Administration said that, based on the available evidence, Leqembis safety risks outweigh its potential benefits. Eisai plans on asking the agency to reconsider its decision. While its approved in the U.S. for people in an early stage of Alzheimers, Leqembi has been met with resistance in Europe and, now, Australia, where estimates hold there are more than 400,000 people with dementia. Jacob BellAmicus has staved off competition for its biggest seller, Fabry disease drug Galafold, until 2037 under the terms of a settlement with Teva Pharmaceuticals. Amicus granted Teva a license to begin selling a generic version of Galafold on Jan. 30 of that year, and the two sides have agreed to drop all federal litigation over Galafold patents. The company continues to fight a second generic manufacturer, Aurobindo, in court. A stay is in place on litigation with a third generic manufacturer, Lupin. Jonathan Gardner '

Amylyx is trying to move forward with its effort to turn its former ALS drug into a treatment for other conditions, and data released Thursday build on a small interim dataset from earlier this year that showed signs of improving outcomes in a rare genetic disease. Wolfram syndrome usually manifests in childhood and patients experience symptoms typically seen in diabetes (high blood sugar, high urine production) that may progress to blindness and deafness. The Phase 2 study of Amylyx’s drug, AMX0035, measured whether patients’ average levels of an amino acid called C-peptide increased after 24 weeks. C-peptide response rates are traditionally used to determine the health of diabetes patients’ pancreatic cells and how well they function, according to the NIH . In order to look at how patients responded to AMX0035, Amylyx asked 12 patients to take a “mixed meal tolerance test,” in which patients ingest a “standardized liquid meal” in the mornings with their C-peptide responses measured over time. Usually, C-peptide responses peak after 30 minutes in non-diabetic individuals, but Wolfram syndrome patients’ levels peak more slowly, after about 120 minutes. After 12 patients took AMX0035 for 24 weeks, the drug improved C-peptide responses at the 120-minute mark by an average of 3.8 minutes by ng/mL compared to baseline levels. Response rates continued to improve at 36 and 48 weeks, Amylyx said. But one of the patients did not meet the trial’s inclusion and exclusion criteria, possessing just one of the two alleles necessary to categorize the disease. Amylyx also presented an 11-patient dataset removing this individual, showing improved C-peptide responses at the 120-minute mark of an average of 20.2 minutes by ng/mL compared to baseline levels. In an investor call Thursday afternoon, co-CEO Josh Cohen said the company would look to implement stricter genetic screening measures in a Phase 3 trial to prevent this error from happening again. The company is continuing to discuss what a study might look like, including whether it will seek accelerated approval, and will reveal more details next year. AMX0035 was previously approved to treat ALS under the brand name Relyvrio. The drug eventually failed a Phase 3 study and forced Amylyx to voluntarily withdraw it from the market. That failure caused a huge plunge in the company’s stock and led to layoffs. Shares $AMLX were up as much as 7% Thursday.

- Improvement observed in pancreatic function, as measured by C-peptide response, following 24 weeks of treatment with AMX0035; worsening is typically expected with disease progression based on natural history studies of Wolfram syndrome - Longer-term data for all participants who have completed Week 36 and Week 48 assessments showed sustained improvement over time - Improvements or stabilization observed across all secondary endpoints, including measures of glycemic control, vision, and patient- and clinician-reported impressions of overall disease burden - AMX0035 was generally well-tolerated in all participants - Amylyx plans to meet with the FDA and other stakeholders to inform a Phase 3 program and expects to provide an update in 2025 - Topline data to be presented during a live webcast today at 1:30 p.m. ET CAMBRIDGE, Mass.--(BUSINESS WIRE)-- $AMLX -- Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX) (“Amylyx” or the “Company”) today announced positive topline data from the Phase 2 open-label HELIOS clinical trial of AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) in 12 adults living with Wolfram syndrome. Wolfram syndrome is a rare, progressive, monogenic disease impacting approximately 3,000 people in the U.S. HELIOS showed improvement in pancreatic function, as measured by C-peptide response after 24 weeks of treatment with AMX0035, the study’s primary efficacy endpoint, in contrast to the expected decrease in pancreatic function with disease progression. Similar overall improvements or stabilization were observed across all secondary endpoints, including hemoglobin A1c (HbA1c), time in target glucose range assessed by continuous glucose monitoring, and visual acuity. Patient- and physician-reported global impressions of change showed disease stability or improvement in all participants, meeting prespecified responder criteria. In addition, longer-term data for all participants who completed Week 36 (n=10) and Week 48 (n=6) assessments showed sustained improvement over time. Data from HELIOS are being presented today at the International Society for Pediatric and Adolescent Diabetes (ISPAD) 50 th Annual Congress and during a webcast held by the Company. “The topline results of HELIOS indicate that AMX0035 has the potential to favorably change the trajectory of Wolfram syndrome, a progressive disease with no approved treatment options. These results build on the interim data presented in April of this year and show an improvement on multiple measures of pancreatic beta cell function, glycemic control, and vision,” said Fumihiko Urano, MD, PhD, 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. “In addition, the participants who reached their Week 36 or Week 48 assessments demonstrated sustained improvement over baseline in C-peptide and HbA1c, which are objective laboratory measures of pancreatic function and glycemic control. These data are encouraging since Wolfram syndrome is a progressive disease.” The analysis performed includes Week 24 data for all 12 participants and data for all participants who completed their Week 36 (n=10) and Week 48 (n=6) assessments as of the data cutoff. The primary efficacy endpoint of the trial measures change from baseline in C-peptide, an established, objective laboratory measure of pancreatic beta cell function and a surrogate marker of glycemic control, assessed using a mixed meal tolerance test (MMTT) at Week 24. Secondary and exploratory outcomes include the assessment of other diabetic measures and other domains affected by the disease. HELIOS showed improvements in its primary endpoint of C-peptide response with a change from baseline to Week 24 at 120 minutes of +3.8 minutes*ng/mL (min*ng/mL) [standard error (SE): 19.3] in the Intent to Treat group (N=12) and +20.2 min*ng/mL [SE: 11.2] in the Per Protocol group (N=11). In addition, as outlined in the table below, participants receiving AMX0035 had improved glycemic control, as measured by markers of glucose metabolism; improved visual acuity in some participants, as measured by the Snellen chart; and improvement or stabilization of the disease, as measured by the Clinician Reported Global Impression of Change (CGIC) and Patient Reported Global Impression of Change (PGIC). Week 24 ITT (N=12) Week 24 Per Protocol † (N=11) Week 36 (n=10) Week 48 (n=6) C-Peptide Response (min*ng/mL) mean change in AUC from baseline over 120 minutes †† +3.8 (SE: 19.3) +20.2 (SE: 11.2) +30.7 (SE: 9.7) +36.7 (SE: 19.6) Hemoglobin A1c (%) change from baseline -0.09 (SE: 0.14) -0.16 (SE: 0.13) -0.35 (SE: 0.18) -0.30 (SE: 0.31) Absolute Time in Target Glucose Range (%) change from baseline +5.2 (SE: 3.6) +5.7 (SE: 3.9) +12.3 (SE: 4.0) +5.8 (SE: 8.9) Mean Exogenous Insulin Dose (units/kg/2 weeks) change from baseline -0.01 -0.01 0.01 0.02 Visual Acuity (LogMAR) change from baseline -0.04 (SE: 0.06) -0.04 (SE: 0.06) Not Collected at this Time Point -0.11 (SE: 0.12) Clinician Report Global Impression of Change (CGIC) % meeting responder criteria ††† 100% 100% 100% 100% Patient Reported Global Impression of Change (PGIC) % meeting responder criteria ††† 100% 100% 100% 100% † Upon genetic review, one participant did not meet the inclusion/exclusion criteria for HELIOS. This participant was found to have an autosomal recessive mutation confirmed to be pathogenic on just one of the two alleles and variant of uncertain significance on the other allele. This participant was within normal range for C-peptide, glycemic measures, and vision suggesting lack of typical Wolfram syndrome phenotype. Data presented with and without this participant who reached Week 24 (Intent to Treat and Per Protocol, respectively). †† In non-diabetic individuals, C-peptide peaks after a meal at approximately ~30 minutes; in Wolfram syndrome, peak is slower but generally was at or before 120 minutes in HELIOS. Area under the curve (AUC) over 120 minutes after meal challenge reflects beta cell response to a meal. Amylyx is currently planning to focus on 120-minute AUC as the C-peptide measure for future studies. ††† HELIOS defines a “responder” on both the CGIC and PGIC as no change or improvement given the progressive nature of Wolfram syndrome. The safety pro AMX0035 in HELIOS was consistent with prior safety data. AMX0035 was generally well-tolerated. All adverse events (AEs) were mild or moderate, and there were no serious AEs related to AMX0035 treatment. The most common AE was diarrhea. “These outcomes indicate that treatment with AMX0035 may result in meaningful improvements across multiple measures of disease progression,” said Camille L. Bedrosian, MD, Chief Medical Officer of Amylyx. “Wolfram syndrome is a progressive disease that is expected to consistently worsen over time, despite best supportive care, because of the underlying endoplasmic reticulum stress and mitochondrial dysfunction that occurs due to mutations in the WSF1 gene. AMX0035 is believed to target both of these critical pathways. In addition, we are encouraged by the sustained improvement observed in all participants who completed Week 36 or Week 48 assessments, and we thank the Wolfram syndrome community for their continued collaboration and support in researching the potential of AMX0035. We continue to engage with stakeholders and plan to meet with the FDA to inform a Phase 3 program.” The FDA and the European Commission granted Orphan Drug Designation to AMX0035 for the treatment of Wolfram syndrome in November 2020 and August 2024, respectively. HELIOS Interim Data in Wolfram Syndrome Virtual Webcast Details Amylyx will host a virtual webcast with management and Fumihiko Urano, MD, PhD, Principal Investigator of the HELIOS clinical trial 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, to discuss topline HELIOS data today, October 17, 2024, at 1:30 p.m. ET. A live webcast of the presentation can be accessed under “Events and Presentations” in the Investor section of the Company’s website, , and will be available for replay for 90 days following the event. About the HELIOS Trial HELIOS ( NCT05676034 ) is a 12-participant, single-site, single-arm, 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. Participants in HELIOS receive AMX0035 for up to 96 weeks followed by a four-week safety follow-up. Primary and secondary outcomes are assessed at Week 24 and at longer-term time points. In September 2022, researchers from Washington University School of Medicine in St. Louis, including Dr. Urano, in collaboration with Amylyx, published preclinical data on AMX0035 in beta cell, neuronal cell, and mouse models of Wolfram syndrome in the peer-reviewed Journal of Clinical Investigation Insight . About Wolfram Syndrome Wolfram syndrome is a rare, monogenic neurodegenerative 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. Genetic and experimental evidence suggests that endoplasmic reticulum (ER) dysfunction is a critical pathogenic component of Wolfram syndrome. The prognosis of Wolfram syndrome is poor, and many people with the disease die prematurely with severe neurological disabilities. 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 targeting endoplasmic reticulum (ER) stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration. We believe that our proprietary combination of PB and TURSO and their complementary mechanisms of action will allow us to synergistically target abnormal cell death to better prevent neurodegeneration than treatment targeted at either mechanism of action alone. AMX0035 is being studied as a potential treatment for Wolfram syndrome and progressive supranuclear palsy, two neurodegenerative diseases. 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 neurodegenerative diseases and endocrine conditions. 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: the potential clinical benefit for AMX0035 to help people living with Wolfram syndrome; and interactions with regulatory authorities. 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’ Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, 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. Contacts Media Amylyx Media Team +1 (857) 799-7274 amylyxmediateam@amylyx.com Investors Lindsey Allen Amylyx Pharmaceuticals, Inc. +1 (857) 320-6244 Investors@amylyx.com