Relyvrio (phenylbutyrate/taurursodiol) / Amylyx, NeoPharm - LARVOL DELTA

An oral drug against decline in the autophagy lysosomal pathway (ALP) and systemic inflammation, two "hallmarks" of ALS/FTD (ALS-MND 2025) - "Background: The two drugs against symptoms of syndromic ALS, riluzole and edavarone were approved in 1995 and 2017...After accelerated approval in 2022, the fixed-dose combination PB-TUDCA (Relyvrio) was withdrawn in Apr 2024 based on negative phase 3 results (2)... HP-beta-CD (HPbCD) has been shown to be effective in models of several NDDs and is in phase 3 against NPC, but the presumed MoA of "depleting cholesterol" (CHO) can cause permanent hearing loss. A reanalysis of GWAS data using a patented discovery platform showed that bCDs act by reducing PLs and SLs (4) and, thus, also ceramides (5), which explains how aCDs (too small to fit CHO), were more effective ex vivo in fibroblasts of patients with seven lysosomal storage diseases (LSDs) and in vivo in a SOD1 ALS model (n = 24, ρ<.0001). Improving lysosomal function via HPaCDs, which reduces endocytosis and, thus, lysosomal load, was hypothesized to improve autophagy by preventing lysosomes from both..."

Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Lysosomal Storage Diseases • Metabolic Disorders • Otorhinolaryngology • Rare Diseases • EIF2B4 • RIPK1

Real-World Clinical Experience With Sodium Phenylbutyrate and Taurursodiol at a Single Amyotrophic Lateral Sclerosis Center in the United States. (PubMed, Eur J Neurol) - "Experience in real-world clinical settings can help supplement trial data with information on the drug performance at various stages of disease progression. Adverse events impacted treatment persistence in routine clinical practice, underscoring the need for vigilant monitoring and tailored supportive interventions to optimize treatment adherence."

Journal • Real-world evidence • Retrospective data • Amyotrophic Lateral Sclerosis • CNS Disorders

Amylyx Pharmaceuticals withdraws FDA approval for Relyvrio treatment. (AInvest)

FDA event • Progressive Supranuclear Palsy

Amylyx Discontinues Investigative Therapy Program In Rare Neurological Disorder (MENAFN news) - "AMX0035 is an oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol. The decision to discontinue the program was made after it did not show differences compared to placebo on primary or secondary outcomes at week 24 in a mid-stage trial. The company will not initiate the late-stage portion of the program, it said."

Discontinued • Progressive Supranuclear Palsy

Latest progress and challenges in drug development for degenerative motor neuron diseases. (PubMed, Neural Regen Res) - "The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis: riluzole, edaravone, AMX0035, and tofersen, with the latter being the most recent to receive approval. Some promising drugs being investigated in preclinical studies, such as ATH-1105, are included in our analysis, and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases. This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs, with the aim of highlighting the latest potentialities for clinical therapy."

IO biomarker • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies

Amylyx Pharmaceuticals Announces Positive Long-Term Results from Phase 2 HELIOS Clinical Trial of AMX0035 in People with Wolfram Syndrome (Businesswire) - P2 | N=12 | HELIOS (NCT05676034) | Sponsor: Amylyx Pharmaceuticals Inc. | "Treatment with AMX0035 from Week 24 to Week 48 also showed sustained improvements or stabilization in glycemic control, as measured by hemoglobin A1c (HbA1c) and time in target glucose range assessed by continuous glucose monitoring, as well as visual acuity. All participants with available measurements met the responder criteria, defined as either improvement or no change, on both the Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change (CGI-C) at Weeks 24 and 48, indicating stability or improvement in their Wolfram syndrome-related symptoms....Safety data were consistent with safety data from prior studies of AMX0035."

P2 data • Genetic Disorders

AMX0035 Mitigates Oligodendrocyte Apoptosis and Ameliorates Demyelination in MCAO Rats by Inhibiting Endoplasmic Reticulum Stress and Mitochondrial Dysfunction. (PubMed, Int J Mol Sci) - "The activation of ER stress and mitochondrial dysfunction pathways following MCAO led to oligodendrocyte damage and apoptosis. AMX0035 can inhibit these pathways, reduce oligodendrocyte apoptosis, and alleviate demyelination, thereby improving PSCI."

Journal • Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • Cardiovascular • Cognitive Disorders • Metabolic Disorders • Solid Tumor • CASP12 • MBP

HELIOS: AMX0035 in Adult Patients With Wolfram Syndrome (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Amylyx Pharmaceuticals Inc. | Trial completion date: Jan 2026 ➔ Dec 2026

Trial completion date • Metabolic Disorders • Nephrology

Amylyx Pharmaceuticals Reports Fourth Quarter and Full Year 2024 Financial Results (Businesswire) - "Unblinded interim analysis of the Phase 2b portion of the Phase 2b/3 ORION trial evaluating AMX0035 for progressive supranuclear palsy (PSP) in the third quarter of 2025. ORION is an operationally seamless Phase 2b/3 clinical trial in people living with PSP. The Phase 2b portion was fully enrolled in January with a total of 139 participants randomized. Amylyx expects safety and efficacy data from an unblinded interim analysis in these participants through Week 24 and will use this data to inform a go/no-go decision on the Phase 3 portion of the trial. Early cohort data from the Phase 1 LUMINA clinical trial of AMX0114 in ALS expected in 2025. LUMINA clinical trial sites were activated in Canada in the beginning of 2025 and are recruiting participants. Amylyx is also working to open U.S. sites for screening, enrollment, and dosing."

P1 data • P2b data • Trial status • Amyotrophic Lateral Sclerosis • Progressive Supranuclear Palsy

Amylyx Pharmaceuticals Reports Fourth Quarter and Full Year 2024 Financial Results (Businesswire) - "Completed a public offering of common stock with net proceeds of approximately $65.5 million, extending the company’s cash runway through the end of 2026; Amylyx plans to share Week 48 data from the ongoing Phase 2 HELIOS trial of AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) in Wolfram syndrome in the coming months; Unblinded interim analysis of the Phase 2b portion of the Phase 2b/3 ORION trial evaluating AMX0035 for progressive supranuclear palsy (PSP) in the third quarter of 2025."

Commercial • P2 data • Genetic Disorders • Progressive Supranuclear Palsy

Amylyx Pharmaceuticals Reports Fourth Quarter and Full Year 2024 Financial Results (Businesswire) - "Completion of enrollment for the pivotal Phase 3 LUCIDITY clinical trial of avexitide in PBH expected in 2025, with a data readout anticipated in the first half of 2026 and, if approved, commercial launch anticipated in 2027....Amylyx plans to share Week 48 data from the ongoing Phase 2 HELIOS trial of AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) in Wolfram syndrome in the coming months. Data from participants at Week 48 and regulatory interactions will inform the design of a Phase 3 trial of AMX0035 in Wolfram syndrome."

Launch • P3 data: top line • Trial status • Genetic Disorders • Hypoglycemia

ALS: A Silent Slayer of Motor Neurons. Traditional Chinese Herbal Medicine as an Effective Therapy. (PubMed, Curr Pharm Des) - "Ongoing investigations explore the potential of neuroprotective drugs like riluzole and edaravone in ALS treatment. Recently approved drugs, Relyvrio (sodium phenylbutyrate and taurursodiol) and Tofersen (Qalsody) have completed the trials, and others are currently undergoing extensive clinical trials. Continuous research and exploration of therapeutic avenues, including gene therapy and neuroprotective treatments, are imperative to address the challenges posed by ALS and other neurodegenerative diseases. Traditional Chinese Medicine (TCM) approaches and clinical trials are being explored for treating ALS symptoms, targeting neuroinflammation, oxidative damage, and muscle weakness, showcasing the potential benefits of integrating traditional and modern approaches in ALS management."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Cognitive Disorders • Gene Therapies • Inflammation

Extension Study Evaluating The Safety And Tolerability of AMX0035 (clinicaltrials.gov) - P3 | N=352 | Completed | Sponsor: Amylyx Pharmaceuticals Inc. | Enrolling by invitation ➔ Completed | N=600 ➔ 352 | Trial completion date: Aug 2026 ➔ Oct 2024 | Trial primary completion date: Mar 2026 ➔ Oct 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

ORION: AMX0035 and Progressive Supranuclear Palsy (clinicaltrials.gov) - P2/3 | N=110 | Active, not recruiting | Sponsor: Amylyx Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Movement Disorders • Parkinson's Disease • Progressive Supranuclear Palsy

Preliminary analysis of treatment combinations in patients with amyotrophic lateral sclerosis enrolled in an US-based administrative claims database (ALS-MND 2024) - "Sodium phenylbutyrate and taurursodiol (PB-TURSO) was FDA-approved in 2022, but voluntarily discontinued in 2024. Tofersen was FDA-approved for patients with ALS with a superoxide dismutase 1 mutation in 2023... Patients with ALS continuously enrolled in Optum's de-identified ClinformaticsV R Data Mart (CDM) from 1 August 2017, through 30 September 2023, were included (intravenous) and Radicava ORSV and grouped based on ALS treatment combination... Patients were grouped based on use of riluzole only (n = 2193) vs. other FDA approved treatment/treatment combinations (n = 967) including Mitsubishi Tanabe Pharma America (MTPA) edaravone, PB-TURSO, riluzole ± edaravone, edaravone ± PB-TURSO, riluzole ± PB-TURSO, or riluzole þ edaravone ± PB-TURSO. Patients were predominantly male (53.5–53.6%), White (72.2–74.4%) and covered by Medicare (68.6–77.8%) rather than commercial insurance."

Claims database • Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders

Canadian regulatory framework and flexibility in the context of rare diseases with unmet medical need such as amyotrophic lateral sclerosis (ALS) (ALS-MND 2024) - "Access to ALS Therapies in Canada: There are currently two available ALS treatments in Canada: RADICAVA (edaravone) and RILUTEK (riluzole)... HC follows rigorous scientific and regulatory processes for drug approval, while exercising flexibility within the regulatory framework to respond to the pressing need for rare diseases therapies, including ALS, for Canadian patients."

Amyotrophic Lateral Sclerosis • CNS Disorders • Rare Diseases

Amylyx Pharmaceuticals Reports Third Quarter 2024 Financial Results (Businesswire) - "Upcoming Expected Milestones: i) The Company plans to initiate the Phase 1 LUMINA clinical trial of AMX0114 in people living with ALS by the end of 2024 or in the beginning of 2025 in Canada...Amylyx expects early cohort data from LUMINA in 2025...ii) Data from an interim analysis of the Phase 2b/3 ORION clinical trial of AMX0035 in progressive supranuclear palsy (PSP) continue to be expected in mid-2025."

P1 data • P2/3 data • Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders • Progressive Supranuclear Palsy

Lessons Learned in Advocating for Access to Therapies in Canada: A Case Study of ALBRIOZA/RELYVRIO (ALS-MND 2024) - "We'll also discuss the implications of Amylyx Pharmaceuticals' recent decision to halt the marketing authorization based on the PHOENIX trial results, highlighting the importance of strong regulatory foundations and ongoing stakeholder engagement. This presentation will share vital lessons from ALBRIOZA's journey and offer insights on how these strategies can shape future global advocacy efforts for ALS/MND therapies."

Case study • Clinical • Amyotrophic Lateral Sclerosis

Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease. (PubMed, Exp Neurol) - "Our results showed that Prp-TDP-43A315T mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD."

Journal • Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Pain • CYP19A1 • CYP3A4 • TARDBP

Amylyx Pharmaceuticals Announces Positive Topline Results from Phase 2 HELIOS Clinical Trial Demonstrating Sustained Improvements with AMX0035 in People Living with Wolfram Syndrome (Businesswire) - P2 | N=12 | HELIOS (NCT05676034) | Sponsor: Amylyx Pharmaceuticals Inc. | "Amylyx plans to meet with the FDA and other stakeholders to inform a Phase 3 program and expects to provide an update in 2025...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...Data from HELIOS are being presented today at the International Society for Pediatric and Adolescent Diabetes...Amylyx will host a virtual webcast....to discuss topline HELIOS data today, October 17, 2024, at 1:30 p.m. ET."

P2 data • Pipeline update • CNS Disorders

The rise and fall of Relyvrio: Lessons learned about how a promising drug for ALS failed (Neuroscience 2024) - "Amylyx has since pulled Relyvrio off the market, and is currently attempting to reposition the active ingredients in Relyvrio - sodium phenylbutyrate and taurursodiol - as a treatment for other, much rarer neurodegenerative diseases: Wolfram Syndrome and Supranuclear Palsy. We explore the nature and ramifications of federal regulatory leniency in drug approval along with the notion of repurposing drugs ineffective for a primary indication as potentially useful for other neurodegenerative diseases as a means of failing to acknowledge that a promising hypothesis could be wrong while at the same time acting to retain profitability."

Amyotrophic Lateral Sclerosis • CNS Disorders

New developments in the diagnosis and management of motor neuron disease. (PubMed, Br Med Bull) - "Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

ORION: A Global Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial of AMX0035 in Progressive Supranuclear Palsy (A35-009) (MDS Congress 2024) - "Updated enrollment status will be presented at the MDS annual meeting. This research was previously presented at the AD/PD 2024 Alzheimer's & Parkinson's Diseases Conference on March 6, 2024."

Clinical • P3 data • Alzheimer's Disease • CNS Disorders • Parkinson's Disease • Progressive Supranuclear Palsy

Role of histone deacetylases and their inhibitors in neurological diseases. (PubMed, Pharmacol Res) - "Additionally, the current pharmacological situation, problems, and developmental prospects of HDAC inhibitors are described. A better understanding of the pathogenic mechanisms of HDACs in the nervous system may reveal new targets for therapeutic interventions in diseases and help to relieve healthcare pressure through preventive measures."

Epigenetic controller • Journal • Review • Alzheimer's Disease • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease

Amylyx Pharmaceuticals Announces Publication of Data Showing the Encouraging Effects of AMX0035 on Cerebrospinal Fluid Biomarkers of Core Alzheimer’s Disease Pathology and Neurodegeneration (Businesswire) - P2 | N=95 | PEGASUS (NCT03533257) | Sponsor: Amylyx Pharmaceuticals Inc. | "Amylyx Pharmaceuticals, Inc...today announced the publication of exploratory analyses on cerebrospinal fluid (CSF) biomarkers from participants with Alzheimer’s disease (AD) from the Phase 2 PEGASUS trial...Of the 95 participants in the intent-to-treat (ITT) cohort of the PEGASUS trial, 67 had CSF samples at baseline and Week 24. Within this CSF subcohort, treatment effects were analyzed for biomarkers spanning multiple pathophysiological processes in AD...The exploratory analyses showed that compared to placebo, AMX0035 reduced levels of p-tau181 and total tau. AMX0035 treatment also reduced levels of synaptic and neuronal degeneration biomarkers in the CSF, specifically neurogranin and FABP3, as well as YKL-40, a biomarker that has been shown to correlate with cortical volume loss and rate of cognitive decline."

Biomarker • P2 data • Alzheimer's Disease • CNS Disorders