The recently launched phase 2 HELIOS clinical trial from Amylyx Pharmaceuticals, aims to explore the potential of AMX0035 (sodium phenylbutyrate and taurursodiol) in treating Wolfram syndrome, a rare and complex genetic disorder.
In a recent interview, Drs. Lahar Mehta and Fumihiko Urano discussed the AMX0035 Wolfram syndrome trial design, objectives and implications for future research in Wolfram syndrome.
Mehta is head, global clinical development at Amylyx Pharmaceuticals and Urano is principal investigator of the HELIOS clinical trial. He is also a professor of medicine and of pathology and immunology in the division of endocrinology, metabolism and lipid research at the Washington University School of Medicine.
Urano and his team informed the study’s design and outcome measures, drawing from their recently published preclinical data in the Journal of Clinical Investigation Insight. AMX0035, which recently won FDA approval for treating amyotrophic lateral sclerosis (ALS) under the name Relyvrio, is now under investigation for its potential applications in Wolfram syndrome.
By focusing on C-peptide levels during a mixed-meal tolerance test, and the safety and tolerability of AMX0035, the researchers aim to better understand the drug’s potential benefits for patients with this rare condition.
In the following interview, Mehta and Urano delve into the details of the HELIOS clinical trial, sharing insights on the study design, objectives and the potential impact of AMX0035 on the treatment landscape for Wolfram syndrome.
How do investigators plan to account for potential biases in this open-label phase 2 study?
Dr. Lahar Mehta: HELIOS is an initial open label, exploratory, proof of biology study designed to determine potential impacts of AMX0035 on outcomes, as well as the performance of outcomes over time. In this study, we are primarily interested in the change in these outcomes from baseline. We will use these data to inform and design future clinical trials which may include concurrent placebo controls and/or historical controls.
Dr. Fumihiko Urano: In HELIOS, we are evaluating the effect of AMX0035 on remaining beta cell functions by monitoring C-peptide levels during a 0-240 minutes Mixed-Meal Tolerance test (MMTT), with every participant serving as their own control. The pathology of Wolfram syndrome is the same across different organ systems, so, we are assessing if in adults, pancreatic function can be an indicator of a possible disease modification.
Why were C-peptide levels and safety and tolerability of AMX0035 chosen as primary outcome measures?
Urano: The primary outcome measures for this study, which include C-peptide levels during a MMTT, and the safety and tolerability of AMX0035, were chosen because they are thought to be the most appropriate short-term indicators of efficacy for AMX0035 in treating Wolfram Syndrome. C-peptide levels are expected to change within this timeframe. By focusing on these outcome measures, we aim to gain a better understanding of AMX0035’s potential benefits for patients with Wolfram syndrome.
Mehta: The study population in HELIOS is >/=17 years of age where we expect to focus on sensitive biomarkers of beta cell function that can change over a 6-month period. Due to the rarity of the condition, there is a lack of sufficient natural history to allow comparison with other endpoints. We are applying lessons learned from Dr. Urano’s earlier study with dantrolene in Wolfram syndrome. While we will also be looking at several additional exploratory endpoints, C-peptide levels represent some of the most powered endpoints and are also potential endpoints of regulatory interest. The findings from the AMX0035 Wolfram syndrome trial are being applied to the HELIOS study, with the aim of advancing progress in collaboration with the Wolfram syndrome community.
How was the sample size determined, and what challenges are anticipated in recruiting participants for this rare disease trial?
Urano: The study was powered based on MMTT for residual β-cell functions of the pancreas. The primary efficacy variable will be the mean change from Baseline at Day 1 pre-dose to the Week 24 assessment of C-peptide (ΔC-peptide) using a 0-240 minutes MMTT. The sample size is estimated based on enrollment feasibility with 15% drop out rate, and the level of precision the study would provide around the estimated mean change from baseline in ΔC-peptide at Week 24 (ΔΔC-peptide).
We acknowledge the challenges in recruiting participants for a rare disease trial, but we are optimistic and do not anticipate recruitment challenges, particularly as there remains a significant unmet need for people living with Wolfram syndrome in terms of new, safe and effective treatment options.
How do past preclinical data and findings inform the design of the HELIOS study?
Mehta: As this is a proof of biology study, we will want to ensure that the study population meets inclusion/exclusion criteria so that the study can detect a change in the primary endpoint. Hence, we want to minimize the signal to noise ratio. Topline results, anticipated in 2024, will inform future powering, design and endpoints for potential follow up studies.
While this is a proof of biology study, we are leveraging past preclinical data to inform the design. Dr. Urano and members of his team from the Washington University School of Medicine in St. Louis, in collaboration with Amylyx, recently published preclinical data exploring the potential of AMX0035 as a novel therapeutic approach for WS in the peer-reviewed Journal of Clinical Investigation Insight. These data characterized a pathogenic variant in the WFS1 gene (WFS1 c.1672C>T, p.R558C), identified a platform for further genotype-phenotype analysis, and provided initial proof-of-concept for the therapeutic development of AMX0035 in WS. The study demonstrated that iPSC-derived WS models can provide a model of genotype-phenotype relationships that correlate with clinical observations. These findings are being applied to the HELIOS study.
Filed Under: clinical trials, Drug Discovery, Drug Discovery and Development, Medical Design & Outsourcing, Orphan Drugs, Rare disease
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