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AMX0035 Continues to Stabilize and Improve Wolfram Syndrome at 48 Weeks, Phase 2 HELIOS Trial Shows
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Key Takeaways
- AMX0035 showed safety and sustained glycemic control improvements in Wolfram syndrome over 48 weeks, with significant C-peptide response and HbA1c level changes.
- Most participants reported meaningful improvements in Wolfram syndrome-related symptoms, including vision, bladder control, and insulin-requiring diabetes.
New data from the HELIOS trial shows AMX0035 improves glycemic control and stabilizes symptoms in Wolfram syndrome, paving the way for future studies.
Fumihiko Urano, MD, PhD
Newly announced 48-week data from the phase 2 HELIOS trial (NCT05676043), an open-label study of AMX0035 (Amylyx Pharmaceuticals) in patients with Wolfram syndrome, revealed that the agent was safe, and resulted in sustained improvements or stabilization in glycemic control during that time. The company noted that these data will be included in discussions with the FDA on a phase 3 trial further testing the drug’s therapeutic potential.1,2
In this single-site, single-arm trial, treatment with AMX0035, a combination of sodium phenylbutyrate [PB] and taurursodiol, led to significant improvements in the primary end point of C-peptide response, as measured by area under the curve (AUC) from 0-120 minutes during a Mixed Meal Tolerance Test (MMTT). The per-protocol group (PPG), which comprised 11 patients, had a mean change of 20.2 min*ng/mL (SE, 11.2) from baseline to week 24, and a +34.5-minute ng/mL (SE, 13.0; P = .0263) change from baseline to week 48 (n = 10).
"The results of the Phase 2, open-label HELIOS trial continue to demonstrate that AMX0035 has the potential to favorably alter the trajectory of Wolfram syndrome, a progressive disorder with no approved treatment options. The consistency of the Week 48 results across multiple measures of disease progression that meaningfully impact the daily lives of those living with Wolfram syndrome, including pancreatic function, glycemic control, and vision, reinforce the previously reported Week 24 findings," Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine at Washington University School of Medicine in St. Louis, said in a statement.1 "Additionally, the majority of participants reported meaningful improvement in at least one Wolfram syndrome-related symptom during interviews, underscoring the real-world importance of these results."
Wolfram syndrome is a rare genetic disorder characterized by a combination of diabetes mellitus, optic atrophy, and hearing loss, often accompanied by additional neurological and psychiatric symptoms. The syndrome is estimated to affect around 1 in 500,000 individuals, though its prevalence may be higher in certain populations. AMX0035, a combination therapy, was previously approved for the treatment of amyotrophic lateral sclerosis (ALS); however, the drug was voluntarily withdrawn in 2024 following disappointing results from a confirmatory phase 3 study. Since then, the agent entered trials of Wolfram and tauopathies like progressive supranuclear palsy.
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The latest data builds on previously announced positive results at 24 weeks, the midpoint of the study. Of note, the long-term data at week 48 included 10 participants in the PPG with genetically confirmed Wolfram syndrome, as 1 patient was excluded from the PPG for not meeting the study’s inclusion criteria. For the per-protocol population, HbA1c levels were decreased by –0.16% (SE, 0.13) at 24 weeks and by –0.40% (SE, 0.22; P = .0998) by 48 weeks. Furthermore, the time in target glucose range was increased by 5.7% (SE, 3.9%) after 24 weeks and by 9.6% (SE, 5.8%; P = .1350) at 48 weeks.
Additional data showed that 8 of the 11 per-protocol participants had improved or stable visual acuity in their best eye from baseline to the latest available time point. Best corrected visual acuity in that eye was decreased by –0.08 (SE, 0.08; P = .3080) at week 48 in the PPG. Of the remaining participants, 1 was stable in 1 eye, and 2 worsened from baseline to week 24, but stabilized from week 24 to 48.
After 24 weeks, in-study interviews with patients showed that most (9 of 11) reported improvements in at least 1 Wolfram syndrome-related symptom with all noting the change being meaningful in at least 1 symptom. Positive changes were observed across issues like vision, bladder control, insulin-requiring diabetes, fatigue, problems swallowing, and headaches/migraines. In addition to being well tolerated with no serious adverse events (AEs), AMX0035 led to 100% of patients meeting responder criteria by self and clinician assessment at week 24 and 48.
In terms of safety, all treatment-emergent AEs were mild or moderate, with the most being diarrhea (58.3% in intent-to-treat; n = 10). Dose reduction or drug interruptions due to TEAEs were present in 25% of patients, and no TEAEs led to study discontinuation. These safety data further reinforced the profile of AMX0035 following the 24-week interim findings announced in April 2024.
"These long-term results reinforce both our positive data at Week 24 and our belief in the potential of AMX0035 to stabilize and even improve key manifestations of Wolfram syndrome, a relentlessly progressive disorder,” Camille L. Bedrosian, MD, chief medical officer at Amylyx, said in a statement.1 "With these findings, we are focused on working closely with the FDA to inform the design of a Phase 3 trial. Our ultimate aim is to address the unmet needs that are still a reality for people living with this devastating disorder. We want to thank the Wolfram syndrome community for their continued collaboration and support."
