AMX0035 Improves Pancreatic Function and Glycemic Control in Wolfram Syndrome, Phase 2 Results Show


All 8 participants met prespecified responder criteria demonstrating either improvement or stabilization of disease according to both the Patient Reported Global Impression of Change and the Clinician Reported Global Impression of Change scales.

Camille L. Bedrosian, MD, chief medical officer, Amylyx

Camille L. Bedrosian, MD

Newly announced interim data from the ongoing phase 2 HELIOS trial (NCT05676034) showed that treatment with AMX0035 (Relyvrio; Amylyx Pharmaceuticals) resulted in clinically meaningful improvements in pancreatic function and glycemic control in patients with Wolfram syndrome, an autosomal recessive neurodegenerative disease.1

HELIOS is a 12-participant, open-label trial designed to assess the effect of AMX0035, an oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol, in adults with Wolfram syndrome. The interim analysis, which included 8 treated participants, showed increases in the primary outcome of total C-peptide response including the 90-minute response at week 24 (change, +15.6 ng*min/mL; 95% CI, 1.3-30.0). This was significant considering progressive decline would be expected on this measure in untreated patients.

Additional data from the analysis revealed that nearly all (7 of 8) patients had at least a 30-minute shorter time to peak C-peptide response, indicating faster pancreatic response. Hemoglobin A1C (HbA1c), a measure of glycosylated hemoglobulin, was reduced by 0.26% (SE, 0.15%) on average after 24 weeks of AMX0035 treatment, with 6 of 8 participants showing improvement in their HbA1c. AMX0035 was also generally well tolerated, with a majority of the adverse events mild to moderate and consistent with prior safety data.

"The improvements in C-peptide, an objective laboratory measure, observed in our HELIOS trial are promising and differ from the normal course of Wolfram syndrome despite best supportive care,” Camille L. Bedrosian, MD, chief medical officer, Amylyx, said in a statement. “The majority of people with Wolfram syndrome carry mutations in the WFS1 gene, which encodes a protein that spans the membrane of the endoplasmic reticulum (ER) called wolframin. Loss of wolframin function leads to ER stress and impaired mitochondrial dynamics, which in turn leads to dysfunction and apoptosis of cells."

She added, "Because of the clear link between WFS1 mutations and ER stress, Wolfram syndrome is considered a prototypical ER stress disorder. AMX0035 is believed to target both ER stress and mitochondrial dysfunction. We believe today’s interim results support the compelling science behind the mechanism of action of AMX0035 and its potential to help people living with Wolfram syndrome."

Wolfram Syndrome is a rare genetic disorder characterized by several symptoms that occur from childhood to adulthood. Typically, the first clinical sign is non-autoimmune diabetes even if other clinical features may be present in an early state and may be diagnosed after diabetes’ onset. Prognosis is poor, and death occurs at the median age of 39 years as a consequence of progressive respiratory impairment, secondary to brain atrophy and neurological failure.

Using continuous monitoring, treatment with AMX0035 resulted in an improvement of 7.1+ (SE, 4.7%) in the absolute time in target glucose range. Increased time in target glucose range, which has been associated with better diabetic outcomes, was found in 5 of the 8 participants. Visual acuity, measured by the Snellen chart, was improved by an average of +0.05 -LogMAR (SE, 0.09), with 5 of 8 participants demonstrating some enhancement. Notably, 1 patient improved to the point where they changed from legally blind to legally sighted.

Justin Klee

Justin Klee

On the Clinician Report Global Impression of Change and Patient Reported Global Impression of Change, 5 (62.5%) and 6 (75%) patients, respectively, saw improvements in their overall burden of disease. Overall, there were no serious adverse events related to AMX0035, and the most common AE was diarrhea.

"The HELIOS trial began as a result of a multi-year collaboration with the Wolfram syndrome community and follows strong preclinical data with clear effects in cellular and animal models. We thank the Wolfram community, including those participating in HELIOS, their loved ones, and the clinical staff at Washington University School of Medicine in St. Louis, for their support of this important trial,” Justin Klee and Josh Cohen, co-chief executive officers of Amylyx, said in a statement.1 "We are planning to engage with regulatory authorities to align on the development path in Wolfram syndrome. We expect topline data for all 12 participants at Week 24 in the second half of this year."

Josh Cohen

Josh Cohen

AMX0035, which remains in development for other conditions like progressive supranuclear palsy, was originally approved as a therapy for patients with amyotrophic lateral sclerosis (ALS). Recently, in early April, Amylyx announced it was voluntarily discontinuing the therapy and removing it from market after it fell short in its phase 3 PHOENIX trial (NCT05021536). In PHOENIX, results showed no significant difference on ALS Functional Rating Scale-Revised, the primary end point, between AMX0035-treated and placebo-treated participants over a 48-week treatment period (P = .667).2,3

In September 2022, in collaboration with Amylyx, investigators published preclinical data on AMX0035 in beta cell, neuronal cell, and mouse models of Wolfram syndrome, highlighting the drug’s potential in this disease state. Results showed that the combination therapy improves insulin secretion and survival in stem cell-derived ß cells with Wolfram syndrome c.1672C>T, p.R558C variant. In the same variant, AMX0035 was found to mitigate cellular stress in SC-inlets. Lastly, the preclinical studies revealed that this treatment delays the diabetic phenotype progression in Wolfram syndrome-deficient mice.4

1. Amylyx Pharmaceuticals announces interim data from ongoing phase 2 HELIOS clinical trial demonstrating improvements in pancreatic function and glycemic control with AMX0035 in people with Wolfram syndrome. News release. April 10, 2024. Accessed April 10, 2024.
2. Amylyx Pharmaceuticals Announces Formal Intention to Remove RELYVRIO®/ALBRIOZA™ from the Market; Provides Updates on Access to Therapy, Pipeline, Corporate Restructuring, and Strategy. News Release. Amylyx Pharmaceuticals. Published April 4, 2024. Accessed April 10, 2024
3. Amylyx Pharmaceuticals announces topline results from global phase 3 PHOENIX trial of AMX0035 in ALS. News release. March 8, 2024. Accessed April 10, 2024.
4. Kitamura RA, Maxwell KG, Ye W, et al. Multidimensional analysis and therapeutic development using patient iPSC-derived disease models of Wolfram syndrome. JCI Insight. Published online September 22, 2022. doi:10.1172/jci.insight.156549
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