An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *

Clinical Trial Interim Data Show Improvements in Pancreatic Function and Glycemic Control with AMX0035 in People with Wolfram Syndrome

On April 11, Amylyx Pharmaceuticals announced interim data from the ongoing Phase 2 HELIOS clinical trial of AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) in adults living with Wolfram syndrome, a rare, progressive genetic disease impacting approximately 3,000 people in the U.S.

The interim data from eight participants who have completed 24 weeks of treatment demonstrated that AMX0035 had a clinically meaningful effect on key outcomes measuring the progression of diabetes, visual decline, and overall disease burden in adult participants living with Wolfram syndrome.

“I have been studying Wolfram syndrome and caring for people with the disease for more than 20 years. This community has an urgent unmet need for disease modifying treatments. Outcomes for people with Wolfram syndrome consistently worsen over time, so disease stabilization alone is clinically meaningful for both patients and their doctors. The interim results from HELIOS that demonstrate improvement across multiple organ systems impacted by this progressive disease are encouraging,” 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, Mo.

HELIOS is an ongoing, open-label Phase 2 study in 12 participants designed to evaluate if AMX0035 slows progression of diabetic, visual, and other measures in people living with Wolfram syndrome and to evaluate safety and tolerability. 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 glycemic control, assessed using a Mixed Meal Tolerance Test (MMTT). Secondary and exploratory outcomes include the measurement of other diabetic responses and other domains affected by the disease. The interim analysis performed is based on a data cutoff as of March 5, 2024, which includes all participants who completed their Week 24 assessments as of the cutoff (n=8).

“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,” said Endocrine Socie

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

In this interim analysis of eight participants treated with AMX0035, increases were observed on average in the primary outcome of total C-peptide response (C-peptide AUC change from baseline) including in the 90-minute response at Week 24 (+15.6 ng*min/mL, 95% CI: [1.3, 30.0]). In Wolfram syndrome, progressive decline would have been expected on this measure. Additionally, seven out of eight participants demonstrated at least a 30-minute shorter time to peak C-peptide response. In Wolfram syndrome, a progressive increase in time to peak C-peptide response, indicating slower pancreatic response, and reduced total C-peptide response would have been expected.

“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,” said Endocrine Society member Camille L. Bedrosian, MD, chief medical officer of Amylyx. “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. 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.”

The following includes additional key data from the interim analysis:

• Hemoglobin A1C (HbA1c) is a measure of glycosylated hemoglobin which serves as a metric of how well sugar levels are being controlled in the blood. HbA1c was reduced by 0.26% (SE: 0.15%) on average after 24-weeks of AMX0035 treatment with six out of eight participants showing improvement in their HbA1c. Many studies have associated reduced HbA1c with better clinical outcomes.
• All participants had continuous glucose monitoring in the study allowing for a rigorous measurement of the time in target glucose range. The absolute time in target glucose range improved on average by +7.1% (SE: 4.7%). Five out of eight participants had improvements in the time in target glucose range. Increased time in target glucose range is associated with better diabetic outcomes.
• Visual acuity was measured by the Snellen chart. Wolfram syndrome results in progressive optic nerve atrophy leading to relentless loss of both visual acuity and color vision, and eventually blindness. On average in HELIOS, visual acuity improved +0.05 -LogMAR (SE: 0.09) with five out of eight participants demonstrating some improvement in vision. Of those who improved, one participant changed from legally blind to legally sighted. Optical coherence tomography outcomes have not yet been assessed and will be included in final data analysis from HELIOS.
• All participants (8 out of 8) showed disease stability or improvement at Week 24, as measured by The Clinician Report Global Impression of Change (CGIC) and Patient Reported Global Impression of Change (PGIC). Improvement was noted by the CGIC in 62.5% of cases (5 out of 8) and by the PGIC for 75% of cases (6 out of 8) with the remainder reporting disease stability on both the CGIC and PGIC. These outcome measures are designed to report if the overall burden of disease has improved, stayed the same, or worsened from the clinician’s or patient’s perspective.
• The safety profile of AMX0035 in HELIOS was consistent with prior safety data. AMX0035 was generally well-tolerated. The majority of adverse events (AEs) were mild or moderate, and there were no serious AEs related to AMX0035 treatment. The most common AE was diarrhea.

In September 2022, researchers from Washington University School of Medicine in St. Louis, including Urano, in collaboration with Amylyx, published positive preclinical data on AMX0035 in beta cell, neuronal cell and mouse models of Wolfram syndrome in the peer-reviewed Journal of Clinical Investigation Insight. Amylyx announced that the FDA granted orphan drug designation to AMX0035 for the treatment of Wolfram syndrome in November 2020.

*Inclusion in Pharma Fridays does not suggest an endorsement by Endocrine News or the Endocrine Society.