TREATWolfram — What’s next? – Virtual Global Research and Trial Updates

Overview

Professor Timothy Barrett presented updates on the Treat Wolfram trial, focusing on the use of sodium valproate for Wolfram syndrome. The trial, involving 42 valproate-treated and 21 placebo-treated patients, aimed to assess vision loss over 36 months. Despite a younger, healthier placebo group, valproate showed trends towards stabilizing HbA1c and insulin-adjusted HbA1c, and increasing C-peptide levels. However, no statistically significant reduction in visual acuity was observed. Future plans include reanalyzing data with a better-matched placebo group and exploring new treatments. The trial’s natural history data will inform future trial designs.

Action Items

• Continue analyzing the TREAT Wolfram trial data to get a more robust comparison between the treatment and placebo groups.
• Initiate a new clinical trial in 2026 to test different treatment approaches for Wolfram syndrome.
• Collaborate with the Audio Wolf trial team to combine their data with the TREAT Wolfram data.
• Explore the potential of using GLP-1 receptor agonists and autophagy inducers as new treatment approaches for Wolfram syndrome.

Outline

Overview of Wolfram Syndrome and Research Background

• Tim Barrett explains the focus of his research on childhood-onset diabetes mellitus and progressive optic atrophy.
• He describes the rarity of Wolfram syndrome and the challenges in conducting clinical trials.
• Barrett discusses the development of cell models to study Wolfram syndrome and the identification of P21WAF1/CIP1 as a key cell cycle regulator.
• He describes the drug screen that led to the identification of sodium valproate as a potential treatment.

Development and Approval of the Treat Wolfram Trial

• Barrett details the regulatory approval process for sodium valproate, including orphan drug designation from the EMA and FDA.
• He explains the co-design of the Treat Wolfram trial with the European Medicines Agency and family support groups.
• The trial’s main endpoint was the rate of change in visual acuity over 36 months.
• Patients were randomized to either sodium valproate treatment or a matched placebo, with strict double-blind protocols to minimize bias.

Trial Design and Patient Recruitment

• Barrett describes the trial’s design, including the number of study visits and the various outcome measures assessed.
• He explains the flow of patients through the trial, including the number of participants and those who withdrew.
• Barrett highlights the baseline characteristics of the participants, noting the younger and healthier population in the placebo arm.
• He discusses the challenges in matching the two arms of the trial and the implications for the trial’s results.

Primary and Secondary Outcomes

• Barrett presents the primary outcome of the trial, focusing on changes in visual acuity over time.
• He explains the limitations of the trial design due to the mismatch between the two arms.
• Barrett discusses the secondary outcomes, including brainstem volume, diabetes control, and quality of life measures.
• He notes the trend towards stabilization in HbA1c and insulin-adjusted HbA1c in the valproate-treated group compared to the placebo group.

Exploration of Additional Data

• Barrett presents new data on glucose-adjusted fasting C-peptide, showing a significant increase in the valproate-treated group.
• He discusses the adverse events observed in the trial, including hypoglycemia, and the higher prevalence in the valproate-treated group.
• Barrett concludes that while there was no statistically significant reduction in visual acuity, there were early indications of a positive effect on C-peptide.
• He outlines the next steps, including reanalyzing the data with a better-matched placebo group and exploring additional outcome measures.

Discussion and Future Directions

• Wolfram Syndrome UK and Stephanie Gebel ask questions about the trial’s design and the implications of the results.
• Barrett explains the randomization process and the challenges in matching the two arms of the trial.
• He discusses the potential for future trials and the importance of finding better biomarkers for Wolfram syndrome.
• Barrett acknowledges the contributions of the research team, funders, and families who participated in the trial.