Preliminary results on the Tirzepatide monotherapy in Wolfram syndrome trial – Virtual Global Research and Trial Updates

Overview

Dr. Giulio Frontino and Amelia Caretto presented preliminary results from a trial on Tirzepatide monotherapy for Wolfram syndrome. The trial, involving 17 patients (including children and adults), showed stabilization of C-peptide levels in half of the patients, with a median increase of 15% over two years. Tirzepatide improved beta-cell function and reduced inflammation markers. However, retinal nerve fiber layer thickness decreased in some patients, possibly due to pubertal hormonal changes. The trial also noted stable BMI and improved HbA1c levels. Side effects were mild and manageable, with no severe adverse events reported.

Action Items

• Explore other potential mechanisms by which Tirzepatide may have indirect effects on the central nervous system, despite the initial concerns about its ability to cross the blood-brain barrier.
• Investigate the potential role of hormonal changes during puberty in the observed decline in some patients’ optic nerve function.
• Continue to follow up and assess the long-term effects of Tirzepatide in the Wolfram syndrome patients.

Outline

Preliminary Results on Tirzepatide Monotherapy in Wolfram Syndrome Trial

• Wolfram Syndrome UK introduces Dr. Giulio Frontino and Amelia Caretto for the presentation.
• Giulio Frontino thanks the audience and mentions the preliminary data from the recently ended trial with Tirzepatide.
• Giulio Frontino explains the history of using liraglutide for Wolfram syndrome, its approval for obesity in children, and its off-label use for diabetes control.
• The initial results showed stabilization of diabetes and neurodegeneration parameters in four patients treated with liraglutide.

Transition to Tirzepatide

• Giulio Frontino discusses the transition to Tirzepatide, a dual GLP-1/GIP receptor agonist, due to its potential synergistic effects.
• The trial aimed to treat 10 patients, including five adults and five children, with funding obtained from a European grant.
• A research paper raised concerns about Tirzepatide’s ability to cross the blood-brain barrier, but Giulio Frontino explains that other routes might be involved.
• The paper’s limitations, such as using healthy mice, are discussed, and the potential indirect mechanisms of Tirzepatide’s effects are highlighted.

Trial Design and Initial Results

• The trial started over a year ago, recruiting five children and five adults with Wolfram syndrome.
• Tirzepatide was administered weekly with increasing doses, and the primary endpoint was C-peptide secretion.
• Giulio Frontino presents preliminary results, showing stable BMI and improved HbA1c in pediatric patients.
• The retinal nerve fiber layer thickness remained stable in most patients, with some showing a slow reduction.

Adult Results and Side Effects

• Amelia Caretto presents the results for the five adult patients, noting a decrease in BMI and improved HbA1c in four patients.
• The main side effects were gastrointestinal, well-controlled with diet and initial medications.
• Ophthalmological evaluations showed stable retinal fiber layer values, with no significant variations.
• The trial’s results suggest that Tirzepatide is well-tolerated and safe, with stable beta-cell function and neurophthalmological parameters over a year.

Challenges and Future Directions

• Giulio Frontino discusses the challenges of heterogeneity in Wolfram syndrome patients, affecting treatment responses.
• The potential impact of puberty on treatment outcomes is mentioned, with ongoing research to address these issues.
• The development of humanized mouse models and inflammatory context simulations is highlighted as part of ongoing research.
• The presentation concludes with a thank you to the audience, and Wolfram Syndrome UK invites questions for further discussion.