8th International Wolfram Symposium Presentation Prof Timothy Barrett, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK, on behalf of the TREATWOLFRAM investigators (Dr Renuka Dias, Dr Ben Wright (UK), Dr Gema Esteban Bueno (Spain), Prof Wojciech Mlynarski (Poland), Dr Christophe Orssaud, Prof Agathe Roubertie (France)
8th International Wolfram Symposium Presentation Prof Timothy Barrett, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK, on behalf of the TREATWOLFRAM investigators (Dr Renuka Dias, Dr Ben Wright (UK), Dr Gema Esteban Bueno (Spain), Prof Wojciech Mlynarski (Poland), Dr Christophe Orssaud, Prof Agathe Roubertie (France)
Sodium Valproate efficacy and safety in WFS1 Spectrum Disorder (TREATWOLFRAM). Update on phase II pivotal international multicentre, double-masked, randomised controlled trial.
ABSTRACT: Introduction
WFS1 spectrum disorder (WFS1-SD) comprises a classic form of progressive neurodegenerative disorder, formerly known as Wolfram syndrome, and non-classic forms including low-frequency sensorineural hearing loss. This is the commonest monogenic syndrome of diabetes and vision impairment, affecting 1:500,000 in the UK. Despite this, there are no licensed pharmacological therapies for WFS1-SD. Sodium valproate (VPA) is an anti-convulsant approved for use for the treatment of epilepsy and bipolar disorder. VPA has been shown to reduce Endoplasmic Reticulum (ER) stress, is known to exert neuroprotective effects in models of neurodegeneration, and in the context of WFS1-SD, VPA is thought to mediate its effect via alteration of cell cycle kinetics, increase in p21cip1 expression levels or nuclear translocation and reduction in apoptosis, and increase in Wolfram protein expression. There is currently a lack of prospective controlled studies investigating therapeutic candidates in people with WFS1-SD.
Methods
TREATWOLFRAM is a phase II, pivotal, international multi-centre, double-masked, placebo-controlled, randomised clinical trial designed to investigate whether a 36 month treatment with up to 800mg/day of VPA in children aged 6-12 years, or up to 1600mg/day for those aged 12 years of over, will slow the rate of change in visual acuity as assessed by corrected visual acuity in each eye, using standardised charts, in participants with WFS1-SD. Children aged 6 years or more and adults with genetically confirmed WFS1-SD and visual acuity with LogMAR score of 1.6 or better on an EDTRS chart, were assessed for eligibility at 6 recruitment centres in Europe. Patients who satisfied the eligibility criteria were randomly assigned (2:1) to receive twice daily tablets of either VPA or VPA-placebo (control). Analysing visual acuity outcomes using longitudinal hierarchical models, and using data on a cohort of 26 patients with Wolfram syndrome kindly provided by Prof Tamara Hershey, (significance level 0.05, power 0.90), and accounting for an estimated 15% withdrawal rate, we estimated a target sample size of 70 patients, so that a minimum of 21 participants were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable participants achieving a decline in the rate of progression of vision loss between baseline and after 36 months of treatment. Visual acuity progression will be defined as the change in LogMAR units over time as measured on EDTRS charts.
Ethics and dissemination
The protocol was designed with assistance from the EU Committee for Medicinal Products for Human Use (CHMP) and approved by The West of Scotland Research Ethics Service (18/WS/0020) and The Medicines and Healthcare Products Regulatory Agency (EudraCT 2017-001215-37; ISRCTN 10176118). Recruitment into TREATWOLFRAM started in January 2019 and ended in October 2021, with 63 patients randomised. The treatment follow-up of TREATWOLFRAM patients is currently ongoing and due to finish in October 2024. The findings of this trial will be disseminated through peer-reviewed publications.
Trial registration: Clinicaltrials.gov NCT03717909 Points noted:
• Visual acuity is the primary endpoint of TreatWolfram. A number of secondary endpoints are also included.
• Sodium valproate targets the final part of the treatment pathway. This drug has decades of use, has been shown to be neuroprotective and as it is off- patent – there is freedom to operate in clinical trials and ongoing licensing.
• TreatWolfram received 2014 orphan drug designation by EMA and FDA. Regulators may not require a gold standard double blind randomised controlled trial today.
• The trial was delayed by a range of issues – as a result some patients were unable to participate as their vision had deteriorated while awaiting trial commencement.
• If starting the study today, Milan would be included as a study site (this group has been developing a clinical trial centre).
• University of Birmingham now has an established clinical trial unit for delivering pivotal trials in rare disease and a network of trial sites that would like to be included in future WS clinical trials in Europe.
• The study clearly highlighted that Brexit has been damaging for rare disease research.
• Better biomarkers are needed that can demonstrate efficacy in around 6 months that are relevant for patients. Researchers need to be able to identify responders to potential treatments in a much shorter timeframe.
• With better biomarkers, new clinical trials could be designed to report in a shorter timeframe (and should therefore be less expensive). This could help attract more commercial partners into WS clinical research.
• It was noted patient samples will be available to help assist in developing biomarkers, including placebo data from clinical trials.