A Phase 1b/2a Clinical Trial of Dantrolene Sodium in Patients with Wolfram Syndrome
Authors: Abreu Damien , Stone Stephen I , Pearson Toni , Bucelli Robert , Simpson Ashley N , Hurst Stacy , Brown Cris M , Kries Kelly , Gu Hongjie , Hoekel James , Tychsen Lawrence , Van Stavern Gregory P. , White Neil H , Marshall Bess A , Hershey Tamara , Urano Fumihiko 
Published: October 2020

Background

Wolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial.

Methods

Based on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.

Results

The results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.

Conclusion

This study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.

Trial registration

ClinicalTrials.gov Identifier NCT02829268

Key Points

Question

Is dantrolene sodium safe and effective for the treatment of adult and pediatric patients with Wolfram syndrome?

Findings

The results of this open-label clinical trial show that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.

Meaning

Dantrolene sodium is well tolerated by patients with Wolfram syndrome. Some patients may experience an increase in β cell function when taking dantrolene.

Importance

Wolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, is an emerging therapeutic strategy.

Objective

The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric subjects with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.

Design

Open-label phase 1b/2a trial of dantrolene sodium over a 6-month treatment period.

Setting

Single site, academic medical center.

Participants

Adult and pediatric subjects with a genetically confirmed diagnosis of Wolfram syndrome.

Interventions

All subjects received increasing doses of dantrolene sodium.

Main Outcomes and Measures

The safety and tolerability of dantrolene sodium administered orally at the upper end of therapeutic dose range for 6 months, and the efficacy of dantrolene sodium on residual pancreatic β-cell functions using a mixed-meal tolerance test, visual acuity using LogMar scores, quality of life measures related to vision using Visual Functioning Questionnaire – 25, and neurological functions using the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.

Results

The results indicate that dantrolene sodium is well tolerated by subjects with Wolfram syndrome. Although the study was small, a select few subjects seemed to have improvements in β-cell function, which might be correlated with a positive trend in visual acuity.

Conclusions and Relevance

This study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.

Trial Registration

Registered with clinicaltrials.gov, NCT02829268, (https://clinicaltrials.gov/ct2/show/NCT02829268?term=NCT02829268&draw=2&rank=1)