A phase 1b/2a clinical trial of dantrolene sodium in patients with Wolfram syndrome

Abstract

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 -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. Overall, -cell functions were not significantly improved by dantrolene, but there was a significant correlation between baseline -cell functions and the change in -cell responsiveness (R 2 , p=0.004) after 6 months of dantrolene therapy. Other outcome measures, including visual acuity and neurological functions, were not improved by dantrolene sodium treatment within 6 months. As previously reported, markers of inflammatory cytokines and oxidative stress, such as IFN, IL-1, TNF, and isoprostane, were elevated in subjects with Wolfram syndrome. Conclusion:This study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome. Abreu & Stone et. al. 3 Trial registration ClinicalTrials.gov Identifier NCT02829268 Conflict of interest statement F. Urano received research funding from Eli Lilly, Ono Pharmaceuticals, and Amarantus BioScience for the development of MANF-based regenerative therapy for Wolfram syndrome, optic nerve atrophy, and diabetes. F. Urano received chemical compounds from Amylyx Pharmaceuticals, Mitochon Pharmaceuticals, Aetas Pharma, and National Center for Advancing Translational Sciences for the development of small molecule-based therapies for ER stress-related disorders, including Wolfram syndrome. F. Urano is an inventor of two patents related to the treatment of Wolfram syndrome, US 9,891,231 SOLUBLE MANF IN PANCREATIC BETA CELL DISORDERS and US 10,441,574 and US 10,695,324 TREATMENT FOR WOLFRAM SYNDROME AND OTHER ER STRESS DISORDERS. F. Urano is a Founder and President of CURE4WOLFRAM, INC.

Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells

“…Perhaps surprisingly, direct β-cell stress–targeting therapies have moved forward more quickly for T1D than T2D. Developments include the use of verapamil in early T1D ( 83 ), dantrolene in Wolfram syndrome ( 84 ), and clinical trials for GLP1RA in Wolfram syndrome and TUDCA chemical chaperone in T1D. Preclinical studies in mice suggest that an inhibitor of IRE1 RNAse activity may offer protection in T1D ( 75 ).…”

Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders

“…The primary objective of the study was to assess the safety and tolerability of the molecule, and the secondary objectives were to evaluate the efficacy of the treatment in improving residual pancreatic β-cell function, visual acuity, quality of life, and measures related to vision and neurological functions. The study showed that dantrolene sodium is well tolerated by Wolfram syndrome patients, but β-cell function, visual acuity, and neurological functions were not significantly improved after 6 months of treatment (Abreu et al, 2021). However, a patient subgroup analysis revealed a significant improvement in β-cell function in subjects who possessed the greatest degree of β-cell function at the baseline.…”

“…Since ER stress is deleterious for pancreatic β-cells and neurons, and is a hallmark of Wolfram syndrome, it has been proposed that reducing ER stress may have beneficial outcomes in this life-threatening disease. Accordingly, different ER stress-targeting approaches are being tested, for example, ER calcium stabilizers, chemical chaperones, GLP-1 analogs, and modulators of ER stress (Urano, 2016;Abreu et al, 2021;Pallotta et al, 2019).…”

“…This drug received orphan designation for Wolfram syndrome from EMA and the FDA. An open-label, phase Ib/IIa trial in pediatric and adult Wolfram syndrome patients with dantrolene sodium was recently performed (Abreu et al, 2021). The primary objective of the study was to assess the safety and tolerability of the molecule, and the secondary objectives were to evaluate the efficacy of the treatment in improving residual pancreatic β-cell function, visual acuity, quality of life, and measures related to vision and neurological functions.…”

Case Report: Off-Label Liraglutide Use in Children With Wolfram Syndrome Type 1: Extensive Characterization of Four Patients

“…We observed no deterioration in C-peptide secretion and OCT parameters, which are important markers of disease progression, while not observing the onset of new WS-related symptoms. Of note, also Valproate (NCT03717909) and Dantrolene (NCT02829268) are under investigation as possible therapeutic options for WS ( 37 – 40 ). WS is a rare orphan disease; consequently, this study suffers from the intrinsic limitations of the absence of a control group, a small sample size.…”