A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome

Abstract

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. 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.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

Keywords: Cell stress; Diabetes; Endocrinology; Genetic diseases; Genetics.

Figure 1. Trial design, enrollment, and retention.

(A) Enrollment and retention diagram for the subjects enrolled in the study. (B) Schematic of 6-month study. Each study visit is noted by a black circle. Study procedures for secondary endpoints are noted in blue. The dose maximization period for dantrolene sodium is noted by the red dashed lines. HbA1c, hemoglobin A1c; MMTT, mixed meal tolerance test; WURS, Wolfram Unified Rating Scale. (C) Histogram demonstrating distribution of final tolerated dantrolene doses in pediatric subjects at the end of the study. For pediatric subjects this is expressed as mg/kg/d. (D) Histogram demonstrating distribution of final tolerated dantrolene doses in adult subjects at the end of the study. For adult subjects this is expressed as mg/d. For both histograms the blue bars represent numbers of subjects taking a dose.

Figure 2. Subgroup analysis to determine responders versus nonresponders.

(A) ΔC-peptide was plotted between all subjects. Then the change in ΔC-peptide (ΔΔC-peptide) was calculated for each subject over the course of the study. Subjects were stratified based on a ΔΔC-peptide < 0.05, 0.05–0.1, and ≥ 0.1 ng/mL, respectively. (B) Linear regression analysis demonstrates a significant positive relationship between baseline ΔC-peptide and ΔΔC-peptide. Statistical significance was determined by the ordinary least squares method.

Figure 3. Secondary study endpoints.

(A) C-peptide during an MMTT. Light boxes represent fasting results, while dark boxes represent 30-minute (stimulated) values. (B) LogMAR (a measure of visual acuity). Lower score correlates to more accurate vision. (C) WURS score. (D) Physician-rated subsection of the WURS. Higher WURS scores represent more severe disease. All study subjects are broken down into adult and pediatric subgroups. Responders are differentiated from nonresponders by having a change in ΔC-peptide (ΔΔC-peptide) ≥ 0.1 ng/mL over the study period. The box shows the quartiles of the data set while the whiskers extend to show the rest of the distribution. Paired analyses among the same group (i.e., adult or pediatric) were performed using the Wilcoxon signed-rank test. The Mann-Whitney U test was used when comparing between groups (adult vs. pediatric subjects or nonresponders vs. responders).