ISIS-DMPKRx in Healthy Volunteers: A Placebo-controlled, Randomized, Single Ascending-Dose Phase 1 Study (P3.166)

Objective: To assess the safety, tolerability, and pharmacokinetics of four single dose levels of ISIS-DMPKRx, a Gen 2.5 antisense oligonucleotide (ASO) drug targeted to DMPK mRNA associated with myotonic dystrophy type 1 (DM1). Background: DM1 is a dominantly-inherited, systemic disorder caused by the nuclear accumulation of toxic mRNA containing a CUG-expanded region transcribed from a DMPK gene with unstable CTG trinucleotide repeats. This mutant mRNA interferes with the functioning of RNA-binding splice regulators muscleblind-like (MBNL) proteins and CUG binding protein, leading to misregulated alternative splicing for a group of transcripts that have key roles in muscle biology and producing skeletal muscle dysfunction, the most prominent clinical feature of DM1. In preclinical studies, ASOs re-established splicing patterns and reduced myotonia in mice via RNase H1-mediated degradation of toxic mRNA. A Phase 1/2a study of multiple-ascending doses of ISIS DMPKRx in adult DM1 patients is ongoing. Methods: This Phase 1 placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics (PK) of single 50, 100, 200, and 400 mg doses of ISIS-DMPKRx given subcutaneously to healthy volunteers. Each dose level was studied in a cohort of 4 subjects, randomized 3 active: 1 placebo (N=16). Results: ISIS-DMPKRx was well-tolerated: serum chemistry, hematology, coagulation, complement, urinalysis, physical examinations, ECGs, and vital signs showed no clinically significant changes. The majority of AEs were mild in severity, and 1 subject reported a moderate AE; there were no severe AEs, SAEs, deaths, or AEs leading to discontinuation. ISIS-DMPKRx was absorbed rapidly into the systemic circulation with median Tmax ranging from 1.50 to 3.07 hours (observed range = 1.50 to 8.00 hours); mean Cmax and AUC values were dose-dependent over the studied dose range with observed PK of ISIS-DMPKRx as expected from preclinical PK and consistent with Gen 2.0 ASOs. Conclusion: This study supports the further clinical development of ISIS-DMPKRx. Disclosure: Dr. Mignon has received personal compensation for activities with Isis Pharmaceuticals, Inc. Dr. Norris has received personal compensation for activities with Isis Pharmaceuticals. Dr. Bishop has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Derosier has received personal compensation for activities with Isis Pharmaceuticals as an employee. Mr. Lane has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Bennett has received personal compensation for activities with Isis Pharmaceuticals, Inc. as an employee.