Interim Results of a Phase 2 Clinical Study of Nusinersen (ISIS-SMNRx) in Patients with Infantile-Onset Spinal Muscular Atrophy (P5.004)

Abstract

Objective:To assess the safety, tolerability, pharmacokinetics and clinical effects of nusinersen (ISIS-SMNRx) in patients with infantile-onset Spinal Muscular Atrophy (SMA). Background:Infantile-onset SMA is a devastating and relentlessly progressive neurodegenerative disease caused by the deficiency of Survival of Motor Neuron (SMN) protein in motor neurons, accounts for over half of all patients with SMA, and is the most common genetic cause of death in infancy. Nusinersen is a novel antisense oligonucleotide drug designed to alter splicing of SMN2 mRNA thereby increasing the amount of functional SMN protein. Methods:This is an interim analysis of an ongoing multicenter, open-label, Phase 2 clinical study designed to evaluate the safety/tolerability, pharmacokinetics, and clinical effects of multiple intrathecal doses of nusinersen in patients with infantile-onset SMA. Twenty participants (4 in a lower-dose cohort, 16 in a higher-dose cohort) were enrolled. Autopsy tissue in 3 participants enabled pharmacodynamic analyses. Results:As of an interim analysis performed in August 2015, the study has been ongoing for 27 months. Nusinersen has been well tolerated with no safety concerns identified. Sixteen of 19 participants in the evaluable population remain alive (median age 20.1 months) and demonstrate significant (p=0.01) improvements in motor function scores, incremental achievement of motor milestones such as head control (10 participants), rolling (9 participants), sitting (6 participants), and improvements in neuromuscular electrophysiology compared to baseline and published natural history data. Pharmacodynamic data support drug delivery, enhancement of full-length SMN2 transcript, and an increase in SMN protein in target neurons. Conclusions:In this open-label Phase 2 study, nusinersen exhibits good safety and tolerability, pharmacology that is consistent with its intended mechanism of action, and encouraging evidence supporting meaningful clinical response. Importantly, a pivotal, sham-controlled Phase 3 clinical study of nusinersen in infantile-onset SMA is currently ongoing.

Disclosure: Dr. Finkel has received personal compensation for activities with Isis Pharmaceuticals and Voyager Therapeutics as a consultant and/or speaker. Dr. Chiriboga has received personal compensation for activities with Up To Date, ISIS pharmaceuticals/Biogen, and Roche pharmaceuticals. Dr. Vajsar has nothing to disclose. Dr. Day has received personal compensation for activities with Sarepta Therapeutics and PTC Therapeutics as a consultant. Dr. Montes has received personal compensation for activities with Isis Pharmeceuticals as a consultant. Dr. De Vivo has received personal compensation for activities with Isis Pharmaceuticals as a consultant. Dr. Yamashita has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Rigo has nothing to disclose. Dr. Hung has nothing to disclose. Dr. Schneider has nothing to disclose. Dr. Norris has received personal compensation for activities with Isis Pharmaceuticals. Dr. Xia 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. Dr. Bishop has received personal compensation for activities with Isis Pharmaceuticals as an employee.