[S6.003] Results of a Phase 2 Open-Label Study of ISIS-SMNRx in Patients with Infantile (Type 1) Spinal Muscular Atrophy

Richard Finkel,1John Day,2Claudia Chiriboga,3Jiri Vajsar,4Dawn Cook,1Karolina Watson,5Shirley Paulose,5Rosangel Cruz,3Jacqueline Montes,3Darryl De Vivo,3Mason Yamashita,6Dawn McGuire,7Katie Alexander,8Daniel Norris,6Frank Bennett,6Kathie Bishop6
1Orlando, FL, USA, 2Stanford, CA, USA, 3New York, NY, USA, 4Toronto, ON, Canada, 5Palo Alto, CA, USA, 6Carlsbad, CA, USA, 7Orinda, CA, USA, 8

Objective: This study was conducted to evaluate the safety, tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of ISIS-SMNRx (ISIS 396443) in patients with infantile-onset (Type 1) SMA.
Background: ISIS-SMNRx is an antisense oligonucleotide (ASO) drug designed to alter splicing of SMN2 mRNA, increasing the amount of functional SMN protein produced. Results from experiments in SMA mouse models showed that ISIS-SMNRx effectively altered SMN2 mRNA splicing, increased SMN protein in the spinal cord, and had significant effects on functional and histological measures of neuromuscular health, including survival, when delivered to the CNS. A single-dose, dose-ascending clinical study of ISIS-SMNRx in children with Type 2/Type 3 SMA has previously been completed.
Multiple doses of ISIS-SMNRx were delivered by intrathecal injection to infants with SMA who were 7 months of age or less at study enrollment. Four subjects were administered multiple 6 mg doses of ISIS-SMNRx and up to 16 subjects will be administered multiple 12 mg doses. Subjects are being monitored for drug safety and tolerability. Plasma drug levels are measured over the first 24 hours and CSF drug levels are assessed prior to each dose administration. Preliminary measures of clinical efficacy include the CHOP-INTEND infant motor exam, CMAP, growth measurements, ventilator use, and survival.
Enrollment of the lower dose cohort has been completed and no safety concerns related to ISIS-SMNRx have been identified to date; enrollment of the higher dose cohort is ongoing. Available safety, tolerability, pharmacokinetic, and clinical data will be presented.
Results from this study will inform the design and conduct of a Phase 3 clinical study of ISIS-SMNRx in infants with SMA.
Study Supported by: Isis Pharmaceuticals, Inc
Category - Neuromuscular and Clinical Neurophysiology (EMG): Clinical Trials/Treatment/Therapeutics

Tuesday, April 29, 2014 1:30 PM

S6: Platform Session: Neuromuscular Disease: Gene Therapy (1:00 PM-2:45 PM)


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