Abstract Details

Title SMN2 splicing modifier RG7800 shows dose-dependent increase of full length SMN2 mRNA in first-in-human study

Topic Child Neurology and Developmental Neurology

Presentation(s) (-)

Poster/Presentation
Number 011

Objective

Background RG7800 is in development for treatment of spinal muscular atrophy (SMA), a neuromuscular disorder that is the leading genetic cause of mortality in infants and toddlers, due to a deletion or mutation of the Survival of Motor Neuron 1 (SMN1) gene. RG7800 is an orally administered small molecule that modifies the splicing of exon 7 of SMN2 towards the production of full length SMN mRNA. This has been shown to increase functional SMN protein levels in the Δ7 mouse model for SMA, with significant efficacy on survival and motor function.

Design/Methods Single oral doses of 0.5 - 90 mg RG7800 were administered to healthy male subjects, age 23-45 years, in a single-ascending-dose, placebo-controlled, double-blind study conducted in the Netherlands. SMN1 full length, SMN2 full length, and SMNΔ7 mRNA levels were quantified in whole blood samples using a newly developed multiplex qRT-PCR assay.

Results RG7800 was safe and well tolerated at all dose levels. The most frequently reported adverse events were headache, influenza like illness, back pain, and musculoskeletal discomfort. No clinically significant changes in vital signs, laboratory safety tests, or ECG were observed. Plasma exposure increased in a more than dose-proportional manner; half-life was 120 hours. A dose- dependent effect on SMN2 splicing was observed in treated subjects: full length SMN2 mRNA increased, and SMNΔ7 mRNA decreased, without any effect on SMN1 mRNA.

Conclusions RG7800 was safe and well tolerated in this first- in-human study in healthy subjects. Proof of mechanism was demonstrated by the shift in SMN2 alternative splicing towards the production of full length SMN2 mRNA. Safety, PK and PD results of this study fully support further clinical development of RG7800 for treatment of SMA.

Authors/Disclosures
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