Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment

Autor: Eugenio, Mercuri, Giovanni, Baranello, Odile, Boespflug-Tanguy, Liesbeth, De Waele, Nathalie, Goemans, Janbernd, Kirschner, Riccardo, Masson, Elena S, Mazzone, Astrid, Pechmann, Maria Carmela, Pera, Carole, Vuillerot, Silvia, Bader-Weder, Marianne, Gerber, Ksenija, Gorni, Janine, Hoffart, Heidemarie, Kletzl, Carmen, Martin, Tammy, McIver, Renata S, Scalco, Wai Yin, Yeung, Laurent, Servais
Rok vydání: 2022
Předmět:
Zdroj: European journal of neurologyREFERENCES.
ISSN: 1468-1331
Popis: BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein. METHODS: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured. RESULTS: There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight
Databáze: OpenAIRE
Externí odkaz: