Correlation of individual survival of motor neuron (SMN) protein with observed efficacy in the risdiplam clinical trials


Clinical Trials

Poster Number: S108


Heidemarie Kletzl, PhD, F. Hoffmann-La Roche Ltd, Yumi Cleary, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland, Paul Grimsey, Roche Products Ltd, Welwyn Garden City, UK, Claudia Chiriboga, MD, MPH, Columbia University, Eugenio Maria Mercuri, MD, PhD, POLICLINICO UNIV A. GEMELLI - DIV NEUROPSICHIATRIA INFANTILE, Tammy McIver, Roche Products Ltd, Welwyn Garden City, UK, Riorge Thomas, Roche Products Ltd, Welwyn Garden City, UK, Renata S Scalco, MD PhD, Pharma Development Neurology, F. Hoffmann-La Roche Ltd, Basel, Switzerland


Risdiplam (EVRYSDI®) is an oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA).

Safety and efficacy of risdiplam were assessed in clinical studies of patients with SMA, from infants to adults, with a body weight ≤109 kg and aged ≤61 years old. Pharmacokinetic and pharmacodynamic data were used to select dosing regimens of 0.2 mg/kg for infants aged between 2 months and 2 years, 0.25 mg/kg for children ≥2 years old with a body weight <20 kg, and 5 mg for patients with a body weight ≥20 kg. Pharmacodynamic markers SMN2 mRNA and SMN protein were assessed in blood samples obtained from all patients over the duration of the study for up to 2 years. Objectives Assess the correlation between individual patient SMN protein level and observed efficacy. Results Risdiplam’s mode of action was confirmed by the shift from SMN2Δ7 mRNA to full-length mRNA. Risdiplam treatment led to a ≥2-fold median increase in SMN protein levels within 4 weeks of the start of treatment, which was maintained throughout treatment. Exposure–response analyses assessed the correlation between individual participant SMN protein level and observed efficacy in pivotal studies in patients with Type 1 (FIREFISH Part 2; NCT02913482) and Types 2/3 SMA (SUNFISH Part 2; NCT02908685). Correlation-efficacy analyses were conducted using absolute SMN protein values during the study treatment period and with the change from baseline in SMN protein level obtained for each patient pre- and post-risdiplam treatment. Conclusions Clinical studies confirmed the risdiplam mode of action and efficacy in patients. The results of the correlation of SMN protein in blood versus the assessed efficacy endpoints (FIREFISH: sitting, head control, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; SUNFISH: 32-item Motor Function Measure, Revised Upper Limb Module) will be presented.