DEVOTE Part C and ONWARD Integrated Results: Higher Doses of Nusinersen in Nusinersen-Experienced Participants with Spinal Muscular Atrophy (SMA)

Topic:

Clinical Trials

Poster Number: 406 O

Author(s):

Richard Finkel, MD, St Jude Children's Research Hospital, Eugenio Mercuri, MD, PhD, Paediatric Neurology, Catholic University, Rome, Italy, Centro Clinico Nemo, IRCCS, Rome, Italy, Thomas Crawford, MD, Johns Hopkins University School of Medicine, John Day, MD, PhD, Stanford, Jacqueline Montes, PT, EdD, Columbia University Irving Medical Center, New York, NY, US, Maria del Mar Garcia Romero, MD, PhD, Hospital La Paz, Madrid, Spain, Charlotte Sumner, MD, Johns Hopkins University School of Medicine, Angela Paradis, ScD, Biogen, Cambridge, MA, USA, Peng Sun, PhD, Biogen, Richard Foster, PhD, Biogen, Giulia Gambino, MSc, Biogen, Maidenhead, UK, Ross Littauer, PhD, Biogen, Cambridge, MA, USA, Stephanie Fradette, PharmD, Biogen, Raechel Farewell, PharmD, Biogen, Cambridge, MA, USA

DEVOTE (NCT04089566; 3-part, Phase 2/3 trial) and ONWARD (NCT04729907; Phase 3 open-label long-term extension) evaluate higher-dose nusinersen in participants with SMA.

DEVOTE Part C (open-label) enrolled 40 participants (aged 4–65 years) with infantile or later-onset SMA who transitioned to higher-dose nusinersen after ≥1 year on 12/12 mg. Participants received one 50 mg loading dose four months ±14 days after their last 12 mg dose, followed by two 28 mg maintenance doses on Days 121 and 241. Safety was the primary endpoint.

Participant demographics were heterogeneous by design, with broad baseline Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores. Adverse events occurred in 37/40 (92.5%) participants: mild or moderate in 32/40 (80%), severe in 5/40 (12.5%). Baseline plasma neurofilament light chain (NfL) levels were within the range of neurologically healthy individuals and remained low after transitioning to 50/28 mg. Most participants had improvements on HFMSE, RULM, and/or Clinical Global Impression–Change (CGI-C) (assessed by investigator/caregiver) after transitioning. At day 302, mean (SD) increases from baseline on HFMSE were +2.5 (4.22) points in ambulatory and +1.1 (3.71) points in non-ambulatory participants. RULM scores improved by +0.6 (1.79) points in ambulatory and +1.8 (2.29) points in non-ambulatory participants. Of 26 participants with baseline scores below the scale maximum, 62% had increased RULM scores after transitioning.

50/28 mg nusinersen was generally well tolerated, with adverse events broadly consistent with 12/12 mg. Some improvements exceeded expectations for individuals having previously received 12/12 mg nusinersen for a median of 3.9 years. These data support transition to 50/28 mg.

At interim cutoff, ONWARD Part C enrolled 39 participants. The primary endpoint is safety and tolerability, and 50/28 mg was generally well tolerated. Pre-dose evaluations of ONWARD day 1 show HFMSE and RULM improvements/stabilization across subgroups. Longer-term results will be debuted.