Exploring Higher Doses of Nusinersen in Spinal Muscular Atrophy (SMA): Integrated Results from the DEVOTE Part B and ONWARD Studies

Topic:

Clinical Trials

Poster Number: 101 S

Author(s):

Richard Finkel, MD, St Jude Children's Research Hospital, Maria del Mar Garcia Romero, MD, PhD, Hospital La Paz, Madrid, Spain, Thomas Crawford, MD, Johns Hopkins University School of Medicine, Eugenio Mercuri, MD, PhD, Paediatric Neurology, Catholic University, Rome, Italy, Centro Clinico Nemo, IRCCS, Rome, Italy, John Day, MD, PhD, Stanford, Jacqueline Montes, PT, EdD, Columbia University Irving Medical Center, New York, NY, US, 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 an investigational higher-dose nusinersen regimen (two 50 mg loading doses 14 days apart, followed by 28 mg maintenance doses every 4 months) in participants with SMA.

DEVOTE Part B randomized (2:1) 75 treatment-naive participants with infantile-onset SMA to 50/28 mg or 12/12 mg nusinersen. A prespecified matched sham group from ENDEAR (NCT02193074) (n=20) served as the primary comparator for 50/28 mg (n=50).

Participants receiving 50/28 mg (baseline mean Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP-INTEND] score: 20.9) showed statistically significant improvement over matched sham (baseline mean CHOP-INTEND: 23.6) on change in CHOP-INTEND from baseline to Day 183 (primary endpoint) (least-squares mean [LSM], +15.1 versus −11.1; LSM difference [95% confidence interval (CI)] 26.19 [20.7–31.7]; joint-rank test LSM, 42.9 versus 16.9; difference [95% CI]: 26.06 [17.9–34.2], p<0.0001). Results favored 50/28 mg over sham across secondary endpoints (Hammersmith Infant Neurological Examination – Section 2 [HINE–2], plasma neurofilament light chain [NfL] levels, event-free survival, and overall survival) and trended in favor of 50/28 mg over 12/12 mg for key biomarkers and efficacy. Benefit of 50/28 mg was also shown in the Part B later-onset cohort. Nusinersen 50/28 mg was generally well tolerated, with adverse events broadly consistent with 12/12 mg. As of the interim data cut, ONWARD has enrolled 35 infantile-onset and 23 later-onset participants from Part B. The primary endpoint of ONWARD is safety, and longer-term 50/28 mg was generally well tolerated. Pre-dose evaluations of ONWARD Day 1 for CHOP-INTEND and HINE-2 in the infantile-onset cohort, and for Hammersmith Functional Motor Scale – Expanded and Revised Upper Limb Module in the later-onset cohort, showed consistent trends compared with DEVOTE. Collectively, these data show the longer-term efficacy and safety of 50/28 mg nusinersen.