Exploring higher doses of nusinersen in spinal muscular atrophy (SMA): final results from Parts B and C of the 3-part DEVOTE study

Topic:

Clinical Trials

Poster Number: O285

Author(s):

Thomas Crawford, MD, Johns Hopkins Hospital, Baltimore, MD, USA, Richard S Finkel, MD, St. Jude Children’s Research Hospital, Eugenio Mercuri, MD, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS, Rome, Italy, John Day, MD, PhD, Stanford School of Medicine, Jacqueline Montes, PT, EdD, Columbia University Irving Medical Center, New York, NY, USA, María del Mar García Romero, MD, PhD, Hospital La Paz, Madrid, Spain, Charlotte Sumner, MD, Johns Hopkins University School Of Medicine, Angela D Paradis, ScD, Biogen, Cambridge, MA, USA, Jihee Sohn, PhD, Biogen, Cambridge, MA, USA, Michael Monine, PhD, Biogen, Peng Sun, PhD, Biogen, Cambridge, MA, USA, Richard Foster, MSc, Biogen, Maidenhead, Berkshire, UK, Giulia Gambino, MSc, Biogen, Corinne Makepeace, MBBS, Biogen, Maidenhead, UK, Stephanie Fradette, PharmD, Biogen, Raechel Farewell, PharmD, Biogen, Cambridge, MA, USA

Submitted on behalf of the DEVOTE Study Group_x000D_
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DEVOTE (NCT04089566), a 3-part, Phase 2/3 trial, was designed to evaluate an investigational higher-dose regimen of nusinersen (two 50mg loading doses 14 days apart, then 28mg maintenance doses every 4 months) in participants with SMA. DEVOTE enrolled 145 participants aged 15 days to 65 years across SMA types. The 50/28mg regimen was generally well tolerated, with adverse events broadly consistent with the 12/12mg regimen of nusinersen. The pivotal Part B cohort enrolled treatment-naïve infantile-onset participants (n=75) randomized (2:1) to receive the 50/28mg regimen or the currently approved 12/12mg regimen. A prespecified matched sham control group from ENDEAR (NCT02193074) (n=20) served as the primary comparator for the 50/28mg regimen (n=50). The 50/28mg regimen (baseline mean CHOP-INTEND score of 20.9) showed statistically significant improvement over the matched sham comparator on the primary endpoint of change in CHOP-INTEND from baseline to Day 183 (LSM +15.1 vs −11.1; difference [95% CI]: 26.19 [20.7, 31.7]; p<0.0001). Results favored the 50/28mg regimen relative to sham across secondary endpoints (HINE-2, plasma NfL, event-free/overall survival). Results also trended in favor of the 50/28mg regimen over the 12/12mg regimen on key biomarker and efficacy measures. Additional analyses on measures of CGI and bulbar function will be debuted. Supportive data from Part B also demonstrated the benefit of the 50/28mg regimen in treatment-naïve later-onset participants. Part C (supportive; open-label) enrolled children and adults with infantile-onset or later-onset SMA who transitioned from the 12/12mg regimen to the 50/28mg regimen (n=40). Participants experienced improvements in motor function after transitioning to the 50/28mg regimen, with mean increases from baseline at Day 302 of 1.8 (SD 3.99) points on HFMSE and 1.2 (SD 2.14) points on RULM. Additional analyses from Part C will be debuted. Collectively, these data demonstrate the safety and efficacy of the 50/28mg regimen of nusinersen.