Impact of baseline characteristics and eligibility criteria on outcomes in children with presymptomatic spinal muscular atrophy (SMA) in NURTURE

Topic:

Clinical Trials

Poster Number: 165

Author(s):

Thomas Crawford, MD, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Richard S Finkel, MD, St. Jude Children’s Research Hospital, Memphis, TN, USA, Darryl C De Vivo, MD, Columbia University Irving Medical Center, New York, NY, USA, Kathryn J Swoboda, MD, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA, Enrico Bertini, MD, PhD, Post-Graduate Bambino Gesù Children’s Research Hospital, IRCCS, Rome, Italy, Wuh-Liang Hwu, MD, PhD, National Taiwan University Hospital, Taipei, Taiwan, Janbernd Kirschner, PhD, University of Freiburg, Freiburg, Germany, Nancy L Kuntz, MD, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA, Aledie Navas Nazario, Nemours Children’s Hospital, Orlando, FL, USA, Julie A Parsons, MD, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA, Astrid Pechmann, MD, University of Freiburg, Freiburg, Germany, Monique M Ryan, Murdoch Children’s Research Institute and University of Melbourne, Melbourne, Australia, Russell J Butterfield, MD,PhD, University of Utah, Salt Lake City, UT, USA, Haluk Topaloglu, Hacettepe University, Ankara, Turkey, Tawfeg Ben-Omran, Sidra Medicine, Doha, Qatar; Hamad Medical Corporation, Doha, Qatar, Valeria A Sansone, MD, University of Milan, Milan, Italy; Universitàdegli Studi di Milano, Milan, Italy, Yuh-Jyh Jong, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Taiwan, Francy Shu, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA, Corinne Makepeace, MBBS, Biogen, Maidenhead, Berkshire, UK, Richard Foster, MSc, Biogen, Maidenhead, Berkshire, UK, Russell Chin, MD, Biogen, Cambridge, MA, USA, Zdenek Berger, PhD, Biogen, Cambridge, MA, USA

Background: NURTURE is an ongoing study (NCT02386553) of nusinersen initiated in the presymptomatic stage of SMA in infants with 2 (n=15) or 3 SMN2 (n=10) copies. Interim results after ~5 years (data cut 15 February 2021) show all participants are alive and most achieved all World Health Organization (WHO) motor milestones, often within normal developmental timeframes. Eight of the 15 children with 2 SMN2 copies either utilized respiratory intervention for ≥6 h/d continuously for ≥7 d (n=4), had gastrostomy tube placement (n=5), and/or developed SMA symptoms by 24 months (n=7). Many of these children had lower compound muscle action potential (CMAP) values and were areflexic at baseline. This led us to assess the potential impact of these baseline characteristics on motor and nonmotor outcomes.
Objectives: To assess the potential impact of baseline characteristics, outcomes were assessed in NURTURE children with 2 SMN2 copies who did not have CMAP <2 mV and who were not areflexic at baseline. Results: Eight children met these criteria (subgroup 1). Compared with all 15 children with 2 SMN2 copies, they had similar ages at first nusinersen dose and similar baseline Hammersmith Infant Neurological Examination Section 2 scores, but higher baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores (median [range]: 45.0 (25–60] vs 54.5 [35–60]). No subgroup 1 participant required respiratory intervention or gastrostomy tube placement; 1 developed SMA symptoms by age 24 months. A higher proportion in subgroup 1 achieved each WHO motor milestone within normal timeframes vs all NURTURE children with 2 SMN2 copies: sitting without support (88% vs 73%), standing with assistance (100% vs 60%), hands and knees crawling (75% vs 40%), walking with assistance (75% vs 40%), standing alone (50% vs 27%), and walking alone (75% vs 40%). In a sensitivity analysis of subgroup 1 plus 3 children with 2 SMN2 copies with missing values (baseline tendon reflex [n=2] or peroneal CMAP [n=1] data), the proportion achieving WHO motor milestones within normal timeframes was generally higher than all NURTURE children with 2 SMN2 copies and lower than subgroup 1. Conclusions: These data suggest that small differences in inclusion/exclusion criteria and baseline characteristics impact both motor and nonmotor clinical outcomes. It is important to consider baseline characteristics when interpreting data from presymptomatic SMA trials. Funding: Biogen