Baseline Characteristics and Initial Safety Results in RESPOND: A Phase 4 Study of Nusinersen in Children with Spinal Muscular Atrophy (SMA) Who Received Onasemnogene Abeparvovec
John Brandsema1, Julie Parsons2, Crystal Proud3, Richard Finkel4, Kathryn Swoboda5, Ricardo Masson6, Yingying Liu7, Corinne Makepeace7, Angela Paradis7, Zdenek Berger7, Joanne Wagner7, Kathleen Somera-Molina7
1Children's Hospital of Philadelphia, 2Children's Hospital Colorado, 3Children's Hospital of the King's Daughters, 4St. Jude Children's Research Hospital, 5Massachusetts General Hospital, 66. Fondazione IRCCS Istituto Neurologico Carlo Besta, 7Biogen
Objective:

To provide baseline characteristics of participants and initial safety findings in RESPOND (NCT04488133), an ongoing, single-arm study evaluating nusinersen treatment in children with SMA previously treated with onasemnogene abeparvovec (OA).

Background:
OA is an adeno-associated viral (AAV) vector gene therapy for SMA in children age <2y. Preclinical studies demonstrated incomplete transduction of neurons by the AAV9 vector. Nusinersen has the potential to increase SMN protein in untransduced motor neurons.
Design/Methods:
In RESPOND, children ≤36 months old who have ≥1 SMN2 copy, are nusinersen-naïve, and had suboptimal clinical response to OA administered ≥3 months previously, receive the approved 12mg nusinersen regimen of 4 loading doses followed by maintenance doses every 4 months. Suboptimal clinical response (investigator-determined) includes ≥1 of the following domains: motor function, respiratory support, swallowing/feeding ability, and other. Study recruitment is ongoing.
Results:

As of 16 August 2021, 9 children (median [range] age 16.4 [5–30] months) were enrolled; 1 discontinued (parent/guardian decision). Most (8/9) had 2 SMN2 copies. Baseline mean±SD Hammersmith Infant Neurological Examination (HINE)-2 total score was 8.1±5.3. At baseline, all participants demonstrated suboptimal clinical status in ≥2 domains; motor and respiratory function were most common. Median duration on nusinersen and safety follow-up period was 64 days (range: 1–183 days). Most common adverse events (AEs) were infections (4 participants, 7 events [ear infection, viral gastroenteritis, parainfluenza virus infection (PIV), pneumonia, upper respiratory tract infection (URTI), viral URTI]) and vomiting (2 participants). Two participants had serious AEs: PIV (2 events in 1 participant) and URTI. No deaths or post-lumbar puncture syndrome events occurred. Additional results will be presented.

Conclusions:
Baseline characteristics of children in RESPOND showed suboptimal clinical status in multiple domains including motor and respiratory functions despite OA treatment. Initial safety findings indicate no AEs or serious AEs were considered related to nusinersen.