Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy

New results from the NURTURE (NCT02386553) clinical trial, published in Muscle & Nerve, indicate that treatment of children with genetically diagnosed but presymptomatic spinal muscular atrophy (SMA) using Spinraza (nusinersen; Biogen, Cambridge, MA) was effective and helped preserve motor function long term. Analysis of results also provides novel insights into early markers of SMA disease progression before the onset of symptoms.

NURTURE is an open-label study examining the efficacy of Spinraza for the treatment of children with genetically diagnosed but presymptomatic SMA. The study includes 25 participants no older than 6 weeks who have multiple copies of survival motor neuron 2 (SMN2). The primary endpoint is time to death or respiratory intervention, with secondary outcomes assessing growth, World Health Organization (WHO) motor milestones, adverse events, and laboratory parameters. After the initial 3-year analysis, participants showed improvements in secondary outcomes.

Data reported in Muscle & Nerve from an additional 2-year follow up period revealed that all 25 participants were still alive, and none discontinued treatment. Nine of the 10 participants with 3 SMN2 copies achieved WHO motor milestones within age-appropriate timelines, with 1 participant walking with assistance late, but then meeting the timeline for walking alone. All participants with 2 SMN2 copies sat without support, 14/15 achieved walking with assistance, and 13/15 walked alone. Overall, 23 of the 25 participants were able to walk after 5 years of treatment. Additionally, researchers identified that the subgroup of participants with 2 SMN2 copies, excluding those with a compound muscle action potential (CMAP) no less than 2 mV or with areflexia, showed better outcomes than the rest of the cohort.

“The NURTURE data show how small differences in baseline characteristics can greatly impact outcomes, including motor function, respiratory function, swallowing and feeding,” said Thomas Crawford, MD, Codirector of the Muscular Dystrophy Association Clinic.

SMA is a rare neuromuscular disorder characterized by progressive muscle weakness due to loss of motor neurons that affects approximately 1 out of every 10,000 people in the United States. It is the most common genetic cause of infant death.

https://practicalneurology.com/news/majority-of-children-with-spinal-muscular-atrophy-treated-with-spinraza-are-able-to-walk-within-age-appropriate-timelines?utm_campaign=Neurologywire&utm_medium=email&_hsmi=267155010&_hsenc=p2ANqtz-8BkGp_CcfeaE5qh1cpD4We3xqE1efc-78-PVYjlsFkg0LpAaMdEhKcRE0s4Mgmj1zcfKqJMecMPohE-F-JnFKSOF0dHpS3ri3q9vWKk8KDG4pr3Uk&utm_content=267155010&utm_source=hs_email

Crawford TO, Swoboda KJ, De Vivo DC, Bertini E, Hwu WL, Finkel RS, Kirschner J, Kuntz NL, Nazario AN, Parsons JA, Pechmann A, Ryan MM, Butterfield RJ, Topaloglu H, Ben-Omran T, Sansone VA, Jong YJ, Shu F, Zhu C, Raynaud S, Lago TR, Paradis AD, Foster R, Chin R, Berger Z; NURTURE Study Group. Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study. Muscle Nerve. 2023 Aug;68(2):157-170. doi: 10.1002/mus.27853. Epub 2023 Jul 6. PMID: 37409780.

Abstract

Introduction/aims: NURTURE (NCT02386553) is an open-label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow-up (data cut: February 15, 2021) are reported.

Methods: The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety.

Results: Median age of children was 4.9 (3.8-5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies.

Discussion: These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.