Nusinersen Shows Long-Term Safety, Benefits for Presymptomatic Infants With SMA

Thomas O. Crawford, MD

Interim results from the ongoing phase 2 NURTURE study (NCT02386553) of intrathecally delivered nusinersen (Spinraza; Biogen) suggest that the treatment is safe and beneficial over long-term use for presymptomatic infants with spinal muscular atrophy (SMA) and 2 or 3 copies of SMN2.¹

The data were presented by Thomas O. Crawford, MD, codirector, Muscular Dystrophy Association Clinic, and professor of neurology, Johns Hopkins Medical Institute, at the 2022 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 13-16, in Nashville, Tennessee.

Data were assessed with a mean of 4.9 years (range, 3.9-5.7) of follow-up from the study, with the data cut off of Feb 15, 2021. A total of 25 infants were enrolled in the study (2 SMN2 copies: n = 15; 3 SMN2 copies, n = 10), and at the data cut off all infants were alive, and none required permanent ventilation. “These data demonstrate the continued long-term safety and benefit of infants who initiated nusinersen before onset of SMA symptoms, emphasizing the value of newborn screening/early treatment,” Crawford et al wrote.

All told, 4 infants—all from the 2 SMN2 copy cohort—required respiratory intervention for ≥6 hours/day continuously for ≥7 days, though investigators noted that all cases were initiated during an acute reversible illness. The median time to death or respiratory intervention could not be estimated because there were no deaths and too few events requiring such interventions.

Every infant in the study cohort achieved the WHO motor milestone of sitting without support, while 96% (n = 24) were able to walk with assistance and 92% (n = 23) were able to walk unassisted. The majority of the children achieved these milestones within the 99th percentile age window for healthy children (84% [n = 21] for sitting without support; 60% [n = 15] for walking assisted; 64% [n = 16] for independent walking). Notably, none of the motor skills gained during the study were lost during the observation period, nor were new safety concerns were identified.

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Almost all the children (88%; n = 22) reached the maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale, and the mean change improvement from baseline at the first evaluable assessment after Day 700 in Hammersmith Functional Motor Scale Expanded (HFMSE) scores continued to show improvement over time. HFMSE scores were a mean of 16.1 (SE, 2.4) at month 36 (n = 11).

In September 2021, Biogen announced plans to initiate a phase 3b trial, called ASCEND (NCT05067790), to study the safety and efficacy of higher doses of nusinersen in patients with SMA who had been treated previously with risdiplam (Evrysdi; PTC Therapeutics).²

The trial is anticipated to span approximately 2.5 years and include 135 patients with later-onset, nonambulatory SMA between the ages of 5 and 39 years. Those in the trial will be given 2 loading, 50-mg doses of nusinersen 2 weeks apart, followed by a 28-mg maintenance dose at 4-month intervals for the duration of the study. The protocol submitted to the FDA featured inclusion criteria of prior treatment with the maximum 5-mg dose of risdiplam and falling within a specific Revised Upper Limb Module measurement range, which will then be used to assess efficacy. Safety, HFMSE scores, and caregiver burden are additional clinical outcomes to be evaluated.

“We believe that lower drug exposure may be contributing to less-than-optimal treatment outcomes for some patients treated with Evrysdi,” Maha Radhakrishnan, MD, chief medical officer, Biogen, said in a statement at the time the trial was announced.² “The ASCEND study seeks to understand if nusinersen may address that unmet medical need and will help inform the future of SMA treatment, with the hope of improving patients’ outcomes for the long term.”

Originally approved in December 2016, nusinersen became the first FDA-approved therapy to treat SMA types 1, 2, and 3. Since the approval, several trials have been initiated to study safety and efficacy of the treatment.

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REFERENCES
1. Crawford TO, Kirschner J, Ryan M, et al. Nusinersen effect in presymptomatic sma infants: 4.9 year interim of the nurture study. Presented at: MDA 2022; March 13-16; Nashville, Tennessee. Poster 71.
2. Biogen plans to initiate phase 3b study evaluating potential benefit of a higher dose of nusinersen in patients previously treated with Evrysdi (risdiplam). News release. Biogen. March 11, 2022. Accessed September 15, 2021. https://investors.biogen.com/news-releases/news-release-details/biogen-plans-initiate-phase-3b-study-evaluating-potential