Initial Safety Findings From Phase 4 RESPOND Study of Nusinersen Announced

After a mean follow-up of 64 days, the most common adverse events were infections and vomiting, with no deaths or reports of post-lumbar puncture syndrome.

At the 2022 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 13-16, in Nashville, Tennessee, new data from the phase 4 RESPOND study (NCT04488133) showed no adverse events (AEs) or serious AEs occurred in children with spinal muscular atrophy (SMA) treated with nusinersen (Spinraza; Biogen).1

The first patient was treated in January 2021, and the main goal of the trial is to understand if the proven efficacy of nusinersen and its mechanism of action, which leads to continuous production of survival motor neuron protein, may also benefit patients who have been insufficiently treated with gene therapy.2

Led by Julie Parsons, MD, professor of clinical pediatrics and neurology, Haberfeld Family Endowed Chair in Pediatric Neuromuscular Disorders, Children’s Hospital Colorado, the study is expected to evaluate 60 patients aged up to 3 years old using total score on Hammersmith Infant Neurological Examination (HINE) Section 2 motor milestones as the primary end point. The primary study group includes 40 infants aged 9 months or younger (at the time of first nusinersen dose) who have 2 copies of SMN2 and received nusinersen at 6 months or older.

As of August 16, 2021, 9 patients with a median age of 16.4 months (range, 5-30) were enrolled, with 1 discontinuing because of parent/guardian decision. All but 1 of the 9 infants had 2 SMN2 copies. All participants demonstrated suboptimal clinical status in at least 2 HINE domains, most commonly in motor and respiratory function, with an overall baseline mean score of 8.1 (±5.3).

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Median duration on nusinersen and safety follow-up period was 64 (range, 1-183) days. The initial safety data showed that 4 participants had a total of 7 infection-related events. They included ear infection, viral gastroenteritis, parainfluenza virus infection, pneumonia, upper respiratory tract infection (URTI), and viral URTI. Two participants reported vomiting as well. Serious AEs, which included parainfluenza virus infection (2 events in 1 participant) and URTI, were unrelated to treatment with nusinersen. No deaths or post-lumbar puncture syndrome events occurred.

Nusinersen, the first FDA-approved drug for the treatment of SMA in pediatric and adult patients, will also be administered in a second study group that will include 20 children within a broader age range (up to 3 years old at the time of first nusinersen dose). According to the trial registration information, patients will receive nusinersen 12 mg administered through intrathecal injection as loading doses on days 1, 15, 29, and 64 followed by maintenance doses every 4 months, on days 183, 302, 421, 540, and 659 over a 2-year study period.

Since its approval in 2016, it has been observed in multiple clinical studies, including the ongoing phase 2 NURTURE study (NTC02386553). New data from that study presented at MDA 2022 suggested that the treatment is safe and beneficial for presymptomatic infants with SMA over a long-term period. The study compiled data with a mean of 4.9 years (range, 3.9-5.7) of follow-up, with all 25 infants alive at data cut off. Additionally, none of them needed permanent ventilation.3

In September 2021, Biogen announced plans to initiate a new phase 3b trial, dubbed ASCEND (NCT05067790), to study the safety and efficacy of higher doses of nusinersen in patients with SMA who had been previously treated with ridsiplam (Evrysdi; PTC Therapeutics). That study is expected to include 135 patients with later-onset nonambulatory SMA between the ages of 5 and 39 years who will be on treatment for approximately 2.5 years.4

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1. Parsons J, Masson R, Proud C, et al. Baseline characteristics/initial safety results in RESPOND: a phase 4 study of nusinersen in children with SMA who received onasemnogene abeparvovec. Presented at: MDA 2022; March 13-16; Nashville, Tennessee. Poster 85
2. Biogen announces first patient treated in RESPOND study evaluating benefit of Spinraza (nusinersen) in patients treated with Zolgensma (onasemnogene abeparvovec). News release. Biogen. January 8, 2021.
3. 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.
4. 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.