New Motor Milestones Achieved or Sustained With Apitegromab in Nonambulatory SMA

Patients with type 2 or type 3 spinal muscular atrophy (SMA) experience sustained motor function benefits from apitegromab (SRK-015; Scholar Rock) therapy. This recent report published in Frontiers in Neurology expands on the phase 2, 12-month TOPAZ (NCT03921528) study, demonstrating the favorable safety and efficacy of apitegromab at 36 months.¹

Apitegromab is a muscle-directed exploratory infusion therapy designed as an add-on intervention for the benefit of motor functioning in patients with SMA.² Although this treatment is currently undergoing phase 3 investigation, the FDA has granted it fast track status and rare pediatric disease and orphan drug designations.

Apitegromab administered at 20 mg/kg via intravenous infusion every 4 weeks lead to improvements in motor functions in patients with SMA | Image credit: Mayava - stock.adobe.com

The present authors note how the novel development of therapies in SMA has dramatically altered patient prognoses; however, these interventions cannot address the partial denervation and muscle weakness and atrophy that occur prior to treatment initiation.¹ Despite these life-changing innovations, they added, there remains a need for interventions that target residual innervated muscle fibers to improve motor functions in partially denervated muscles.

Previously, in the phase 2, 12-month TOPAZ study, the Revised Upper Limb Module (RULM) and the Hammersmith Functional Motor Scale-Expanded (HFMSE) were used to quantify the observed benefits apitegromab had for patients with type 2 or 3 SMA. These scales were further utilized in the TOPAZ open-label, extension study to assess the long-term impact of apitegromab for patients with SMA who have lost ambulation.

Participants where organized into 3 cohorts: patients with type 3 SMA who were ambulatory and aged 5 to 21 years (cohort 1; n = 23), patients with type 2 SMA or nonambulatory type 3 SMA aged 5 to 21 years (cohort 2; n = 15), and patients with nonambulatory type 2 SMA aged at least 2 years (cohort 3; n = 20). Nearly 50% of cohort 1 had been receiving nusinersen, all of cohort 2 was receiving nusinersen after 5 years of age, and cohort 3 began nusinersen treatment after 5 years of age.

In 4-week increments throughout the primary testing period, each patient would receive an intravenous infusion of apitegromab. For those in cohorts 1 or 2, open-label apitegromab was administered at a dose of 20 mg/kg. Individuals in cohort 3 were randomized and double-blinded to receives either 20-mg/kg apitegromab or a lower dose of 2 mg/kg. When the extension period to 36 months was initiated, all continued with or were transitioned to a dosage of 20 mg/kg.

The primary focus during the extension period was the efficacy and safety of apitegromab for nonambulatory patients (n = 35). Their average age was 7.3 years.

Results from the HFMSE demonstrated motor function improvements, with an average improvement of 4 or more points from baseline. Sustained improvements were also seen in upper limb function, measured by RULM, by an average of more than 2 points. Throughout the 36-month period, the authors also noted that 28 patients maintained or improved features of the World Health Organization (WHO) motor milestones. Six of the 20 patients who received nusinersen before age 5 years notably achieved new WHO motor milestones; 2 patients could walk independently. Overall, there was also a favorable safety profile at 36 months, with no adverse events thought of as related to apitegromab and no deaths, serious and unexpected events, or hypersensitivity reactions reported.

These findings support the long-term use of apitegromab in SMA, the authors concluded, adding, “the data highlight the therapeutic potential of apitegromab to address persistent weakness and fatigue in individuals with [nonambulatory] SMA, enabling patients to potentially improve their motor function and be able to maintain these improvements.”

At present, the ongoing phase 3 SAPPHIRE trial (NCT03906071) will continue investigating the safety and efficacy of apitegromab therapy for those receiving nusinersen or risdiplam.

References

1. Crawford TO, Day JW, Vivo DCD. Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study. Front Neuro. Published online July 21, 2024. doi:10.3389/fneur.2024.1419791

2. Wexler M. Apitegromab (SRK-015) for spinal muscular atrophy. SMA News Today. Updated July 18, 2024. Accessed August 1, 2024. https://smanewstoday.com/apitegromab-srk-015/