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BLA Submitted for Muscle-Promoting Therapy Apitegromab as New Treatment for Spinal Muscular Atrophy
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Key Takeaways
- Scholar Rock submitted a BLA for apitegromab, targeting myostatin to enhance muscle growth in SMA patients.
- Phase 3 SAPPHIRE trial showed significant motor function improvement with apitegromab, meeting its primary endpoint.
The submission was based on promising data from a phase 3 and phase 2 study, where treatment with apitegromab led to significant improvements in motor function among patients with SMA on SMN-targeted treatments.
Jing Marantz, MD, PhD
According to a new announcement from Scholar Rock, the company has formally submitted a biologics license application (BLA) for its investigational agent apitegromab, a muscle-targeting therapy, as a potential new add-on medication for patients with spinal muscular atrophy (SMA). In addition, Scholar Rock remains on track to submit a marketing authorization application (MAA) the European Medicines Agency by Q1 2025.1
Apitegromab is built to inhibit myostatin activation by targeting its pro- and latent forms, promoting muscle growth and improving motor function in SMA. To date, the therapy has received fast track, orphan drug, and rare pediatric disease designations in SMA. The BLA submission for the monoclonal antibody was based on data from the pivotal phase 3 SAPPHIRE trial (NCT05156320) as well as phase 2 TOPAZ trial (NCT03921528).
SAPPHIRE, a 156-person trial of individuals with types 2 and 3 SMA aged 2-12 years old, met its primary end point, with apitegromab-treated patients demonstrating a statistically significant improvement in motor function vs those on placebo. Using Hammersmith Functional Motor Scale Expanded (HFMSE) as the primary end point, the combined apitegromab groups (10 mg/kg and 20 mg/kg) demonstrated a mean difference of 1.8 points (P = .0192) in comparison to those on placebo (n = 50). Those in the 20 mg/kg group of apitegromab showed a 1.4-point mean difference vs placebo (P = .1149).2
"We are gratified that in patients already on a SMN-targeted treatment, the SAPPHIRE trial met its primary endpoint for the main efficacy population showing a statistically significant 1.8-point improvement for patients receiving apitegromab compared to placebo, as measured by the Hammersmith Functional Motor Scale-Expanded at week 52," Jing Marantz, MD, PhD, chief medical officer at Scholar Rock, said in a statement.1 "With the strength of our Phase 3 data as the foundation of our submission, we look forward to continuing to work closely with the FDA through the review of our BLA on behalf of patients and families living with SMA."
Apitegromab was considered safe and well tolerated in SAPPHIRE, with no study discontinuations due to adverse events (AEs), and all serious AEs were related to SMA and not to the study drug. Overall, there were no differences between apitegromab and placebo in the incidence of AEs, and 98% of participants who completed the trial went on to the ongoing ONYX open-label extension study.2
In the main efficacy population, patients receiving 10 mg/kg of apitegromab (n = 10) demonstrated a significant improvement of 2.2 points on the HFMSE compared with placebo (P = .0121). Both the 10 and 20 mg/kg dose groups showed similar levels of target engagement throughout the study.
In an exploratory population of patients aged 13-21, 30% of those treated with apitegromab (n = 22) achieved at least a 3-point improvement on the HFMSE, compared with 12.5% of those on placebo (n = 10). Motor function improvements in the apitegromab-treated group began to emerge as early as 8 weeks post-treatment initiation, with sustained benefits observed at 52 weeks.
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Apitegromab’s potential as a treatment for SMA type 2 and 3 was first established in the phase 2 TOPAZ trial, which demonstrated both efficacy and safety. Long-term data from this study, including patients treated for up to 48 months, revealed sustained motor function improvements. Among nonambulatory patients aged 2-21 treated with 20 mg/kg of apitegromab in combination with nusinersen (Spinraza; Biogen), HFMSE scores increased by 5.3 points (95% CI, 1.5-9.2; n = 23). Younger patients aged 2-12 exhibited an even greater benefit, with a mean change of 6.4 points (95% CI, 1.8-11.0; n = 19).3
The analysis pooled nonambulatory patients (Cohorts 2 and 3) and included those receiving low-dose (2 mg/kg) or high-dose (20 mg/kg) apitegromab. Notably, some Cohort 3 patients transitioned from 2 mg/kg to 20 mg/kg in Year 2. Data from patients who underwent scoliosis surgery during the study were excluded from HFMSE and Revised Upper Limb Module (RULM) assessments at 48 months. Among the remaining cohort, RULM scores improved by a mean of 3.6 points (95% CI, 2.0-5.3) in the 2-21 age group (n = 22) and 4.5 points (95% CI, 2.7-6.3) in the 2-12 age group (n = 18).
Treatment with apitegromab also showed quality-of-life benefits for nonambulatory SMA patients, as evidenced by data presented at the 2022 International Scientific Congress on SMA. Assessments of daily living activities, fatigue, and muscle endurance were conducted using tertiary endpoints such as the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), Patient-Reported Outcome Measurement Information System (PROMIS), and the Endurance Shuttle Box and Block Test (ESBBT).4
For nonambulatory type 2 SMA patients, 24 months of apitegromab treatment resulted in stabilization or continuous improvement in activities of daily living (ADL). PEDI-CAT scores improved by a mean of 3 points (n = 14), and PROMIS scores improved by a mean of 5 points (n = 10). These tools assess various aspects of functional ability, with PEDI-CAT focusing on daily activities, mobility, and social cognition, and PROMIS evaluating levels of fatigue, ranging from mild to debilitating.
