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Muscle-Directed Therapy Apitegromab Meets Primary End Point in Phase 3 SAPPHIRE Trial of Spinal Muscular Atrophy
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Key Takeaways
- Apitegromab showed significant motor function improvement in SMA patients, meeting the primary endpoint in the SAPPHIRE trial.
- Scholar Rock plans to submit a biologics license application to the FDA and EU in Q1 2025 for apitegromab.
Jay Backstrom, MD, MPH
Newly announced findings from the phase 3 SAPPHIRE trial (NCT05156320) showed that apitegromab (Scholar Rock), an investigational agent, met its primary end point, demonstrating a statistically significant improvement in motor function relative to placebo among patients with spinal muscular atrophy (SMA). Based on these data, Scholar Rock is expected to submit a biologics license application (BLA) to the FDA and European Union for marketing authorization in Q1 2025.1
The main efficacy population of SAPPHIRE included 156 patients with types 2 and 3 SMA aged 2-12 years old who were randomly assigned 1:1:1 to either apitegromab 10 mg/kg, apitegromab 20 mg/kg, or placebo by intravenous infusion every 4 weeks for a 12-month period. Using Hammersmith Functional Motor Scale Expanded (HFMSE) as the primary end point, the combined apitegromab groups demonstrated a mean difference of 1.8 points (P = .0192) relative to placebo (n = 50). Those in the 20 mg/kg group of apitegromab showed a 1.4 point mean difference vs placebo (P = .1149).
Apitegromab, a monoclonal antibody inhibiting myostatin activation by selectively binding the pro- and latent forms of myostatin in skeletal muscle, was considered safe and well tolerated, with no differences in adverse events (AEs) based on dosage. Overall, there were no study discontinuations because of AEs, and 98% (185 of 188) of participants who completed the trial went on to the ongoing ONYX open-label extension study. All serious AEs observed were related to SMA, and none were assessed as related to apitegromab.
"We are thrilled that apitegromab met the primary endpoint in our Phase 3 SAPPHIRE clinical study. The results clearly demonstrate robust and clinically meaningful improvement in motor function in patients with SMA," Jay Backstrom, MD, MPH, president and chief executive officer at Scholar Rock, said in a statement.1 "At Scholar Rock, we are working with urgency to deliver the potentially transformative benefits of apitegromab to children and adults with SMA in the US, Europe, and around the world."
In the main efficacy population, a prespecified analysis of the 10 mg/kg dose group of apitegromab (n = 10) revealed an improvement 2.2 points (P = .0121) on HFMSE compared with placebo. Notably, the 10 and 20-mg/kg groups of apitegromab showed similar levels of target engagement throughout the study.
The trial also included an exploratory population patients aged 13-21 who were assigned to either apitegromab (n = 22) or placebo (n = 10). Between the 2 groups, 30% of those on active drug had at least a 3-point improvement on HFMSE vs 12.5% of those on placebo. In addition, apitegromab-treated patients started showing early splits in motor function improvement vs placebo 8 weeks after treatment initiation, with benefits observed 52 weeks out.
"The positive Phase 3 SAPPHIRE trial, along with over 4 years of TOPAZ clinical trial data, clearly demonstrate the potentially transformative benefit of apitegromab to drive clinically meaningful improvements in motor function as measured by HFMSE in a broad SMA population, where motor function would normally be expected to generally decline over time," Jing Marantz, MD, PhD, chief medical officer at Scholar Rock, said in a statement.1 "We look forward to submitting our applications to the FDA and the EMA in Q1 2025.”
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Apitegromab first demonstrated its efficacy and safety as a potential treatment in the phase 2 TOPAZ trial (NCT03921528), a proof-of-concept study of SMA type 2 and 3. The latest data, which features patients on the drug for up to 48 months, showed continued and sustained motor function with apitegromab. At 48 months, a combination of 20 mg/kg of apitegromab and nusinersen (Spinraza; Biogen), a previously approved therapy for SMA, resulted in change of 5.3 points (95% CI, 1.5-9.2; n = 23) in HFMSE in nonambulatory patients aged 2-21. For those aged 2-12, the clinical effect was even greater, with changes of 6.4 points (95% CI, 1.8-11.0; n = 19).2
The analysis population pooled the nonambulatory patients (Cohorts 2 and 3) and included patients who received either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2). A total of 11 patients in the population had scoliosis surgery during the study and their data was excluded from any HFMSE or RULM assessments at 48 months. Using the remaining patient cohort, the mean change in RULM for the 2-21 age group (n = 22) was 3.6 points (95% CI, 2.0-5.3) and 4.5 (95% CI, 2.7-6.3) for the 2-12 age group (n = 18).
In TOPAZ, data also showed that treatment with apitegromab helped improve quality of life in nonambulatory patients with SMA. Presented at the 2022 International Scientific Congress on SMA, the analysis assessed activities of daily living (ADL), fatigue, and muscle endurance by 3 tertiary end point measures. They included the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), Patient Reported Outcome Measurement Information System (PROMIS), and Endurance Shuttle Box and Block Test (ESBBT).3
For nonambulatory type 2 patients, 24-month treatment with apitegromab resulted in stabilization or continuous improvements in ADL, as demonstrated by a mean change from baseline of 3 points (n = 14) in PEDI-CAT scores and a mean change of 5 points (n = 10) in PROMIS scores. PEDI-CAT measures pediatric abilities through 3 functional domains, daily activities, mobility, and social cognition, while PROMIS measures mild subjective feelings of tiredness to debilitating, and sustained feelings of exhaustion.
