Muscle-Targeting Therapy Apitegromab Effective in Spinal Muscular Atrophy Over 4 Year Period
Scholar Rock's TOPAZ phase 2 trial shows sustained motor function improvements in SMA patients treated with apitegromab over 48 months, with phase 3 results expected soon.
Jay Backstrom, MD, MPH
In a company update, Scholar Rock reported new positive 48-month data from its phase 2 TOPAZ trial (NCT03921528), with results showing continued and sustained motor function in patients with spinal muscular atrophy (SMA) treated with investigational apitegromab, a muscle-targeting agent. Additionally, the company reported it expects topline data from its ongoing phase 3 SAPPHIRE trial (NCT05156320) of apitegromab in SMA in the fourth quarter of this year.1
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 Hammersmith Functional Motor Scale (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).
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).
"With the only muscle-targeted program to demonstrate clinical proof-of-concept in SMA, our confidence in our lead program apitegromab continues to be supported by the clinical data generated over the past four years," Jay Backstrom, MD, MPH, president and chief executive officer at Scholar Rock, said in a statement.1 "At 48 months, over 90% of TOPAZ patients with nonambulatory SMA remained on apitegromab treatment on top of SMN therapy and we continued to observe sustained clinical benefit. We look forward to reporting topline data from the Phase 3 SAPPHIRE trial of apitegromab in SMA in the fourth quarter of this year."
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Of the 35 participants in the pooled nonambulatory population, 33 remained in the study over 4 years. The company also noted that more than 90% of the patients on combination therapy in TOPAZ have completed 4 years of apitegromab treatment and enrolled in ONYX, a long-term, open-label extension that continues to evaluate the efficacy and safety of apitegromab. It includes those with type 2 and 3 SMA who completed the TOPAZ or SAPPHIRE clinical trials.
SAPPHIRE, a randomized, double-blind, placebo-controlled study, has an efficacy population that includes approximately 156 patients aged 2-12 years old with type 2 or 3 SMA. Patients in the study are randomly assigned 1:1:1 to either apitegromab 10 mg/kg, 20 mg/kg, or placebo, for a 12-month treatment. The study includes an additional exploratory population comprised of 48 patients aged 13-21 years old who are randomly assigned 2:1 to either apitegromab 20 mg/kg or placebo.
In the update, Scholar Rock also noted that enrollment for a phase 2 proof-of-concept study, dubbed EMBRAZE, evaluating apitegromab in obesity has been advancing ahead of schedule, with topline data expected in the second quarter of 2025. This double-blind, placebo-controlled trial includes adults with a body mass index (BMI) of greater than 27 (overweight) or a BMI of greater than 30 (obese) who are taking a GLP-1 receptor agonist (tirzepatide or semaglutide).
EMBRAZE is expected to comprise 100 adults aged 18-65 who are overweight or obese without diabetes. As part of the study, the treatment period is 24 weeks, and all patients will receive a GLP-1 receptor agonist. In addition, all participants will be randomly assigned 1:1 to either apitegromab or placebo by intravenous infusion every 4 weeks during the 24 week period. Investigators will primarily assess change in lean mass through x-ray absorptiometry, while other end points include weight loss measures, safety and tolerability, and pharmacokinetic outcomes.
