Open-Label Extension Data Highlights Continued Benefits of Apitegromab in Spinal Muscular Atrophy


Over the 36-month treatment period, nonambulatory patients with SMA treated with apitegromab showed improvements in patient-reported outcomes of daily living and fatigue.

Thomas Crawford, MD, pediatric neurologist, Johns Hopkins Medicine

Thomas Crawford, MD

At the recently concluded Cure SMA Research & Clinical Care Meeting, new data from the phase 2 TOPAZ trial (NCT03921528) showed substantial and sustained improvement in motor function for up to 36 months among individuals with spinal muscular atrophy (SMA) treated with apitegromab (Scholar Rock). Apitegromab, the first muscle-targeting agent to demonstrate clinical proof of concept in SMA, continues to be assessed in the ongoing phase 3 SAPPHIRE trial (NCT05156320), a double-blind, placebo-controlled study.

Also known as SRK-015, treatment with the investigational agent resulted in a mean change of 4.0 (95% CI, 1.0-6.9) points in Hammersmith Functional Motor Scale-Expanded (HFMSE) over the 36-month treatment period. The trial, which featured nonambulatory patients with SMA types 2 or 3, aged 2 to 21 years, also showed a mean change of 2.4 (95% CI, 1.1-3.7) points in Revised Upper Limb Module (RULM) scores over the same period. Of note, more than 90% of nonambulatory patients remained on treatment in the extension study.

"These promising long-term data highlight the therapeutic potential of muscle-targeting therapies, such as apitegromab, to help those with SMA address persistent weakness,” lead investigator Thomas Crawford, MD, pediatric neurologist, Johns Hopkins Medicine, said in a statement. “While SMN-targeting therapies play an important role in preventing further loss of motor neurons, many people still experience persistent or progressive symptoms due to preexisting motor neuron degeneration. Incorporating a muscle-targeting therapy with apitegromab’s clinical profile into the treatment paradigm could allow patients to sustain or potentially achieve new gains in motor functioning."

Additional findings showed that improvements in patient-reported outcomes, such as the PEDI-CAT and PROMIS-Fatigue, were consistent with improvements in motor function observed at 36 months. Treated patients showed a mean change of 2.2 (95% CI, –0.1 to 4.5; n = 17) in the PEDI-CAT daily activity domain and a mean change of –4.6 (95% CI, –8.7 to –0.5; n = 14) in PROMIS-Fatigue, improvements that were consistent and sustained throughout the trial.

Safety data was consistent with previous observations at 12 and 24 months, with treatment-emergent adverse events (TEAEs) that were mild-to-moderate in severity, and generally consistent with the underlying patient population. Headache, pyrexia, COVID-19, nasopharyngitis, and upper respiratory tract infection were among the 5 most common TEAEs recorded. Throughout the 36-month period, no patients displayed positive titers for apitegromab antibodies, and no deaths or suspected serious adverse reactions or hypersensitivity reactions were observed.

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"We are excited to share these new phase 2 data that support apitegromab’s long-term durability of effect and consistent tolerability and safety profile,” Jay Backstrom, MD, MPH, president and chief executive officer at Scholar Rock, said in a statement.1 "These results further strengthen our confidence in apitegromab’s therapeutic potential for patients with SMA, as well as validate Scholar Rock’s unique approach to selectively inhibiting the pro and latent forms of myostatin."

The agent is currently being assessed in SAPPHIRE, a phase 3, double-blind, placebo-controlled study currently enrolling, is expected to include 156 patients aged 2-12 years old with Type 2 and 3 SMA. Patients will be randomly assigned 1:1:1 to either apitegromab 10 mg/kg or 20 mg/kg, or placebo, by intravenous infusion every 4 weeks for a 12-month period. The trial also includes an exploratory population of 48 patients aged 13-21 years old who will be randomly assigned 2:1 to either apitegromab 20 mg/kg or placebo.2

Similar to TOPAZ, patients in the study will be on either nusinersen (Spinraza; Biogen) or risdiplam (Evrysdi; PTC Therapeutics) while receiving apitegromab. Once 50% of the main efficacy population completes their 12 months of treatment, Scholar Rock will provide an interim analysis update. Investigators will use change from baseline on the HFMSE total score as the primary end point, and several other additional end points including safety, the proportion of patients with at least a 3-point HFMSE increase, RULM scores, and World Health Organization motor developmental milestones. The trial will also assess pharmacodynamics, pharmacokinetics, and antidrug antibodies.

Previously, 24-month findings from TOPAZ showed a 4.0-point (95% CI, 1.5-6.5) change in HFMSE scores in the pooled ambulatory cohort, an increase from 3.6 points (95% CI, 1.2-6.0) observed at the 12-month mark. Additionally, after excluding those with scoliosis surgery (n = 3), the mean change from baseline increased to 4.4 points (95% CI, 2.0-6.9) at the end of the 24-month period.3

1. New 36-month apitegromab extension data reinforce long-term substantial and sustained improvement of motor function in phase 2 TOPAZ trial patients with nonambulatory spinal muscular atrophy. News release. Scholar Rock. June 30, 2023. Accessed August 15, 2023.
2. Scholar Rock announces design of phase 3 SAPPHIRE clinical trial evaluating apitegromab in non-ambulatory patients with type 2 and type 3 spinal muscular atrophy. News release. Scholar Rock. November 30, 2021. Accessed August 15, 2023.
3. Positive phase 2 TOPAZ trial extension data demonstrate sizable and sustained motor function improvement at 24 months with apitegromab for non-ambulatory patients with types 2 and 3 spinal muscular atrophy (SMA). News release. June 17, 2022. Accessed August 15, 2023.
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