Muscle-Directed Therapy Apitegromab Reports Positive 24-Month Results in Spinal Muscular Atrophy


Over a 2-year period, apitegromab-treated patients demonstrated sizable and sustained improvements in Hammersmith Functional Motor Scale-Expanded and substantial increases in Revised Upper Limb Module scores.

George Nomikos, MD, PhD, senior vice president of Clinical Sciences, head of Muscle Therapeutic Area, Scholar Rock

George Nomikos, MD, PhD

Recently announced 24-month results from the phase 2 TOPAZ trial (NCT03921528) showed that nonambulatory patients with types 2 and 3 spinal muscular atrophy (SMA) had sustained and continued improvement with apitegromab (SRK-015; Scholar Rock), a muscle-directed therapy, when used in conjunction with nusinersen (Spinraza; Biogen).1

Following 24 months of treatment with apitegromab, investigators documented a 4.0-point (95% CI, 1.5-6.5) change in Hammersmith Functional Motor Scale Expanded (HFMSE), the primary end point, in the pooled ambulatory patient 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.

"The 24-month results provide long-term data and evidence, underscoring the findings of the 12-month primary treatment period of the TOPAZ trial in which patients receiving apitegromab experienced sizable motor function gains," George Nomikos, MD, PhD, senior vice president of Clinical Sciences, head of Muscle Therapeutic Area, Scholar Rock, said in a statement.1 "This durability and continued increase in motor function support the transformative potential of apitegromab for patients suffering with SMA."

The study, presented at the 2022 Cure SMA Research & Clinical Care Meeting, June 15-17, in Anaheim, California, evaluated apitegromab, a selective inhibitor of the activation of myostatin, in 35 nonambulatory patients (Cohorts 2 and 3) and 23 ambulatory patients (Cohort 1). All of those in cohorts 2 and 3 received nusinersen maintenance therapy in addition to apitegromab, whereas slightly more than half (12 of 23) of those in cohort 1 were on both medications. The analysis population included individuals receiving low-dose (2 mg/kg) or high-dose (20 mg/kg) apitegromab and did not exclude those who missed doses due to study site restrictions from COVID-19.

At 24 months, the pooled nonambulatory group experienced a change of 1.9 points (95% CI, 0.8-3.0) in Revised Upper Limb Module (RULM), an increase from 1.3 points (95% CI, 0.2-2.3) observed at the 12-month period. Excluding those with scoliosis surgery, the change increased to 2.3 points (95% CI, 1.2-3.4). Dose response continued to be observed across the 24-month treatment period based upon HFMSE scores and pharmacodynamic data, measured by serum latent myostatin concentrations, with signs that there may be further HFMSE increases as nonambulatory patients originally receiving the low dose switched to the high-dose treatment.

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In cohort 1, ambulatory patients with type 3 SMA showed stable scores on Revised Hammersmith Scale after receiving 20 mg/kg of apitegromab and nusinersen (n = 10), as demonstrated by change of –0.7 points (95% CI, –3.1 to 1.7) compared with change of –2.8 points (95% CI, –8.4 to 2.8) for the apitegromab monotherapy subgroup (n = 11). A subset of ambulatory individuals (n = 21) had RHS improvements, with 42.9% (n = 9) and 23.8% (n = 5) of patients achieving at least 1 or 3-point increases from baseline at 24 months, respectively.

Similar to the 12-month data, apitegromab had a safe treatment profile, with incidence and severity of adverse events that were consistent with the underlying patient population and background therapy. Notably, no deaths or serious adverse reactions were observed with apitegromab, and a total of 14 serious treatment-related adverse events were reported throughout the trial. Among both groups, 54 of the 55 individuals who completed the 24-month period continued on into the 36-month extension period.

"These data support apitegromab’s potential to meaningfully improve the lives of non-ambulatory patients with types 2 and 3 SMA,” Nagesh Mahanthappa, PhD, founding chief executive officer, and president, Scholar Rock, said in a statement.1 "As a company, we are dedicated to the SMA community and are urgently enrolling patients in our ongoing pivotal phase 3 SAPPHIRE trial."

Announced in December 2021, SAPPHIRE (NCT05156320) will evaluate the efficacy and safety of apitegromab in a cohort of 156 patients aged 2 to 12 years old with nonambulatory SMA types 2 and 3. Patients included in the pivotal study will be randomly assigned 1:1:1 to receive apitegromab 10 mg/kg or 20 mg/kg, or placebo, by intravenous infusion every 4 weeks for a 12-month period. The drug will be assessed in conjunction with nusinersen—similar to TOPAZ—however, those receiving background SMN treatment with risdiplam (Evrysdi; PTC Therapeutics) will also be eligible for the study. Once 50% of the main efficacy population completes their 12 months of treatment, Scholar Rock is expected to provide an interim analysis update.2

SAPPHIRE will also include an exploratory population that includes 48 patients aged 13 to 21 years old with nonambulatory SMA types 2 and 3. These patients will be randomly assigned 2:1 to receive either apitegromab 20 mg/kg or placebo added to background SMN treatment with nusinersen or risdiplam. At the conclusion of the 12-month treatment period in SAPPHIRE, patients will have the choice to enroll in an open-label extension, which will continue to evaluate the safety and tolerability of the drug, as well as an exploratory characterization of longer-term efficacy.

1. 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 July 11, 2022.
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 July 11, 2022.
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