BACKGROUND AND OBJECTIVES:Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA. METHODS:In this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants ≥2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points. RESULTS:Fifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported. DISCUSSION:Apitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA. TRIAL REGISTRATION INFORMATION:This trial is registered with ClinicalTrials.gov (NCT03921528). CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

Background and ObjectivesCurrently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA.MethodsIn this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants >= 2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points.ResultsFifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported.DiscussionApitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA.Trial Registration InformationThis trial is registered with ClinicalTrials.gov (NCT03921528).Classification of EvidenceThis study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

Objective: To evaluate patient treatment effects beyond TOPAZ trial endpoint measures to provide a deeper understanding of the potential benefit of apitegromab. Background: SMA is caused by deletion or mutation in SMN1 gene and is characterized by motor neuron deterioration that contributes to progressive muscle weakness and loss of motor function. Current SMN treatments have shown improvements in motor function; however, limitations remain that contribute to unmet needs. In a Phase 2 trial (TOPAZ, NCT03921528), we have reported safety and efficacy of apitegromab, a selective myostatin inhibitor, in patients with Types 2/3 SMA. HFMSE and RHS scales were used to evaluate efficacy. Design/Methods: This qualitative, cross-sectional study aimed to gain insights into the impact of SMA and potential treatment benefits based on patient's/caregiver's perceptions of SMA and experience with treatment during the TOPAZ trial through 24 months. A subset of 15 patients were invited to participate in a 2 hour semi-structured interview about their experience with SMA and perceptions of meaningful treatment benefit during the trial. Treatment effects observed during the trial were compared to pre-treatment signs and symptoms. Results: Twelve patients/caregivers were interviewed. Participants reported substantial burden in signs and symptoms associated with SMA including muscle weakness, fatigue, problems with balance, respiratory problems, and bowel difficulties. They also reported impacts of SMA on physical function, dependency, daily activities, and social activities. Improvements in signs, symptoms and impacts of SMA after treatment will be reported. Conclusions: The symptoms and impacts of living with SMA as reported by 12 patients/caregivers provided insight related to meaningful treatment benefits experienced while receiving apitegromab during the TOPAZ trial, particularly around activities of daily living, fatigue, muscle weakness, physical functioning, independence, and balance. These data provide supplemental insights beyond what may be captured in a standardized questionnaire and give insight to the holistic improvement in the patient's quality of life. Disclosure: Dr. Pokrzywinski has received personal compensation for serving as an employee of Evidera. Katelyn Cutts has nothing to disclose. The institution of Dr. Shah has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Scholar Rock. Dr. Kertesz has received personal compensation for serving as an employee of Scholar Rock Inc.. Dr. Lesh has received personal compensation for serving as an employee of Scholar Rock, Inc.. Mrs. E Sadanowicz has nothing to disclose. Guochen Song has received personal compensation for serving as an employee of Scoloar Rock. An immediate family member of Guochen Song has received personal compensation for serving as an employee of United Health Group. Guochen Song has stock in Scholarrock. Guochen Song has stock in BIogen. Ms. ONeil has nothing to disclose. Doreen Barrett has received personal compensation for serving as an employee of Scholar Rock. Mrs. Barnobi has received personal compensation for serving as an employee of Scholar Rock. Scott Baver has received personal compensation for serving as an employee of Scholar Rock.

Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin—promyostatin and latent myostatin—thereby inhibiting myostatin activation.

Apitegromab is an investigational, fully human, monoclonal antibody that inhibits myostatin activation by specific binding to myostatin proforms, promyostatin and latent myostatin. We will present data, from the Phase 2 TOPAZ clinical trial (NCT03921528), on the relationships of pharmacokinetics (PK) and pharmacodynamic (PD) (marker of target engagement, latent serum myostatin levels) to apitegromab efficacy.

Apitegromab (SRK-015) is an anti-promyostatin monoclonal antibody under development to improve motor function in patients with spinal muscular atrophy, a rare neuromuscular disease. This phase 1 double-blind, placebo-controlled study assessed safety, pharmacokinetic parameters, pharmacodynamics (serum latent myostatin), and immunogenicity of single and multiple ascending doses of apitegromab in healthy adult subjects. Subjects were administered single intravenous ascending doses of apitegromab of 1, 3, 10, 20, 30 mg/kg or placebo, and multiple intravenous ascending doses of apitegromab of 10, 20, 30 mg/kg or placebo. Following single ascending doses, the pharmacokinetic parameters of apitegromab appeared to be similar across all dose groups, following a biphasic pattern of decline in the concentration–time curve. The mean apparent terminal t1/2 after single intravenous doses of apitegromab ranged from 24 to 31 days across dose groups. Dose-related increases were observed in Cmax following multiple ascending doses. Single and multiple apitegromab doses resulted in dose-dependent and sustained increases in serum latent myostatin, indicating robust target engagement. Apitegromab was safe and well tolerated, on the basis of the adverse event (AE) profile with no clinically meaningful changes in baseline vital signs, electrocardiograms, or clinical laboratory parameters and no anti-drug antibody formation. These results support continued investigation of apitegromab for the treatment of patients with milder forms (type 2 and 3) of spinal muscular atrophy.