Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study

Abstract

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.

Figure 1. Open-Label Interventional Study (12 Months)

Participants received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts to investigate participant suitability and treatment regimens. Cohort 1 assessed apitegromab 20 mg/kg in ambulatory type 3 SMA participants age 5–21 years, who were stratified into 2 equal arms receiving chronic nusinersen initiated at age ≥5 years, or who had not received SMN-targeted therapy for ≥6 months before screening. Cohort 2 assessed apitegromab 20 mg/kg in nonambulatory participants age 5–21 years who were receiving chronic nusinersen treatment initiated at age ≥5 years. Cohort 3 assessed 2 and 20 mg/kg apitegromab administered in a blinded manner to younger, earlier treated nonambulatory participants age 2 years or older who were receiving chronic nusinersen treatment initiated before age 5 years. ^aParticipants stratified based on previous treatment with approved SMN therapy. ^bParticipants randomized to receive 2 or 20 mg/kg apitegromab. ^cNumber of participants who completed the 12-month treatment period. ^dFor the primary analysis, if participants missed 3 consecutive doses because of site restrictions caused by COVID-19, records after dose skipping were excluded from analysis. This resulted in 14 participants in cohort 2, 9 participants in the cohort 3 2-mg/kg, and 8 participants in the cohort 3 20-mg/kg subcohorts having results for the 12-month end point. LOCF was used for data missing from non-COVID-19–related reasons. ^eFor this cohort 1 subset, 11 participants completed the treatment period; however, the analysis population remained at n = 12 because data from the discontinued participant was included in 12-month primary analysis. COVID-19 = coronavirus disease 2019; LOCF = last observation carried forward; SMA = spinal muscular atrophy.

Figure 2. Intermediate Pharmacodynamics (A) and Pharmacokinetics (B)

Pharmacokinetic and intermediate pharmacodynamic data support clinically observed dose response and sustained drug exposure after administration of apitegromab. Both 2-mg/kg and 20-mg/kg doses yielded high levels of target engagement (>100-fold increase from baseline) assessed by serum latent myostatin levels. The 20-mg/kg dose offers higher levels of target engagement than the 2-mg/kg dose. The ambulatory cohort had the highest mean baseline latent myostatin concentrations and the highest increase in response to apitegromab; however, the percent changes from baseline were the same in both nonambulatory and ambulatory cohorts. ^‡Cohort 1: ambulatory (type 3), age 5–21 years. Participants enrolled equally into cohorts either receiving chronic nusinersen or not. Unblinded. ^†Cohort 2: nonambulatory (types 2 and 3), age 5–21 years. Unblinded. *Cohort 3: nonambulatory (type 2) participants (age ≥2 years). Blinded, randomized 1:1.

Figure 3. Cohort 3 Dose-Related Changes in HFMSE (A) and Time to Achieve a 1-Point, 3-Point, or 5-Point Increase in HFMSE Score During the 12-Month Treatment Period (B)

Nonambulatory age ≥2 years cohort: Dose-related changes in HFMSE scores demonstrated and both dosage arms manifested early benefit; a greater latency of the low-dose arm supports effect attributable to apitegromab. Dose-responsive improvement correlates with time to reach HFMSE motor function benefit. Benefits in both dose arms manifested as early as 2 months of treatment initiation. HFMSE = Hammersmith Functional Motor Scale Expanded.