Effect of apitegromab on motor function at 36 months in patients with nonambulatory spinal muscular atrophy aged 2-12 years old

Neuronal degeneration and muscle atrophy contribute to functional decline in spinal muscular atrophy (SMA). Apitegromab inhibits the pro- and latent forms of myostatin, a negative regulator of skeletal muscle growth, directly targeting muscle atrophy. Improvements in motor function measures were observed with apitegromab in Type 2 and nonambulatory Type 3 SMA receiving nusinersen in the phase 2 TOPAZ study. The aim of the present analysis is to determine the effects of apitegromab (20 mg/kg) on muscle function as measured by HFMSE, RULM, and WHO motor development milestones at 36 months in patients with non-ambulatory SMA aged 2-12 years, the population that is the focus of the ongoing pivotal phase 3 SAPPHIRE trial. Of 58 patients, aged 2-21, enrolled in the TOPAZ study, 57 completed the primary treatment period and enrolled in the extension study (1 patient withdrew from the study). Of 57 patients enrolled in the extension period, 7 discontinued: 2 withdrew consent due to concerns with COVID-19; 5 patients receiving apitegromab monotherapy discontinued due to lack of benefit or scheduling difficulty. Patients randomized to 2 mg/kg switched to 20 mg/kg in the extension study while all patients on 20 mg/kg continued their dose. Of the 35 patients with non-ambulatory SMA, 29 were aged 2-12 years; motor function as assessed by HFMSE and RULM showed sustained improvements throughout 36 months. Analysis of WHO motor milestones of the younger cohort (2-5 years) showed achievement of new milestones. The safety profile was consistent with previous reports. When added to nusinersen, treatment with apitegromab in patients with nonambulatory SMA aged 2-12 years old was associated with sustained clinical benefit for 36 months as measured by HFMSE, RULM, and WHO motor development milestones in patients with Type 2 and nonambulatory Type 3 SMA. These results support further development of apitegromab in SMA. Neuronal degeneration and muscle atrophy contribute to functional decline in spinal muscular atrophy (SMA). Apitegromab inhibits the pro- and latent forms of myostatin, a negative regulator of skeletal muscle growth, directly targeting muscle atrophy. Improvements in motor function measures were observed with apitegromab in Type 2 and nonambulatory Type 3 SMA receiving nusinersen in the phase 2 TOPAZ study. The aim of the present analysis is to determine the effects of apitegromab (20 mg/kg) on muscle function as measured by HFMSE, RULM, and WHO motor development milestones at 36 months in patients with non-ambulatory SMA aged 2-12 years, the population that is the focus of the ongoing pivotal phase 3 SAPPHIRE trial. Of 58 patients, aged 2-21, enrolled in the TOPAZ study, 57 completed the primary treatment period and enrolled in the extension study (1 patient withdrew from the study). Of 57 patients enrolled in the extension period, 7 discontinued: 2 withdrew consent due to concerns with COVID-19; 5 patients receiving apitegromab monotherapy discontinued due to lack of benefit or scheduling difficulty. Patients randomized to 2 mg/kg switched to 20 mg/kg in the extension study while all patients on 20 mg/kg continued their dose. Of the 35 patients with non-ambulatory SMA, 29 were aged 2-12 years; motor function as assessed by HFMSE and RULM showed sustained improvements throughout 36 months. Analysis of WHO motor milestones of the younger cohort (2-5 years) showed achievement of new milestones. The safety profile was consistent with previous reports. When added to nusinersen, treatment with apitegromab in patients with nonambulatory SMA aged 2-12 years old was associated with sustained clinical benefit for 36 months as measured by HFMSE, RULM, and WHO motor development milestones in patients with Type 2 and nonambulatory Type 3 SMA. These results support further development of apitegromab in SMA.