Apitegromab is an investigational, fully human, monoclonal antibody that by selectively inhibiting activation of myostatin aims to improve patients' motor function. TOPAZ is a 3-cohort, phase 2 study (NCT03921528) of patients (n=58) designed to identify clinical and protocol features that will best enable further study of its potential therapeutic effect. Subjects with later-onset SMA were dosed with IV apitegromab Q4W for 52 weeks. One cohort of 20 Type 2 SMA patients (? 2-21 years continuing on nusinersen that had been started before age 5) were assigned on a blinded basis, 1:1 to high or low dose regimens. Motor function improvements were observed after both dose levels, with the high 20mg/kg dose reaching higher levels of: drug exposure, serum latent myostatin as an initial measure of target engagement, and HFMSE scores. Patients receiving this high dose had a mean increase of 7.1 HFMSE points; for 63% this was > 6 points. In the second nonambulatory cohort of 15 Type 2/3 patients (5-21 years continuing on nusinersen that had been started after age 5) receiving high dose apitegromab, 64% obtained meaningful increases (> 1 point) in HFMSE from baseline.
Another cohort explored the relationship between PK/PD and efficacy in ambulatory subjects (5-21 years, n=23), as well as apitegromab in isolation or combined with chronic nusinersen. 22% of pooled patients experienced ?3-point RHS increases from baseline, with stability of function experienced in majority of patients within both subgroups. Post hoc analysis suggests scoliosis or contractures constrains measurable benefit. The relationships between efficacy, other parameters such as PK/PD, age, and weight were explored.
Incidence and severity of AEs from TOPAZ were consistent with underlying patient population and background therapy.
Apitegromab has the potential to be a muscle-directed therapy, adjunctive to SMN-augmenting therapy, in patients with SMA. This study informs design of definitive blinded trials.