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(2024)Objective
Apitegromab 2 or 20 mg/kg IV every 4 weeks (alone or with nusinersen) — to assess safety and efficacy of a selective promyostatin inhibitor in 58 patients aged 2-21 years with later-onset SMA types 2 and 3 over 12 months.
Study Summary
• Cohort 2 (nonambulatory types 2/3, 5-21 years, + nusinersen): +0.6 points HFMSE — modest gain on top of SMN-targeted therapy.
• Ambulatory cohort 1: -0.3 RHS — stabilization rather than improvement, but baseline was higher.
• ≥3-point HFMSE improvement in 55.6-62.5% of cohort 3 patients, with 20 mg/kg dose more rapid and robust than 2 mg/kg.
• Latent myostatin rose >100-fold in both dose arms confirming target engagement; greater rise at 20 mg/kg.
• Safety favorable: most common AEs headache, pyrexia, cough, nasopharyngitis; no deaths, no anti-drug antibodies.
Intervention
Apitegromab IV infusion every 4 weeks for 12 months — 20 mg/kg (all cohorts) or 2 mg/kg (cohort 3 only, blinded randomization). Cohort 1: apitegromab alone or with nusinersen (open-label); cohorts 2 and 3: apitegromab + nusinersen; cohort 3: blinded 2 vs 20 mg/kg.
Inclusion Criteria
Genetically confirmed 5q SMA type 2 or 3 diagnosed before SMA-approved therapy; age 5-21 years (cohorts 1-2) or ≥2 years (cohort 3); stable background SMA therapy ≥6 months; cohort 1 required RHS ≤63; cohorts 2/3 required HFMSE ≥10.
Study Design
Arms: Cohort 1 ambulatory (apitegromab 20 mg/kg ± nusinersen); Cohort 2 nonambulatory 5-21y (apitegromab 20 mg/kg + nusinersen); Cohort 3 type 2, ≥2y blinded 2 or 20 mg/kg + nusinersen
Patients per Arm: Cohort 1: 23; Cohort 2: 15; Cohort 3: 20 (10 per dose)
Outcome
• ≥1-point HFMSE in cohort 3: 77.8% (2 mg/kg), 87.5% (20 mg/kg); ≥3-point: 55.6%, 62.5%; ≥5-point: 55.6%, 62.5%
• Target engagement: latent myostatin >100-fold rise from baseline across both doses
• Most common TEAEs: headache 24.1%, pyrexia 22.4%, URTI 22.4%, cough 22.4%, nasopharyngitis 20.7%
• No deaths, no anti-apitegromab antibodies, 5 unrelated serious AEs; Class III evidence for motor improvement
Clinical Question
In patients aged 2-21 years with later-onset SMA types 2 and 3, does apitegromab (a selective inhibitor of promyostatin/latent myostatin) improve motor function measured by HFMSE or RHS over 12 months, alone or in combination with nusinersen?
Bottom Line
In 58 patients aged 2-21 with later-onset SMA types 2 and 3, apitegromab given monthly IV for 12 months improved HFMSE score in nonambulatory cohorts (cohort 2: +0.6, cohort 3 20 mg/kg: +7.1 points 95% CI 1.8-12.5) while ambulatory cohort 1 remained near baseline (-0.3 on RHS). Dose-response and target-engagement (increased latent myostatin) supported a specific effect, motivating the phase 3 SAPPHIRE trial in SMA.
Major Points
- Multicenter phase 2 pilot study at 16 US/European sites (Crawford 2024)
- N=58 patients aged 2-21 with genetically confirmed type 2 or 3 SMA
- Three cohorts to inform phase 3 design: Cohort 1 ambulatory type 3 (5-21 y, n=23); Cohort 2 nonambulatory 5-21 y (n=15); Cohort 3 nonambulatory type 2 ≥2 y blinded 2 vs 20 mg/kg (n=20)
- IV apitegromab 2 or 20 mg/kg every 4 weeks for 12 months on top of stable background SMA therapy (mostly nusinersen)
- Primary efficacy: HFMSE (cohorts 2, 3) or RHS (cohort 1) change at day 364
- Cohort 3 20 mg/kg: +7.1 HFMSE (95% CI 1.8-12.5); 2 mg/kg: +5.3 (-1.5 to 12.2) — dose-related improvement
- Cohort 2: +0.6 HFMSE (-1.4 to 2.7); cohort 1: -0.3 RHS (-2.1 to 1.4) — stabilization
- ≥3-point HFMSE improvement in 55.6-62.5% of cohort 3 — clinically meaningful gains
- Target engagement confirmed: latent myostatin rose >100-fold at both doses; 20 mg/kg higher than 2 mg/kg
- Safety excellent: most common AEs headache, pyrexia, URTI, cough, nasopharyngitis; 5 serious AEs unrelated; no deaths; no anti-drug antibodies; no hypersensitivity
- Post-hoc: younger patients (<12 y) and those without baseline scoliosis/contractures showed larger gains
- Established Class III evidence for myostatin inhibition in SMA and motivated the pivotal phase 3 SAPPHIRE (SRK-015-003) trial — apitegromab approved FDA 2025
Study Design
- Study Type
- Phase 2 multicenter open-label study with blinded dose-randomized cohort 3 (NCT03921528)
- Randomization
- Yes
- Blinding
- Cohorts 1-2 open-label; Cohort 3 double-blind 1:1 to 2 or 20 mg/kg
- Sample Size
- 58
- Follow-up
- 12 months primary; open-label extension ongoing
Primary Outcome
Definition: Change from baseline in HFMSE or RHS at day 364 (12 months), by cohort
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| No control group; paired within-patient comparison | Cohort 1 RHS -0.3; Cohort 2 HFMSE +0.6; Cohort 3 HFMSE +5.3 (2 mg/kg) / +7.1 (20 mg/kg) | - (Cohort 3 20 mg/kg 1.8 to 12.5) | Cohort 3 20 mg/kg statistically significant by paired t-test |
Limitations & Criticisms
- Small cohort sizes (n=8-23 per cohort) limit statistical power and precision, especially for 2 vs 20 mg/kg dose comparison
- Cohorts 1 and 2 are open-label with no placebo — background SMN therapy (nusinersen) alone could explain some gains
- Only nusinersen was studied as background therapy; generalizability to onasemnogene or risdiplam uncertain (phase 3 SAPPHIRE addresses this)
- Post-hoc subgroup analyses (age, scoliosis) are hypothesis-generating only and may not replicate
- Durability beyond 12 months not assessed in this report (open-label extension ongoing)
- Class III evidence rating reflects uncontrolled design; phase 3 SAPPHIRE is the definitive trial