Apitegromab: Research & Studies
Scientific evidence, clinical trials, and research findings
📌TL;DR
- •3 clinical studies cited
- •Overall evidence level: moderate
- •7 research gaps identified
Research Studies
A randomized phase 1 safety, pharmacokinetic and pharmacodynamic study of the novel myostatin inhibitor apitegromab (SRK-015): a potential treatment for spinal muscular atrophy
Barrett D, Bilic S, Chyung Y, Cote SM, Iarrobino R, Kacena K, Kalra A, Long K, Nomikos G, Place A, Still JG, Vrishabhendra L (2021) • Advances in Therapy
Phase 1 double-blind, placebo-controlled study of single and multiple ascending doses of apitegromab (1-30 mg/kg IV) in healthy adult subjects. Demonstrated linear, dose-proportional pharmacokinetics with a half-life of 24-31 days. Dose-dependent increases in serum latent myostatin confirmed robust target engagement. Safe and well-tolerated with no anti-drug antibodies detected.
Key Findings
- Linear, dose-proportional PK profile across 1-30 mg/kg IV dose range
- Mean terminal half-life of 24-31 days across dose groups
- Dose-dependent and sustained increases in serum latent myostatin (pharmacodynamic target engagement)
- Safe and well-tolerated at all doses tested
- No anti-drug antibodies detected in any subjects
Limitations: Phase 1 study in healthy adults, not SMA patients. Small sample sizes per dose group. Short duration. Did not assess motor function outcomes.
Safety and efficacy of apitegromab in patients with spinal muscular atrophy types 2 and 3: the phase 2 TOPAZ study
Crawford TO, Darras BT, Day JW, Dunaway Young S, Duong T, Nelson LL, Barrett D, Song G, Bilic S, Cote S, Sadanowicz M, Iarrobino R, Xu TJ, O'Neil J, Rossello J, Place A, Kertesz N, Nomikos G, Chyung Y (2024) • Neurology
Phase 2 multicenter active treatment study at 16 US and European sites evaluating apitegromab in 58 participants aged 2-21 with Types 2 and 3 SMA receiving nusinersen. Participants received IV apitegromab (2, 10, or 20 mg/kg) every 4 weeks for 12 months. Apitegromab led to improved motor function with an acceptable safety profile. Among nonambulatory patients aged 2+ who started nusinersen before age 5, 59% had clinically meaningful HFMSE improvements.
Key Findings
- Motor function improved in participants with later-onset Types 2 and 3 SMA
- 59% of younger nonambulatory patients (nusinersen started <5 years) had clinically meaningful improvements
- Acceptable safety profile at doses up to 20 mg/kg for 12 months
- No deaths, no serious adverse reactions, no anti-drug antibodies
Limitations: Open-label active treatment design without placebo control. Modest sample size (n=58). Background SMN therapy may confound attribution. Single-arm design limits causal inference.
Safety and efficacy of apitegromab in nonambulatory type 2 or type 3 spinal muscular atrophy (SAPPHIRE): a phase 3, double-blind, randomised, placebo-controlled trial
Crawford TO, Servais L, Mercuri E, Kolbel H, Kuntz N, Finkel RS, Krueger J, Batley K, Dunaway Young S, Marantz JL, Song G, Yao B, Zhao G, Rossello J, Tirucherai GS, Mazzone ES, Butterfield RJ, Gomez Garcia de la Banda M, Seferian AM, Sansone VA, De Waele L, van der Pol WL, Cances C, Pechmann A, Darras BT (2025) • Lancet Neurology
Pivotal Phase 3 double-blind, placebo-controlled trial at 48 sites globally. Enrolled 188 nonambulatory patients with Types 2 and 3 SMA aged 2-21 receiving nusinersen or risdiplam. Randomized to apitegromab 10 or 20 mg/kg or placebo IV Q4W for 12 months. Met primary endpoint with statistically significant 1.8-point HFMSE improvement vs placebo (p=0.019). 30.4% of apitegromab patients achieved >=3-point HFMSE improvement vs 12.5% placebo. Well-tolerated with AE rates similar to placebo.
Key Findings
- Primary endpoint met with 1.8-point HFMSE improvement vs placebo (p=0.019) in ages 2-12
- 30.4% achieved >=3-point HFMSE improvement vs 12.5% placebo
- 19.6% achieved >=4-point HFMSE improvement vs 6.3% placebo
- Consistent effect across 2-12 and 13-21 age populations
- AE incidence and severity similar between apitegromab and placebo
- No patients discontinued due to adverse events
Limitations: Modest absolute HFMSE improvement (1.8 points). SMA-specific population may not generalize to other muscle conditions. IV administration required. Background SMN therapy mandatory (not tested as monotherapy).
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🔍Research Gaps & Future Directions
- •FDA BLA received Complete Response Letter for manufacturing issues; regulatory path to approval still pending
- •EMBRAZE obesity trial results are Phase 2 proof-of-concept only (n=100, 24 weeks); Phase 3 confirmation needed for obesity indication
- •Long-term safety and efficacy beyond 48 months not fully characterized
- •Head-to-head comparison with trevogrumab or bimagrumab not available
- •SRK-439 (next-generation myostatin inhibitor from Scholar Rock) may supersede apitegromab for obesity indication
- •Ambulatory SMA patients and Type 1 SMA not adequately studied
- •Optimal dosing (10 vs 20 mg/kg) not clearly differentiated in SAPPHIRE
Research Overview#
Apitegromab has the most extensive clinical evidence base among myostatin pathway inhibitors for neuromuscular disease, with data from Phase 1 through Phase 3 trials in SMA and emerging data in obesity. The program has progressed from Scholar Rock's discovery of the upstream myostatin activation mechanism to a BLA submission.
Phase 1: Safety and Pharmacology#
Barrett et al. (Advances in Therapy 2021)#
Barrett et al. (PMID 33963971) conducted the first-in-human study of apitegromab in healthy adults:
Design: Double-blind, placebo-controlled, single and multiple ascending dose study (1-30 mg/kg IV)
Key Pharmacokinetic Results:
| Parameter | Finding |
|---|---|
| PK profile | Linear, dose-proportional |
| Half-life | 24-31 days (mean across doses) |
| Target engagement | Dose-dependent latent myostatin increase |
| Anti-drug antibodies | None detected |
| Safety | Well-tolerated at all doses |
Phase 2: TOPAZ Trial (SMA)#
Crawford et al. (Neurology 2024)#
Crawford et al. (PMID 38330285) evaluated apitegromab in 58 SMA patients aged 2-21 years at 16 sites:
- Open-label design with three dose cohorts (2, 10, 20 mg/kg IV Q4W)
- All patients on background nusinersen therapy
- 12-month treatment with extension to 48 months
Key Results:
- Motor function improved across cohorts
- 59% of younger nonambulatory patients showed clinically meaningful HFMSE gains
- 36-month extension showed sustained +4.0-point HFMSE improvement
- 48-month data showed continued sustained motor function (+5.3-point HFMSE)
Phase 3: SAPPHIRE Trial (SMA)#
Crawford et al. (Lancet Neurology 2025)#
Crawford et al. (PMID 40818473) reported the pivotal Phase 3 results:
Design: Double-blind, placebo-controlled, 48 sites, 188 patients (156 main efficacy population aged 2-12, 32 exploratory aged 13-21), randomized 1:1:1 to apitegromab 10 mg/kg, 20 mg/kg, or placebo IV Q4W for 12 months.
Primary Endpoint Results (Ages 2-12):
| Treatment | HFMSE Change from Baseline |
|---|---|
| Apitegromab (pooled) | +0.6 points |
| Placebo | -1.2 points |
| Difference | +1.8 points (p=0.019) |
Responder Analysis:
| Response Threshold | Apitegromab | Placebo |
|---|---|---|
| >=3-point HFMSE improvement | 30.4% | 12.5% |
| >=4-point HFMSE improvement | 19.6% | 6.3% |
Phase 2: EMBRAZE Trial (Obesity)#
Scholar Rock reported positive results from the EMBRAZE proof-of-concept trial evaluating apitegromab with tirzepatide in 100 adults with overweight or obesity (June 2025):
| Outcome (24 weeks) | Apitegromab + Tirzepatide | Placebo + Tirzepatide |
|---|---|---|
| Weight loss | -12.3% | -13.4% |
| Fat mass loss composition | 85% from fat | 70% from fat |
| Lean mass preserved (vs control) | 54.9% (p=0.001) | Reference |
| Lean mass difference | +4.2 lbs (1.9 kg) | Reference |
No serious adverse events or discontinuations related to apitegromab treatment.
Evidence Quality Assessment#
| Criterion | Assessment | Details |
|---|---|---|
| Phase 1 clinical | Published | Advances in Therapy 2021, n=healthy adults |
| Phase 2 clinical | Published | Neurology 2024, n=58 SMA patients |
| Phase 3 clinical | Published | Lancet Neurology 2025, n=188, primary endpoint met |
| Long-term data | Strong | Up to 48 months (TOPAZ extension) |
| Publication quality | High | Lancet Neurology, Neurology |
| Motor function effects | Proven | Statistically significant HFMSE improvement |
| Safety profile | Favorable | AE rates comparable to placebo |
| Regulatory progress | Advanced | BLA filed (CRL for manufacturing only) |
| Obesity application | Early | Phase 2 proof-of-concept (EMBRAZE) |
Related Reading#
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