Apitegromab (development code SRK-015) is a fully human monoclonal antibody made by Scholar Rock. It blocks myostatin, a protein that limits how much muscle the body builds. Unlike most drugs aimed at this pathway, it does not bind the active hormone. Instead it locks myostatin in its inactive precursor forms so the active hormone is never released.
On September 11, 2026, the FDA approved apitegromab as Isembyld (apitegromab-mstn) for spinal muscular atrophy (SMA) in patients aged 2 years and older who are already on an SMN2-targeted drug (nusinersen or risdiplam). It is given as an intravenous infusion every 4 weeks. It is not approved in the EU: the first EU application was withdrawn in August 2026 over a manufacturing-site problem, and the company refiled it in October 2026. A phase 2 trial has also tested it for preserving lean mass during tirzepatide weight loss. WADA bans it at all times.
This page summarizes what the FDA label, the clinical trials and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Fully human IgG4 lambda monoclonal antibody; myostatin activation inhibitor |
| Brand / approval | Isembyld (Scholar Rock); FDA approved September 11, 2026 for SMA |
| Route | Intravenous infusion over 60–120 minutes |
| Strength | 150 mg/3 mL (50 mg/mL) single-dose vial |
| Labeled dose | 10 mg/kg every 4 weeks |
| Half-life (label) | ≈31 days (31.2 days, population PK model in SMA patients) |
| Mechanism | Binds pro- and latent myostatin and prevents its activation; does not bind mature myostatin |
| Main warning | Fractures, including serious femur fractures |
| EU status | Not approved; first application withdrawn August 2026, resubmitted October 2026 |
| WADA | Prohibited at all times (S4.3, named as an example) |
What it is
Myostatin, also called GDF8, is a member of the TGF-β family of growth factors. It acts as a brake on skeletal muscle growth, which is why blocking it has been studied as a way to treat muscle-wasting disease (Dagbay et al., J Biol Chem 2020).
Myostatin is made as an inactive precursor. It needs two cuts by enzymes (proteases) before the active growth factor is released from its “prodomain” wrapper (Pirruccello-Straub et al., Sci Rep 2018). Scholar Rock’s approach was to block this release step rather than the active hormone or its receptor. WADA’s list groups the different ways of interfering with this pathway (WADA 2026 Prohibited List):
| Approach (WADA S4.3 wording) | Example named by WADA |
|---|---|
| Myostatin- or precursor-neutralizing antibodies | Apitegromab, domagrozumab, landogrozumab, stamulumab |
| Myostatin-binding proteins | Follistatin (see Follistatin-344), myostatin propeptide |
| Decoy activin receptors | ACE-031 |
| Anti-activin receptor IIB antibodies | Bimagrumab |
A crystal structure shows that the antibody binds the “arm” region of the prodomain. This region looks very different from the same part of related growth factors. Binding holds the complex in its latent state and makes the protease cutting sites harder to reach (Dagbay et al., J Biol Chem 2020). The developers report that apitegromab does not bind mature myostatin or closely related growth factors (Welsh et al., Int J Toxicol 2021). The aim of this selectivity is to avoid side effects seen with broader blockers of the activin pathway.
Before human trials, a mouse version of the antibody increased muscle mass, function and bone measures in a mouse model of SMA treated with an SMN-restoring drug (Long et al., Hum Mol Genet 2019). These are mouse data.
The label describes apitegromab-mstn as a 147 kDa antibody made in Chinese hamster ovary cells (FDA label).
Pharmacokinetics
Like other antibodies, apitegromab is broken down into peptides and amino acids, not by the liver’s drug-metabolizing enzymes or by the kidneys. Data from the label, based on a population model in SMA patients aged 2–21 years:
| Parameter | Value |
|---|---|
| Terminal half-life | 31.2 days (CV 32%) |
| Clearance | 0.055 L/day |
| Volume of distribution at steady state | 2.16 L |
| Accumulation with dosing every 4 weeks | ≈2-fold |
| Time to steady state | ≈16–20 weeks |
| Dose proportionality | Linear between 10 and 20 mg/kg |
The phase 1 study in healthy adults gave single doses of 1–30 mg/kg and repeated doses of 10–30 mg/kg. It found a mean terminal half-life of 24–31 days across dose groups (Barrett et al., Adv Ther 2021). Blood levels of latent myostatin, the drug’s target, rose in a dose-dependent and sustained way. This marker shows the drug is binding its target, not that muscle is growing. No anti-drug antibodies formed in that study. In SAPPHIRE, 1 of 128 treated patients (0.8%) tested positive once, with no neutralizing antibodies.
The label expects no drug interactions through metabolism. In the population model, nusinersen and risdiplam did not change apitegromab levels.
Regulatory status
| Date | Event | Source |
|---|---|---|
| December 14, 2018 | EU orphan designation for SMA | EMA |
| September 2025 | FDA complete response letter (CRL), citing only inspection findings at the Catalent Indiana fill-finish plant | Scholar Rock, Sept 23, 2025 |
| 2026 | Resubmitted application under FDA review with a second fill-finish site added; action date September 30, 2026 | Scholar Rock, Aug 6, 2026 |
| August 13, 2026 | EU application withdrawn | EMA |
| September 11, 2026 | FDA approval as Isembyld | Scholar Rock, Sept 11, 2026 |
| October 8, 2026 | EU application resubmitted with the alternate fill-finish site | Scholar Rock, Oct 8, 2026 |
The company said the 2025 CRL raised no concerns about efficacy or safety data. In the EU, the EMA’s provisional view at the time of withdrawal was that the drug could not yet be authorized, because the company had not confirmed that the manufacturing site met EU good manufacturing practice (GMP) standards. After resubmitting, the company said it expects an opinion from the EMA’s human-medicines committee (CHMP) in the first half of 2027. That is a company forecast, not an EMA decision.
The company states it also received a rare pediatric disease priority review voucher with the approval. It is running a phase 2 trial (FORGE) in facioscapulohumeral muscular dystrophy, which plans to randomize about 60 patients to 10 mg/kg or placebo every 4 weeks for 52 weeks.
Approved medical use
The FDA label covers SMA in adults and children aged 2 years and older who are currently receiving an SMN2-targeted treatment (FDA label). SMA is a genetic disease in which the motor neurons that control muscles are lost, causing progressive weakness. SMN2-targeted drugs act on the nerve side of the disease. Apitegromab is meant to add a muscle-side treatment on top of them.
- Dose: 10 mg/kg every 4 weeks by IV infusion, at a rate no faster than 150 mL/hour.
- Higher dose: 20 mg/kg was tested but is not recommended, because it did not add efficacy.
- Contraindications: none listed.
- Not established: safety and efficacy under age 2. No patients aged 65 or older were studied.
What the research shows
SAPPHIRE: phase 3 in SMA
SAPPHIRE was a double-blind, placebo-controlled trial at 48 hospitals in Europe and the US (Crawford et al., Lancet Neurol 2025). It enrolled 188 patients aged 2–21 with type 2 or 3 SMA who could not walk. All were already on nusinersen or risdiplam.
- Children aged 2–12 (n = 156) were randomized 1:1:1 to apitegromab 20 mg/kg, 10 mg/kg or placebo every 4 weeks for 12 months.
- Patients aged 13–21 (n = 32) were randomized 2:1 to 20 mg/kg or placebo.
- The main outcome was the Hammersmith Functional Motor Scale-Expanded (HFMSE): 33 motor tasks scored to a maximum of 66, where higher is better.
Results at 12 months in children aged 2–12:
| Comparison | Mean HFMSE change, drug vs placebo | Difference (95% CI) | p |
|---|---|---|---|
| Both doses combined (prespecified primary) | +0.6 vs −1.2 | 1.8 (0.30–3.32) | 0.019 |
| 20 mg/kg alone | +0.2 vs −1.2 | 1.4 (−0.34 to 3.13) | 0.11 |
| 10 mg/kg alone (labeled dose) | +1.0 vs −1.2 | 2.2 (0.49–3.95) | 0.0121 (nominal) |
The 10 mg/kg row comes from the FDA label. “Nominal” means the p-value was not part of the formal testing hierarchy.
According to the label, 34.2% of children on 10 mg/kg gained 3 or more HFMSE points, compared with 13.5% on placebo (odds ratio 3.8, 95% CI 1.33–10.90). In practical terms, the placebo group slowly lost function while the treated group gained a little. The higher dose did no better than the lower one.
Earlier SMA trials
The phase 2 TOPAZ trial enrolled 58 patients aged 2–21, given apitegromab with or without nusinersen (Crawford et al., Neurology 2024). It had no placebo group. After 12 months, HFMSE changed by −0.3 points in older patients who could walk and +0.6 in older patients who could not. In the youngest nonambulatory group, scores rose by 5.3 points on 2 mg/kg and 7.1 points on 20 mg/kg. In an open-label extension, 35 nonambulatory patients on 20 mg/kg had a mean HFMSE gain of +4.0 points at 36 months (Crawford et al., Front Neurol 2024). Without a control group, these numbers are harder to interpret than SAPPHIRE’s.
Lean mass during tirzepatide weight loss (EMBRAZE)
This is the only trial in people without a muscle disease. The phase 2 EMBRAZE study randomized 102 adults with overweight or obesity to tirzepatide plus apitegromab 10 mg/kg every 4 weeks, or tirzepatide plus placebo, for 24 weeks (Pratley et al., Nat Med 2026). Tirzepatide was titrated up to 15 mg/week. Most participants were women (84% and 80% in the two arms). Lean mass was measured by DEXA (dual-energy X-ray absorptiometry), and the main analysis covered the 43 and 44 participants per arm who completed treatment with a week-24 scan.
| Week 24 outcome | Apitegromab + tirzepatide | Placebo + tirzepatide |
|---|---|---|
| Total weight loss | 11.2 kg | 12.5 kg |
| Lean mass loss | 1.6 kg | 3.5 kg |
| Fat mass loss | 8.5 kg | 8.0 kg |
| Lean mass as share of weight lost | 14.6% | 30.2% |
The drug preserved 1.9 kg more lean mass than placebo (80% CI 1.2–2.7). The authors describe this as 54.9% retention of the lean mass that would otherwise have been lost. Eight weeks after both drugs were stopped, the difference had shrunk to 0.9 kg (80% CI 0.3–1.5).
Several limits are important:
- The trial reported 80% rather than 95% confidence intervals, and the p-values are nominal.
- It found no difference in physical function (handheld dynamometer strength, chair sit-to-stand) and no difference in cardiometabolic markers.
- DEXA “lean mass” here included the trunk and its organs, not only skeletal muscle.
- The trial was small, lasted 24 weeks and was sponsored by the company.
Healthy or trained people
No published trial has tested apitegromab for muscle growth or strength in healthy or trained people. The phase 1 study in healthy adults measured safety, drug levels and target binding, not muscle (Barrett et al., Adv Ther 2021). The muscle-growth data in healthy animals come from mice (Pirruccello-Straub et al., Sci Rep 2018).
Side effects and risks
Fractures
The label’s only warning is a higher risk of fractures, including serious ones (FDA label):
| Group | Patients with fractures |
|---|---|
| SAPPHIRE, 10 mg/kg | 5 of 53 (9%) |
| SAPPHIRE, 20 mg/kg | 3 of 53 (6%) |
| SAPPHIRE, placebo | 1 of 50 (2%) |
| Open-label extension, 20 mg/kg | 22 patients (9%), including 5 serious femur fractures |
Three SAPPHIRE patients on apitegromab had femur fractures. Most patients who broke a bone already had low bone density, earlier fractures or joint contractures. Some fractures had no clear cause such as a fall. The label advises caution in people with low bone density or multiple past fractures.
In rats, the label describes damage to the femoral head and neck: fissures, thinning, loss of the femoral head and fractures. These appeared at all doses tested, at drug exposures lower than those in humans at 10 mg/kg. A 2021 company paper had reported no treatment-related adverse findings in rat studies of up to 26 weeks (Welsh et al., Int J Toxicol 2021). The 2026 FDA label is the more recent and complete regulatory assessment.
Common side effects
In SAPPHIRE, reactions that occurred in 20% or more of patients on 10 mg/kg and more often than on placebo:
| Adverse reaction | Apitegromab 10 mg/kg (n = 53) | Placebo (n = 50) |
|---|---|---|
| Upper respiratory tract infections | 66% | 54% |
| Vomiting | 30% | 16% |
| Cough | 28% | 22% |
| Other viral infections | 26% | 16% |
| Headache | 23% | 16% |
| Gastroenteritis | 23% | 8% |
| Pharyngitis | 21% | 14% |
| Hypersensitivity (rash, hives, flushing and similar) | 21% | 16% |
| Diarrhea | 17% | 0% |
| Injection-site reactions | 13% | 0% |
Serious pneumonia occurred in 3 patients on 10 mg/kg and none on placebo. No patient in SAPPHIRE stopped treatment because of an adverse event (Crawford et al., Lancet Neurol 2025).
In EMBRAZE, adverse events occurred in 76% on apitegromab and 71% on placebo, with tirzepatide in both arms. Nausea, fatigue and headache were more common with apitegromab.
Creatine kinase
Creatine kinase (CPK, an enzyme released from muscle) rose more often on the drug: in 28% vs 12% on placebo. Three patients (6%) had levels above 2.5 times the upper limit of normal. By month 12, mean CPK had risen by 91 U/L on the drug and by 3 U/L on placebo. These rises were generally without symptoms. In EMBRAZE, one participant stopped the drug after a CPK rise that followed a vigorous new strength-training program.
Pregnancy and fertility
Human data are lacking. The rat findings in the label include:
- Pregnancy and lactation: offspring of treated mothers showed delayed sexual maturation, changes in startle behavior and, at the highest dose, impaired male reproductive function.
- Adult fertility: dosing before and during mating lowered sperm concentration, disrupted estrous cycles and reduced fertility at all doses.
- Juvenile animals: female rats dosed in youth had reduced fertility as adults.
No dose without effects was found, and the lowest doses tested gave drug exposures below those in humans. The label states that apitegromab may cause fetal harm and may affect reproductive function, based on these animal data.
Legal status and use outside medicine
In the US, apitegromab is a prescription biologic given as an IV infusion. It is an antibody, not a steroid, and it is not listed among the anabolic steroids in 21 CFR 1308.13.
The WADA 2026 Prohibited List names apitegromab under S4.3 among “myostatin- or precursor-neutralizing antibodies.” S4.3 substances are banned in and out of competition and are non-Specified Substances. The same class covers activin-receptor antibodies such as bimagrumab, decoy receptors such as ACE-031, and follistatin.
Key takeaways
- A different kind of myostatin blocker. Apitegromab binds myostatin’s inactive precursor and stops it from being activated, rather than blocking the active hormone or its receptor.
- FDA approved for SMA in September 2026. It is approved as Isembyld, given at 10 mg/kg IV every 4 weeks alongside nusinersen or risdiplam. The EU application was withdrawn over a manufacturing site and was resubmitted in October 2026.
- Modest benefit in SMA. At 10 mg/kg, HFMSE scores improved by 2.2 points vs placebo over 12 months. A double dose added nothing.
- Lean mass, not proven strength. With tirzepatide, it cut lean mass loss by 1.9 kg over 24 weeks, with no measured difference in physical function. There are no muscle-growth trials in healthy people.
- Bone and fertility signals. Fractures were more common on the drug in SMA trials (9% vs 2%), and rat studies showed femoral head damage and reduced fertility at exposures below human levels.
- Banned in sport. WADA lists it by name under S4.3, prohibited at all times.
Sources
- Scholar Rock. Isembyld (apitegromab-mstn) injection, for intravenous use, prescribing information. Initial US approval 2026. DailyMed.
- Scholar Rock. Scholar Rock announces FDA approval of ISEMBYLD (apitegromab-mstn), the first and only muscle-targeted treatment for children and adults with spinal muscular atrophy (SMA). Press release, September 11, 2026 (Form 8-K, Exhibit 99.1). SEC.
- Scholar Rock. FDA issues complete response letter (CRL) for apitegromab as a treatment for patients with spinal muscular atrophy (SMA) solely related to observations identified at Catalent Indiana LLC fill-finish facility. Press release, September 23, 2025 (Form 8-K, Exhibit 99.1). SEC.
- Scholar Rock. Scholar Rock reports second quarter 2026 financial results and recent business highlights. Press release, August 6, 2026 (Form 8-K, Exhibit 99.1). SEC.
- European Medicines Agency. Withdrawal of application for the marketing authorisation of Isembyld (apitegromab). EMEA/H/C/005909. August 21, 2026. EMA.
- Scholar Rock. Scholar Rock resubmits apitegromab marketing authorisation application (MAA) to European Medicines Agency (EMA) for treatment of children and adults with spinal muscular atrophy (SMA). Press release (Business Wire), October 8, 2026. BioSpace.
- Crawford TO, Servais L, Mercuri E, et al. 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. Lancet Neurol. 2025;24(9):727–739. PubMed.
- Crawford TO, Darras BT, Day JW, et al. Safety and efficacy of apitegromab in patients with spinal muscular atrophy types 2 and 3: the phase 2 TOPAZ study. Neurology. 2024;102(5):e209151. PubMed.
- Crawford TO, Day JW, De Vivo DC, et al. Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study. Front Neurol. 2024;15:1419791. PubMed.
- Barrett D, Bilic S, Chyung Y, et al. A randomized phase 1 safety, pharmacokinetic and pharmacodynamic study of the novel myostatin inhibitor apitegromab (SRK-015): a potential treatment for spinal muscular atrophy. Adv Ther. 2021;38(6):3203–3222. PubMed.
- Pratley RE, Denham DS, Trivedi R, et al. Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Med. 2026;32(7):2673–2678. PubMed.
- Pirruccello-Straub M, Jackson J, Wawersik S, et al. Blocking extracellular activation of myostatin as a strategy for treating muscle wasting. Sci Rep. 2018;8(1):2292. PubMed.
- Dagbay KB, Treece E, Streich FC Jr, et al. Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015. J Biol Chem. 2020;295(16):5404–5418. PubMed.
- Long KK, O’Shea KM, Khairallah RJ, et al. Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy. Hum Mol Genet. 2019;28(7):1076–1089. PubMed.
- Welsh BT, Cote SM, Meshulam D, et al. Preclinical safety assessment and toxicokinetics of apitegromab, an antibody targeting proforms of myostatin for the treatment of muscle-atrophying disease. Int J Toxicol. 2021;40(4):322–336. PubMed.
- World Anti-Doping Agency. 2026 Prohibited List. In effect January 1, 2026. WADA 2026 Prohibited List.
- US Drug Enforcement Administration. Schedules of controlled substances: Schedule III. 21 CFR 1308.13. 21 CFR 1308.13.