Isembyld
apitegromab
Sources:FDA integrated review ↗
Species
MonkeyRat
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“General toxicology studies were conducted in Sprague-Dawley rat (durations of up to 26 weeks) and cynomolgus monkey (4 weeks’ duration) using weekly IV administration.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 182Source ↗
Why that species
Binds promyostatin of all five species tested (2-8 nM); myostatin at least 96% and the apitegromab epitope 100% conserved
“showed binding to promyostatin from all five species with affinities between 2 and 8nM (Table 48). The sequence of myostatin is at least 96% conserved among these species, and the epitope for apitegromab within myostatin is 100% conserved among these species.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 184Source ↗
Surrogate molecule
Yes: muSRK-015P (apitegromab on a mouse IgG1 backbone) in the SMA mouse efficacy model; not used in toxicology
“Inhibition of myostatin activation by muSRK-015P, the parenteral version of apitegromab on a mouse IgG1 backbone, in combination with a small molecule SMN splice modulator (SMN-C1), increased muscle size and function in a mouse model of SMA.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 181Source ↗
Species: general tox
Rat (4-, 12- and 26-week) and cynomolgus monkey (4-week)
“The HD was 100 mg/kg in the 4-week rat and monkey studies and 300 mg/kg in the 12- and 26-week rat studies.”
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Increased postimplantation loss was also seen in the embryo-fetal development (EFD) studies in rat and rabbit; however, variability and lack of dose-response in both species and confounding by possible drug contamination in the rabbit study made it difficult to reach definite conclusions. Effects on reproductive system development were also observed in the pre- and postnatal development (PPND) and juvenile animal (JAS) studies in rat.”
Species: carcinogenicity
Not conducted (waived on weight of evidence)
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
Surrogate used in
Yes: muSRK-015P (apitegromab on a mouse IgG1 backbone) in the SMA mouse efficacy model
“Inhibition of myostatin activation by muSRK-015P, the parenteral version of apitegromab on a mouse IgG1 backbone, in combination with a small molecule SMN splice modulator (SMN-C1), increased muscle size and function in a mouse model of SMA.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“General toxicology studies were conducted in Sprague-Dawley rat (durations of up to 26 weeks) and cynomolgus monkey (4 weeks’ duration) using weekly IV administration.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 182Source ↗
Longest repeat-dose study and recovery
26-week rat (weekly IV) with 8-week recovery
“A 26-Week Toxicity and Toxicokinetic Study With SRK-015 Administered by Intravenous Injection to Rats With an 8-Week Recovery Phase”
Pivotal GLP studies
Rat 4-, 12- and 26-week and cynomolgus monkey 4-week studies (high dose 100 or 300 mg/kg)
“The HD was 100 mg/kg in the 4-week rat and monkey studies and 300 mg/kg in the 12- and 26-week rat studies.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 182Source ↗
Route in tox
Intravenous (weekly)
“General toxicology studies were conducted in Sprague-Dawley rat (durations of up to 26 weeks) and cynomolgus monkey (4 weeks’ duration) using weekly IV administration.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 182Source ↗
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 183Source ↗
Carcinogenicity
Not conducted; FDA waived the requirement after reviewing the sponsor's weight-of-evidence justification
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 183Source ↗
Reproductive & developmental
Rat fertility study: decreased sperm concentration, estrous disruption, reduced mating/fertility indices, increased postimplantation loss
“Reproductive and developmental toxicity: In the fertility and early embryonic development study in rat, decreased sperm concentration, estrous cycle disruption, decreased male and/or female mating and fertility indices, and increased postimplantation loss were observed.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 126Source ↗
Safety pharmacology
Incorporated into 4-week GLP monkey study (up to 100 mg/kg/week): no effects on respiration, neurological exams or ECG
“Safety pharmacology assessments were incorporated into the good laboratory practice (GLP) monkey toxicology study in which apitegromab (0, 10, 30, or 100 mg/kg/week) was administered weekly by IV bolus for 4 weeks. No apitegromab-related effects on respiration rate, neurological examinations, or ECGs were observed.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 181Source ↗
Genotox: Ames
Not conducted
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
Genotox: in vitro mammalian
Not conducted
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
Genotox: in vivo
Not conducted
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
Carcinogenicity model
Not conducted; FDA waived the requirement based on the sponsor's weight-of-evidence justification
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
Carcinogenicity timing
Not required: carcinogenicity requirement waived by FDA on the sponsor's weight-of-evidence justification
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
hERG / QT
No ECG, respiratory or neurological effects in 4-week GLP monkey study up to 100 mg/kg/week
“Safety pharmacology assessments were incorporated into the good laboratory practice (GLP) monkey toxicology study in which apitegromab (0, 10, 30, or 100 mg/kg/week) was administered weekly by IV bolus for 4 weeks. No apitegromab-related effects on respiration rate, neurological examinations, or ECGs were observed.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Isembyld don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: No NOAEL in rat (adverse bone effects); bone LOAELs 10 and 30 mg/kg in 12- and 26-week studies, below human AUC at MRHD (FDA integrated review, p. 170)
NOAEL / key findings
No NOAEL in rat (adverse bone effects); bone LOAELs 10 and 30 mg/kg in 12- and 26-week studies, below human AUC at MRHD
“The lowest effect doses for adverse effects on bone in the 12- and 26-week rat studies (10 and 30 mg/kg, respectively) were associated with apitegromab exposures (AUC) lower than that in humans at the MRHD.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 170Source ↗
Risksopen answer page →
Immune & cytokine safety
Low immunogenicity: 1/128 (0.8%) SAPPHIRE patients ADA-positive at a single time point; no neutralizing antibodies
“In up to 52 weeks of treatment in SAPPHIRE, 1/128 (0.8%) of subjects treated with apitegromab tested positive for treatment-emergent anti-apitegromab antibodies (ADA) at a single time point. No neutralizing antibodies were detected.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 270Source ↗
Biodistribution & persistence
Rat single 10 mg/kg IV dose: Cmax 203 µg/mL, AUCinf 42936 µg*h/mL, half-life 222 hours
“In female rats, administration of a single IV dose of apitegromab (10 mg/kg) resulted in maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC)inf values of 203 µg/mL and 42936 µg*h/mL, respectively and a half-life (t1/2) of 222 hours.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 181Source ↗
Modality-specific risk
Drug-related adverse bone effects in 12- and 26-week rat studies
“This and the previous findings in the 12-week study suggest an SRK-015-related effect on bone.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 183Source ↗
Anti-drug antibodies: animals
26-week rat: ADA in a few low-dose rats (dosing Days 43, 99; recovery Day 42); exposure apparently reduced in 2
“Anti-SRK-015 antibodies were detected during the dosing period in 1 LD male (Day 43) and 1 LD female (Day 99) and during the recovery period in 1 LD female (Day 42). TK data from the latter 2 animals were excluded from the analysis due to the apparent impact of ADA on serum drug concentrations.”
Anti-drug antibodies: patients
1/128 (0.8%) in SAPPHIRE (up to 52 weeks), at a single time point; no neutralizing antibodies
“In up to 52 weeks of treatment in SAPPHIRE, 1/128 (0.8%) of subjects treated with apitegromab tested positive for treatment-emergent anti-apitegromab antibodies (ADA) at a single time point. No neutralizing antibodies were detected.”
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Isembyld don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: No NOAEL in rat (adverse bone effects); bone LOAELs 10 and 30 mg/kg in 12- and 26-week studies, below human AUC at MRHD (FDA integrated review, p. 170)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week rat (weekly IV) with 8-week recovery
“A 26-Week Toxicity and Toxicokinetic Study With SRK-015 Administered by Intravenous Injection to Rats With an 8-Week Recovery Phase”
Pivotal GLP studies
Rat 4-, 12- and 26-week and cynomolgus monkey 4-week studies (high dose 100 or 300 mg/kg)
“The HD was 100 mg/kg in the 4-week rat and monkey studies and 300 mg/kg in the 12- and 26-week rat studies.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 182Source ↗
DART package
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Increased postimplantation loss was also seen in the embryo-fetal development (EFD) studies in rat and rabbit; however, variability and lack of dose-response in both species and confounding by possible drug contamination in the rabbit study made it difficult to reach definite conclusions. Effects on reproductive system development were also observed in the pre- and postnatal development (PPND) and juvenile animal (JAS) studies in rat.”
Reproductive & developmental
Rat fertility study: decreased sperm concentration, estrous disruption, reduced mating/fertility indices, increased postimplantation loss
“Reproductive and developmental toxicity: In the fertility and early embryonic development study in rat, decreased sperm concentration, estrous cycle disruption, decreased male and/or female mating and fertility indices, and increased postimplantation loss were observed.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 126Source ↗
PPND / ePPND: when
Rat PPND completed before the marketing application; no no-effect dose identified (LOAEL 30 mg/kg)
“A no-effect dose for adverse effects on pre- and postnatal development was not identified. The LOAEL was 30 mg/kg (no TK).”
Carcinogenicity
Species: carcinogenicity
Not conducted (waived on weight of evidence)
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
Carcinogenicity model
Not conducted; FDA waived the requirement based on the sponsor's weight-of-evidence justification
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
Carcinogenicity timing
Not required: carcinogenicity requirement waived by FDA on the sponsor's weight-of-evidence justification
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL in rat; bone-effect LOAELs (10 and 30 mg/kg, 12- and 26-week) gave AUC lower than human at MRHD
“The lowest effect doses for adverse effects on bone in the 12- and 26-week rat studies (10 and 30 mg/kg, respectively) were associated with apitegromab exposures (AUC) lower than that in humans at the MRHD.”
NOAEL / key findings
No NOAEL in rat (adverse bone effects); bone LOAELs 10 and 30 mg/kg in 12- and 26-week studies, below human AUC at MRHD
“The lowest effect doses for adverse effects on bone in the 12- and 26-week rat studies (10 and 30 mg/kg, respectively) were associated with apitegromab exposures (AUC) lower than that in humans at the MRHD.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 170Source ↗
Efficacy evidenceopen answer page →
Efficacy evidence
SMA mouse model with muSRK-015P (apitegromab on a mouse IgG1 backbone) plus SMN splice modulator SMN-C1
“Inhibition of myostatin activation by muSRK-015P, the parenteral version of apitegromab on a mouse IgG1 backbone, in combination with a small molecule SMN splice modulator (SMN-C1), increased muscle size and function in a mouse model of SMA.”
Why that model
Myostatin at least 96% and the epitope 100% conserved across the five species tested, with similar binding (2-8 nM)
“showed binding to promyostatin from all five species with affinities between 2 and 8nM (Table 48). The sequence of myostatin is at least 96% conserved among these species, and the epitope for apitegromab within myostatin is 100% conserved among these species.”
Reviewer's view of the efficacy data
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity (or genotoxicity) studies; carcinogenicity requirement waived by the division
Why: Sponsor's weight-of-evidence justification, reviewed by the division · Weight of evidence
“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 183Source ↗
Safety marginAccepted with a conditionBeyond the letter
No NOAEL for bone effects in rat; lowest bone-effect doses gave exposures below human AUC at the MRHD
Why: Agency added a labeling subsection because of the adverse bone effects in the rat toxicology study
“The lowest effect doses for adverse effects on bone in the 12- and 26-week rat studies (10 and 30 mg/kg, respectively) were associated with apitegromab exposures (AUC) lower than that in humans at the MRHD.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 170Source ↗
“The Applicant had not proposed inclusion of this subsection; however, because of the adverse effects on bone that were observed in the rat toxicology study, the Agency added this subsection per 21 CFR 201.57(c)(14)(ii).”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 303Source ↗
DARTQuestioned
Rabbit embryo-fetal study low-dose findings attributed to possible endotoxin contamination of the dose formulation, not clearly established
“All findings in the LD group were thought to be attributable to the presence of endotoxin contamination in the dose formulation, but this was not clearly established as a cause.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 183Source ↗
Juvenile toxQuestioned
3-week SC juvenile rat study (PNDs 7 to 28) assessed bone only by femur length and routine histopathology
“A 3-week juvenile rat study with subcutaneous (SC) dosing from PNDs 7 to 28 was conducted to support dosing of pediatric patients less than 2 years of age. There were no apparent effects on juvenile development; however, the assessment of possible bone effects consisted only of femur length measurement and routine histopathology.”
✓ VerifiedFDA integrated review (BLA 761463, original application, approved Sep 2026), p. 184Source ↗
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