Elevidys
delandistrogene moxeparvovec
Sources:FDA pharmacology/toxicology review ↗FDA summary basis for approval ↗US prescribing information ↗
Species
MonkeyMouse
Longest study
24 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse only (wild-type C57BL/6J and mdx disease model); NHP only in non-GLP supporting studies
“The following toxicology studies were conducted to evaluate the safety of ELEVIDYS following administration in WT and mdx mice.”
Why that species
Disease-model rodents (mdx mice, Dmdmdx rats) used to show micro-dystrophin expression and efficacy; no explicit species-relevance argument
“The pharmacology studies of ELEVIDYS were conducted in rodent models of DMD including mdx mice and Dmdmdx rats.”
Surrogate molecule
No surrogate; clinical vector (Process B) tested in WT and mdx mice
“A 12-week GLP toxicology and biodistribution study (Report No. SR-20-066) evaluated single IV administration of 1.33 × 1014 and 4.01 × 1014 vg/kg ELEVIDYS (manufactured by Process B at Catalent) in 7 to 8 weeks old C57BL/6J WT and mdx mice.”
Species: general tox
Mouse only (wild-type and mdx mice)
“The following toxicology studies were conducted to evaluate the safety of ELEVIDYS following administration in WT and mdx mice.”
Species: DART
Not conducted (patient population; no adverse findings in toxicology studies)
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Species: carcinogenicity
Not conducted (patient population; no adverse findings in toxicology studies)
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Surrogate used in
No surrogate used; clinical vector (Process B, Catalent) tested in WT and mdx mice
“A 12-week GLP toxicology and biodistribution study (Report No. SR-20-066) evaluated single IV administration of 1.33 × 1014 and 4.01 × 1014 vg/kg ELEVIDYS (manufactured by Process B at Catalent) in 7 to 8 weeks old C57BL/6J WT and mdx mice.”
Study lengthopen answer page →
Longest pivotal study
24 weeks
“A 6-month good laboratory practice (GLP) toxicology and biodistribution study (Report No. SR-19-050) evaluated single IV administration of 1.33 × 1014 and 4.01 × 1014 vg/kg ELEVIDYS”
Pivotal GLP studies
GLP single-dose IV mouse studies: 24-week (WT+mdx), 12-week (WT+mdx, Catalent lot), 13-week neonatal juvenile tox
“A 3-month GLP toxicology study (Report No. SR-20-015) evaluated single IV administration of ELEVIDYS (manufactured by Process B at Catalent) in neonatal C57BL/6J WT mice administered 1.33 × 1014 and 4.01 × 1014 vg/kg at post-natal day 1.”
Route in tox
Single intravenous injection (temporal vein in neonates)
“Dosing Regimen Single administration”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (low-frequency random AAV integration per literature)
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
Carcinogenicity
Not conducted (no cancers in AAV clinical trials; dystrophin possible tumor suppressor)
“Based on the indication of X-linked DMD which occurs primarily in males and lack of concerning findings in the completed toxicology studies, further assessment of developmental and reproductive toxicology, carcinogenicity/tumorigenicity, and genotoxicity are not warranted at this time.”
Instead of carcinogenicity
Class data: AAV vectors studied in 162 clinical trials with no cancer reported
“AAV of various serotypes including AAV2 and AAVrh74, have been studied in 162 clinical trials; thus far, no cancer of any type has been reported.”
DRG histopathology
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.
Reproductive & developmental
Not conducted (male population, no reproductive lesions); neonatal juvenile tox done; low germline signal in testes
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Safety pharmacology
Not conducted
“There were no safety pharmacology studies performed with SRP-9001.”
Genotox: Ames
Not conducted (low-frequency random AAV integration per literature)
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
Genotox: in vitro mammalian
Not conducted (low-frequency random AAV integration per literature)
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
Genotox: in vivo
Not conducted (low-frequency random AAV integration per literature)
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
Carcinogenicity model
Not conducted; applicant cited no cancer reported across 162 AAV clinical trials
“AAV of various serotypes including AAV2 and AAVrh74, have been studied in 162 clinical trials; thus far, no cancer of any type has been reported.”
Carcinogenicity timing
Not conducted: acceptable given patient population and no ELEVIDYS-related adverse toxicology findings
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
hERG / QT
No safety pharmacology studies conducted
“There were no safety pharmacology studies performed with SRP-9001.”
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 Elevidys 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 gene therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: NOAEL 4.01x10^14 vg/kg (WT, mdx, neonatal mice); 1.33x10^14 in mdx 12-wk study (hydrocephalus); non-adverse minimal liver findings (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
NOAEL 4.01x10^14 vg/kg (WT, mdx, neonatal mice); 1.33x10^14 in mdx 12-wk study (hydrocephalus); non-adverse minimal liver findings
“This study identified NOAELs of 4.1 × 1014 vg/kg in WT mice and 1.33 × 1014 vg/kg in mdx mice.”
Risksopen answer page →
Immune & cytokine safety
Anti-AAV antibodies in mice; NHP: capsid/transgene T-cell responses, liver enzymes, anaphylaxis on redosing with rituximab/sirolimus
“increased antibody titers against AAVrh74 vector capsid from Weeks 5 to 12, increased cellular immune response against AAVrh74 vector capsid and micro-dystrophin at Week 2 compared to baseline”
Biodistribution & persistence
Systemic; highest in liver, then adrenal, aorta, heart, muscle; low in testes; shedding in urine/feces/plasma cleared by Day 44
“Systemic ELEVIDYS distribution was observed, with the highest vector levels in the liver, followed by the adrenal gland, aorta, heart, muscle, and esophagus.”
Modality-specific risk
AAV capsid immunity and liver/muscle inflammation; germline transmission; AAV integration (deemed low)
“The potential for the histopathology findings in the liver, heart, and skeletal muscles to be related to test article could not be determined due to the lack of a control group.”
Anti-drug antibodies: animals
Anti-AAV antibodies rose in WT and mdx mice by Weeks 3-4 and plateaued by Weeks 20-25
“Increased anti-AAV antibodies were observed in C57BL/6J and mdx mice administered SRP-9001 at ≥1.3 x 1014 vg/kg compared to baseline when assessed at Weeks 3 or 4, and plateaued by Weeks 20 or 25.”
Anti-drug antibodies: patients
Elevated anti-AAVrh74 total binding antibodies in all 156 patients after infusion
“Across clinical studies evaluating a total of 156 patients, elevated anti-AAVrh74 total binding antibodies titers were observed in all patients following a one-time ELEVIDYS infusion.”
Label warnings
Boxed warning: Acute serious liver injury and acute liver failure
- Acute Serious Liver Injury and Acute Liver Failure
- Serious Infections
- Myocarditis
- Infusion-related Reactions
- Immune-mediated Myositis
- Pre-existing Immunity against AAVrh74
HepatotoxicityInfectionsCardiovascularHypersensitivity & infusion reactionsImmune-mediated reactions
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
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 Elevidys 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 gene therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: NOAEL 4.01x10^14 vg/kg (WT, mdx, neonatal mice); 1.33x10^14 in mdx 12-wk study (hydrocephalus); non-adverse minimal liver findings (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose toxicity study (single administration); longest is single-dose IV mouse study with 24-week observation
“To evaluate the toxicity of SRP-9001 when administered as a single dose via IV injection to male mice; animals were observed for either 12 or 24 weeks”
Pivotal GLP studies
GLP single-dose IV mouse studies: 24-week (WT+mdx), 12-week (WT+mdx, Catalent lot), 13-week neonatal juvenile tox
“A 3-month GLP toxicology study (Report No. SR-20-015) evaluated single IV administration of ELEVIDYS (manufactured by Process B at Catalent) in neonatal C57BL/6J WT mice administered 1.33 × 1014 and 4.01 × 1014 vg/kg at post-natal day 1.”
DART package
Species: DART
Not conducted (patient population; no adverse findings in toxicology studies)
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Reproductive & developmental
Not conducted (male population, no reproductive lesions); neonatal juvenile tox done; low germline signal in testes
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
PPND / ePPND: when
Not conducted: acceptable given patient population and no ELEVIDYS-related adverse toxicology findings
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Carcinogenicity
Species: carcinogenicity
Not conducted (patient population; no adverse findings in toxicology studies)
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Carcinogenicity model
Not conducted; applicant cited no cancer reported across 162 AAV clinical trials
“AAV of various serotypes including AAV2 and AAVrh74, have been studied in 162 clinical trials; thus far, no cancer of any type has been reported.”
Carcinogenicity timing
Not conducted: acceptable given patient population and no ELEVIDYS-related adverse toxicology findings
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
NOAEL 4.01x10^14 vg/kg (WT, mdx, neonatal mice); 1.33x10^14 in mdx 12-wk study (hydrocephalus); non-adverse minimal liver findings
“This study identified NOAELs of 4.1 × 1014 vg/kg in WT mice and 1.33 × 1014 vg/kg in mdx mice.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent DMD models: mdx mice and Dmdmdx rats (force, muscle pathology, micro-dystrophin expression)
“The pharmacology studies of ELEVIDYS were conducted in rodent models of DMD including mdx mice and Dmdmdx rats.”
Why that model
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.
Reviewer's view of the efficacy data
FDA found no nonclinical deficiencies in the pharmacology and toxicology studies
“There are no nonclinical deficiencies in the pharmacology and toxicology studies or outstanding information requests for ELEVIDYS.”
Test articleopen answer page →
Test article vs clinical lot
Nonclinical material from Process A (Nationwide Children’s), Process B at ThermoFisher and Process B at Catalent. Bridging: Process A and Process B products not analytically comparable; commercial product is Process B (Catalent)
“ELEVIDYS (also named SRP-9001 in the nonclinical studies) has been produced from different manufacturing processes and manufacturing sites including Process A at Nationwide Children’s Hospital, Process B at ThermoFisher, and Process B at Catalent.”
Vector and route
AAV administered intravenously to transduce skeletal, diaphragmatic and cardiac muscle
“ELEVIDYS is intended to be administered intravenously (IV) to transduce muscle cells in skeletal, diaphragmatic, and cardiac muscles”
First approval
2023 (FDA)
“Summary Basis for Regulatory Action Date: June 21, 2023”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No developmental and reproductive toxicology studies
Why: Patient population nearly exclusively male; no adverse findings in toxicology studies · Other reason · Weight of evidence
“Per the applicant, developmental and reproductive toxicology studies have not been conducted with SRP-9001 for the following reasons:”
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity/tumorigenicity studies
Why: No cancer reported across 162 AAV clinical trials; no concerning findings in completed toxicology studies · Human data · Class precedent · Weight of evidence
“Per the applicant, carcinogenicity/tumorigenicity studies have not been conducted with SRP-9001 for the following reasons: • AAV of various serotypes including AAV2 and AAVrh74, have been studied in 162 clinical trials; thus far, no cancer of any type has been reported.”
“Reviewer Comment: Based on the indication of X-linked DMD which occurs primarily in males and lack of concerning findings in the completed toxicology studies, further assessment of developmental and reproductive toxicology, carcinogenicity/tumorigenicity, and genotoxicity are not warranted at this time.”
GenotoxicityAcceptedBeyond the letter
No genotoxicity studies; integration risk addressed by literature
Why: Literature supports random AAV integration at low frequencies · Class precedent · Low-risk modality
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
“Reviewer Comment: Based on the indication of X-linked DMD which occurs primarily in males and lack of concerning findings in the completed toxicology studies, further assessment of developmental and reproductive toxicology, carcinogenicity/tumorigenicity, and genotoxicity are not warranted at this time.”
Safety pharmacologyVerdict not stated
No safety pharmacology studies
“There were no safety pharmacology studies performed with SRP-9001.”
Similar precedents
ItvismaGene therapy · onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)Monkey + rodent · 52 wkKebilidiGene therapy · eladocagene exuparvovec · AADCMonkey + rodent · 26 wkZolgensmaGene therapy · onasemnogene abeparvovec · SMN1Monkey + rodent · 26 wkFayuviGene therapy · rebisufligene etisparvovec · SGSH (AAV9)Rodent only · 26 wkLenmeldyGene therapy · atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)Rodent only · 52 wkAmondys 45Oligos · casimersen · DMD exon 45 (PMO)Monkey + rodent · 39 wk