Genglycos
pariglasgene brecaparvovec
Species
MonkeyMouse
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
Mouse (adult and juvenile C57BL/6N) and juvenile cynomolgus monkey; GLP single-dose studies
“Three separate 92-day, single-dose toxicology studies were conducted in healthy adult and juvenile mice.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For biologics, ICH S6(R1) asks for species in which the product is pharmacologically active (target binding and activity), usually a cynomolgus monkey.
“A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).”
✓ VerifiedICH 2011: ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived…, p. 7Source ↗
Surrogate molecule
No surrogate; clinical vector DTX401 tested in mouse and NHP
“Test Article DTX401 (lot # D401-500P-W22-02)”
Species: general tox
Mouse (C57BL/6, adult and juvenile) and non-human primate (juvenile cynomolgus); single-dose studies
“Vector biodistribution analyses were conducted in C57BL/6 mice and NHPs as part of toxicology studies (Studies #8, 9, and 11).”
Species: DART
Mouse only (embryo-fetal development study; separate pre-mating germline transmission study)
“Similarly, IV administration of DTX401 at 7 × 1013 gc/kg to pregnant dams at presumed gestational day (GD) 6 resulted in DTX401 DNA detection in placenta but not offspring livers, and there was no impact on embryofetal development on GD 18.”
Species: carcinogenicity
Not conducted
“Per the Applicant, studies were not conducted to evaluate carcinogenicity/tumorigenicity for the following reasons:”
Surrogate used in
No surrogate; early pharmacology studies used earlier vector versions encoding the same protein
“The earlier versions of the product evaluated in Studies #1- 4 do not contain the of DTX401 but support the activity of DTX401 as they encode the same protein product.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“To evaluate potential toxicity of IV DTX401 administration in NHPs with a 6-month recovery period.”
Pivotal GLP studies
Three 92-day single-dose IV studies in adult/juvenile mice; one 6-month single-dose IV GLP study in juvenile cynomolgus monkeys
“One 6-month, single-dose toxicology study was conducted in healthy juvenile non-human primates (NHPs)”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Not conducted (low AAV integration risk); vector integration assessed in germline transmission study
“studies were not conducted to evaluate genotoxicity as they expect that the risk of DTX401 insertion is low.”
Carcinogenicity
Not conducted (AAV8 predominantly episomal; no link between AAV integration and hepatic tumors)
“studies were not conducted to evaluate carcinogenicity/tumorigenicity”
Instead of carcinogenicity
Vector integration assessed in Study 13; AAV8 vectors predominantly non-integrating and episomal
“Potential vector integration was assessed in Study #13. Carcinogenicity/Tumorigenicity Studies: Per the Applicant, studies were not conducted to evaluate carcinogenicity/tumorigenicity for the following reasons: • AAV8 vectors are predominantly non-integrating and persist as episomes with low likelihoods of genomic integration.”
DRG histopathology
Minimal neuronal degeneration in cervical or thoracic DRG in male mice at 6.5x10¹³ gc/kg on Day 29
“Minimal neuronal degeneration in the cervical or thoracic dorsal root ganglia (DRG) was observed in male mice administered 6.5 × 1013 gc/kg of DTX401 on Day 29.”
Reproductive & developmental
Embryo-fetal development and germline transmission studies in mice; NOAEL 7.0x10^13 gc/kg; no germline integration
“IV administration of DTX401 at 7 × 1013 gc/kg to pregnant dams at presumed gestational day (GD) 6 resulted in DTX401 DNA detection in placenta but not offspring livers”
Safety pharmacology
Incorporated into 6-month monkey study (respiratory, cardiovascular, neurological); no in vitro studies
“Relevant safety pharmacology endpoints (respiratory, cardiological, and neurological endpoints) were evaluated in Study #11”
Genotox: Ames
Not conducted (low expected risk of vector insertion)
“Per the applicant, studies were not conducted to evaluate genotoxicity as they expect that the risk of DTX401 insertion is low.”
Genotox: in vitro mammalian
Not conducted (low expected risk of vector insertion)
“Per the applicant, studies were not conducted to evaluate genotoxicity as they expect that the risk of DTX401 insertion is low.”
Genotox: in vivo
Not conducted (low expected risk of vector insertion)
“Per the applicant, studies were not conducted to evaluate genotoxicity as they expect that the risk of DTX401 insertion is low.”
Carcinogenicity model
Not conducted; AAV8 vectors predominantly non-integrating and episomal
“AAV8 vectors are predominantly non-integrating and persist as episomes with low likelihoods of genomic integration.”
Carcinogenicity timing
Not conducted: AAV8 vectors predominantly non-integrating and episomal
“Per the Applicant, studies were not conducted to evaluate carcinogenicity/tumorigenicity for the following reasons: • AAV8 vectors are predominantly non-integrating and persist as episomes with low likelihoods of genomic integration.”
hERG / QT
No in vitro safety pharmacology (hERG) studies performed
“No in vitro safety pharmacology studies were performed with DTX401.”
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 Genglycos 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 1.0x10^13 gc/kg adult mouse (hepatic necrosis, Kupffer cell changes above); 7.0x10^13 juvenile mouse; ~1.3x10^14 gc/kg NHP (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
NOAEL 1.0x10^13 gc/kg adult mouse (hepatic necrosis, Kupffer cell changes above); 7.0x10^13 juvenile mouse; ~1.3x10^14 gc/kg NHP
“identified a NOAEL equivalent to 1.3 × 1014 gc/kg of GENGLYCOS”
Risksopen answer page →
Immune & cytokine safety
Anti-AAV8 nAbs in all dosed mice and NHPs; AAV8 T-cell responses in mice; sporadic cytokine elevations; juvenile immune stimulation
“T-cell responses to the AAV8 peptide pool were observed in 2/10 mice on Day 29 and in 6/10 mice on Day 92.”
Biodistribution & persistence
Highest in liver; vector DNA in all tissues incl. gonads (DNA and RNA); clearance from blood ~24 weeks in patients
“DTX401 biodistribution (BD) was highest in the liver and vector DNA was detected in all evaluated tissues, including the ovaries and testes”
Modality-specific risk
AAV8 hepatotoxicity (ALT elevations, hepatic necrosis), immune responses, and theoretical integration/tumorigenicity
“In adult mice, the no observed adverse effect level (NOAEL) for IV administration of DTX401 was 1.0 × 1013 gc/kg, based on findings of single-cell hepatic necrosis”
Anti-drug antibodies: animals
Anti-AAV8 neutralizing antibodies in all DTX401-dosed mice
“DTX401 administration led to detectable anti-AAV8 nAbs in all samples from groups administered DTX401.”
Anti-drug antibodies: patients
Humoral and cellular responses evaluated; anti-AAV8 antibodies had no apparent impact on efficacy or safety; incidence not given
“Both humoral and cellular immune responses against GENGLYCOS were evaluated. There was no apparent impact of anti-AAV8 antibodies on efficacy or safety.”
Label warnings
- Hypersensitivity and Infusion Reactions
- Hepatotoxicity
- Adrenal Insufficiency
- AAV Vector Integration and Risk of Tumorigenicity
Hypersensitivity & infusion reactionsHepatotoxicityNephrotoxicityMetabolic & endocrineSecondary malignancy
US prescribing information, 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 Genglycos 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 1.0x10^13 gc/kg adult mouse (hepatic necrosis, Kupffer cell changes above); 7.0x10^13 juvenile mouse; ~1.3x10^14 gc/kg NHP (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration); longest is 6-month single-dose juvenile NHP study
“One 6-month, single-dose toxicology study was conducted in healthy juvenile non-human primates (NHPs)”
Pivotal GLP studies
Three 92-day single-dose IV studies in adult/juvenile mice; one 6-month single-dose IV GLP study in juvenile cynomolgus monkeys
“One 6-month, single-dose toxicology study was conducted in healthy juvenile non-human primates (NHPs)”
DART package
Species: DART
Mouse only (embryo-fetal development study; separate pre-mating germline transmission study)
“Similarly, IV administration of DTX401 at 7 × 1013 gc/kg to pregnant dams at presumed gestational day (GD) 6 resulted in DTX401 DNA detection in placenta but not offspring livers, and there was no impact on embryofetal development on GD 18.”
Reproductive & developmental
Embryo-fetal development and germline transmission studies in mice; NOAEL 7.0x10^13 gc/kg; no germline integration
“IV administration of DTX401 at 7 × 1013 gc/kg to pregnant dams at presumed gestational day (GD) 6 resulted in DTX401 DNA detection in placenta but not offspring livers”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted
“Per the Applicant, studies were not conducted to evaluate carcinogenicity/tumorigenicity for the following reasons:”
Carcinogenicity model
Not conducted; AAV8 vectors predominantly non-integrating and episomal
“AAV8 vectors are predominantly non-integrating and persist as episomes with low likelihoods of genomic integration.”
Carcinogenicity timing
Not conducted: AAV8 vectors predominantly non-integrating and episomal
“Per the Applicant, studies were not conducted to evaluate carcinogenicity/tumorigenicity for the following reasons: • AAV8 vectors are predominantly non-integrating and persist as episomes with low likelihoods of genomic integration.”
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 1.0x10^13 gc/kg adult mouse (hepatic necrosis, Kupffer cell changes above); 7.0x10^13 juvenile mouse; ~1.3x10^14 gc/kg NHP
“identified a NOAEL equivalent to 1.3 × 1014 gc/kg of GENGLYCOS”
Efficacy evidenceopen answer page →
Efficacy evidence
G6PC-deficient GSDIa mouse model: dose-dependent increases in hepatic G6Pase activity and fasting glucose
“In vivo pharmacology studies conducted in 2-week-old glucose-6-phosphatase, catalytic subunit 1 (G6PC) demonstrated that IV administration of DTX401 at dose levels of 5.0 × 1011 or 1.0 × 1013 gc/kg led to dose-dependent increases in hepatic G6Pase activity and fasting glucose levels.”
Why that model
Disease mouse model available that mimics human GSDIa (hypoglycemia, growth retardation, hepatomegaly, nephromegaly)
“model is associated with high early mortality at weaning and mimics features of human GSDIa including hypoglycemia, growth retardation, hepatomegaly, and nephromegaly”
Reviewer's view of the efficacy data
Mouse disease-model data accepted as confirmatory mechanistic evidence of effectiveness
“These data provide confirmatory mechanistic evidence in support of the effectiveness of DTX401.”
Test articleopen answer page →
Test article vs clinical lot
Clinical vector DTX401 in toxicology studies; earlier vector versions encoding the same protein only in pharmacology Studies 1–4. Bridging: Titers from the initial assay converted to the final titer method by a conversion factor; doses reported as equivalents
“The earlier versions of the product evaluated in Studies #1- 4 do not contain the of DTX401 but support the activity of DTX401 as they encode the same protein product. Note: The Applicant initially evaluated titers of DTX401 using which was later replaced with a method. A conversion factor of is applied to convert titers to equivalents.”
Vector and route
AAV8, single intravenous infusion
“The Applicant’s proposed dosing regimen, a single dose of GENGLYCOS at 1.0 x 1013 genome copies/kg body weight administered via intravenous (IV) infusion, is acceptable.”
First approval
2026 (FDA)
“Summary Basis for Regulatory Action Date: August, 19, 2026”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityVerdict not stated
No carcinogenicity/tumorigenicity studies; justified by low integration risk of episomal AAV8 vector and literature
Why: AAV8 vectors predominantly non-integrating and episomal, with low likelihood of genomic integration · Low-risk modality
“Per the Applicant, studies were not conducted to evaluate carcinogenicity/tumorigenicity for the following reasons: • AAV8 vectors are predominantly non-integrating and persist as episomes with low likelihoods of genomic integration.”
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