Zynteglo
betibeglogene autotemcel
Species
Mouse
Longest study
26 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse only (beta-thalassaemic Hbbth1/th1 and wild-type C57BL/6; immunodeficient NSG for human HSC); murine surrogate product
“BB305 LVV-transduced cells were evaluated in the β-thalassaemic (Hbbth1/th1) mouse model and in the NSG mice.”
Why that species
Thalassaemic mouse model gives disease-relevant POC; NSG mice cannot reject human CD34+ HSCs
“they are therefore unable to reject the human CD34+ HSCs.”
Surrogate molecule
Yes: test articles were surrogates - murine BB305-transduced thalassaemic BM cells or human healthy-donor HSCs in NSG mice
“the test articles used during non-clinical studies were surrogates, and consisted of either thalassaemic mouse bone marrow cells transduced with BB305 LVV”
Species: general tox
Mouse only: β-thalassemic (primary transplant) and wild-type C57BL/6 (secondary transplant) mice given transduced murine BMCs
“In vivo pharmacology and toxicology studies were conducted to evaluate the activity and safety of BB305 LVV-transduced murine BM cells (BMCs) following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice, respectively.”
Species: DART
Not conducted (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Species: carcinogenicity
Not conducted (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Surrogate used in
Yes: BB305-transduced thalassaemic mouse BM cells in Hbbth1/th1 mice and healthy-donor human HSCs in NSG mice
“the test articles used during non-clinical studies were surrogates, and consisted of either thalassaemic mouse bone marrow cells transduced with BB305 LVV, or human healthy donor HSCs transduced with BB305 LVV, administered to β-thalassaemic (Hbbth1/th1) mice and immunodeficient NOD scid gamma (NSG) mice, respectively.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Findings observed in the animals that survived to the Month 6 scheduled sacrifice included the following:”
Pivotal GLP studies
Combined pivotal POC/biodistribution/single-dose tox/genotox studies in thalassaemic mice (primary and secondary transplant), NSG mice; single IV dose after busulfan
“These in vivo studies (NC-11-002, NC-12-019, B2-15-161 and B2-16-200) were pivotal and combined pharmacology, biodistribution, single-dose toxicity and genotoxicity studies”
Route in tox
Single IV injection after busulfan myeloablation (BM transplantation)
“Route of Administration IV injection”
Skipped studiesopen answer page →
Genotoxicity
Insertional mutagenesis assessed instead of standard genotox: in vitro immortalization assay (low potential) and integration site analysis (no clonal dominance)
“Results from an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced murine BMCs showed low mutagenic potential of BB305 LVV.”
Carcinogenicity
Not conducted (not warranted; insertional mutagenesis risk assessed by IVIM/ISA)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel.”
Reproductive & developmental
Not conducted; no adverse findings in reproductive tissues of mice given murine product
“No developmental and/or reproductive toxicity (DART) studies were submitted to support the use of Zynteglo for the treatment of TDT.”
Safety pharmacology
Not conducted; no adverse circulatory, respiratory, neurologic or digestive effects in in vivo studies
“No safety pharmacology studies with beti-cel or with murine beti-cel were conducted.”
Genotox: Ames
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.
Genotox: in vitro mammalian
In vitro immortalization (IVIM) assay with BB305 LVV-transduced murine BMCs: low mutagenic potential
“Results from an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced murine BMCs showed low mutagenic potential of BB305 LVV.”
Genotox: in vivo
Integration site analysis of transplanted β-thalassaemic mouse BMCs (months 4 or 6): no preferred integration in MDS1-EVI1, LMO2 or HMGA2
“In the nonclinical studies conducted, ISA profiles of BB305 LVV-transduced β-thalassaemic mouse BMCs at Months 4 or 6 post-transplantation suggested that there was no preferred integration in the MDS1-EVI1 (MECOM), LMO2 or HMGA2 genes.”
Carcinogenicity model
Not conducted; no tumorigenicity or insertional oncogenesis in studies with transduced β-thalassaemic mouse BMCs or human HSCs
“No tumorigenicity and no evidence of an oncogenesis event related to insertional mutagenesis were observed in the nonclinical studies using BB305 LVV-transduced β-thalassaemic mouse BMCs or human healthy donor HSCs.”
Carcinogenicity timing
Not required (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies with beti-cel or with murine beti-cel were conducted.”
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 Zynteglo 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: No NOAEL defined; no test-article-related mortality or adverse effects at 42x10^6 cells/kg; lymphomas judged incidental (radiation/strain background) (FDA pharmacology/toxicology review, p. 12)
NOAEL / key findings
No NOAEL defined; no test-article-related mortality or adverse effects at 42x10^6 cells/kg; lymphomas judged incidental (radiation/strain background)
“No test article-related mortality or adverse effects on any parameter was observed.”
Risksopen answer page →
Immune & cytokine safety
No immunotoxicity studies; immunogenicity of beta-A-T87Q-globin not anticipated; patients immunosuppressed by busulfan
“No immunotoxicity studies have been performed since immunogenicity with βA-T87Q-globin is not anticipated.”
Biodistribution & persistence
Traditional ADME/PK not done; distribution assessed by VCN in bone marrow and blood of engrafted cells
“Cell distribution was assessed by the applicant in the target tissues, BM, and peripheral blood, by VCN measurements.”
Modality-specific risk
Insertional oncogenesis from lentiviral integration (clonal expansion); low risk per IVIM and ISA
“Integration site analysis (ISA) of beti-cel ZYNTEGLO showed no clonal dominance or enrichment for LVV integration in or near known oncogenes.”
Anti-drug antibodies: animals
Not assessed: no immunotoxicity studies as immunogenicity of βA-T87Q-globin not anticipated
“No immunotoxicity studies have been performed since immunogenicity with βA-T87Q-globin is not anticipated.”
Anti-drug antibodies: patients
Low immunogenicity of βA-T87Q-globin observed clinically; incidence not given
“Due to the low immunogenicity of βA-T87Q-globin observed in clinical studies, it is not anticipated that this would cause an adverse effect.”
Label warnings
- Delayed Platelet Engraftment
- Risk of Neutrophil Engraftment Failure
- Risk of Insertional Oncogenesis
- Hypersensitivity Reactions
- Anti-retroviral and Hydroxyurea Use
- Interference with Serology Testing
ThrombocytopeniaCytopeniasSecondary malignancyHypersensitivity & infusion reactions
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 Zynteglo 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: No NOAEL defined; no test-article-related mortality or adverse effects at 42x10^6 cells/kg; lymphomas judged incidental (radiation/strain background) (FDA pharmacology/toxicology review, p. 12)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration)
“No repeated dose toxicity studies were performed as the treatment foresees only one unique injection”
Pivotal GLP studies
Combined pivotal POC/biodistribution/single-dose tox/genotox studies in thalassaemic mice (primary and secondary transplant), NSG mice; single IV dose after busulfan
“These in vivo studies (NC-11-002, NC-12-019, B2-15-161 and B2-16-200) were pivotal and combined pharmacology, biodistribution, single-dose toxicity and genotoxicity studies”
DART package
Species: DART
Not conducted (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Reproductive & developmental
Not conducted; no adverse findings in reproductive tissues of mice given murine product
“No developmental and/or reproductive toxicity (DART) studies were submitted to support the use of Zynteglo for the treatment of TDT.”
PPND / ePPND: when
Not conducted: DART not warranted based on product characteristics and safety profile
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity model
Not conducted; no tumorigenicity or insertional oncogenesis in studies with transduced β-thalassaemic mouse BMCs or human HSCs
“No tumorigenicity and no evidence of an oncogenesis event related to insertional mutagenesis were observed in the nonclinical studies using BB305 LVV-transduced β-thalassaemic mouse BMCs or human healthy donor HSCs.”
Carcinogenicity timing
Not required (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
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
No NOAEL defined; no test-article-related mortality or adverse effects at 42x10^6 cells/kg; lymphomas judged incidental (radiation/strain background)
“No test article-related mortality or adverse effects on any parameter was observed.”
Efficacy evidenceopen answer page →
Efficacy evidence
β-thalassaemic mouse model given BB305 LVV-transduced mouse BMCs: correction of the β-thalassaemic phenotype
“were evaluated in of pivotal pharmacology studies in the β-thalassaemic murine animal model. Results showed that treatment of thalassaemic mice resulted in the correction of the β-thalassaemic phenotype.”
Why that model
Product is human autologous thalassaemic CD34+ cells, so surrogate test articles were used
“Considering the nature of the final drug product (human autologous thalassaemic CD34+ haematopoietic stem cells transduced with the BB305 lentiviral vector), the test articles used during non-clinical studies were surrogates”
Reviewer's view of the efficacy data
Four combined in vivo studies, though not fully GLP, allowed assessment of primary pharmacodynamics and toxicity
“Even if not fully compliant to GLP principles, these four in vivo combined studies allowed the assessment of both primary pharmacodynamics and toxicity.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies; low risk of oncogenic transformation concluded from the available vector data
Why: Low risk of oncogenic transformation; postmarketing observational study of insertional oncogenesis required · Weight of evidence
“These data support the conclusion that transduction of HSCs with BB305 LVV has a low risk for oncogenic transformation. Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel.”
“As insertional oncogenesis is a potential risk of treatment with ZYNTEGLO, the Applicant agreed to conduct the following postmarketing study as a safety Postmarketing Requirement.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: No adverse findings in reproductive tissues of mice given murine beti-cel; not warranted given product characteristics and safety profile · Weight of evidence · Low-risk modality
“Developmental and Reproductive Toxicology Studies: Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no adverse findings in the male and female reproductive tissues of mice administered murine beti-cel, based on the results of Study #4”
“These studies are not warranted based on the product characteristics and safety profile.”
GLPCriticised but acceptedBeyond the letter
Pivotal in vivo studies were combined pharmacology-toxicity studies in mice, not fully GLP-compliant
Why: Combined studies still allowed assessment of primary pharmacodynamics and toxicity · Other reason
“Even if not fully compliant to GLP principles, these four in vivo combined studies allowed the assessment of both primary pharmacodynamics and toxicity.”
SpeciesVerdict not stated
In vivo pharmacology and toxicology used a murine surrogate (BB305-transduced mouse bone marrow cells) in thalassemic and wild-type mice
“In vivo pharmacology and toxicology studies were conducted to evaluate the activity and safety of BB305 LVV-transduced murine BM cells (BMCs) following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice, respectively.”
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology studies
Why: No circulatory, respiratory, neurologic or digestive effects in any in vivo study · Weight of evidence
“No safety pharmacology studies were performed which is considered acceptable as there was no evidence of adverse effects on the circulatory, respiratory, neurologic or digestive systems observed in any of the in vivo studies conducted.”
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