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”
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.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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.”