Lyfgenia
lovotibeglogene 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-thalassemic and wild-type C57BL/6 transplant models; immunodeficient mice for human cells)
“The following toxicology studies were conducted to evaluate the safety of human HSCs or mBMCs transduced with BB305 LVV following administration in mice.”
Why that species
Beta-thalassemic (Hbbth1/th1) mouse disease model allowed pharmacology and toxicity assessment of transduced syngeneic marrow
“To evaluate the pharmacologic and toxicologic effects of mBMCs transduced with BB305 LVV or mBMCs transduced with HPV569 LVV following IV administration in β-thalassemic mice.”
Surrogate molecule
Yes: murine bone marrow cells transduced with clinical BB305 vector (homologous cell product); human CD34+ in immunodeficient mice
“Test Articles • mBMCs transduced with BB305 LVV (Lot No. • mBMCs transduced with HPV569 LVV (Lot No. Control Article mBMCs; mock-transduced”
Species: general tox
Mouse only (β-thalassemic and wild-type C57BL/6 primary/secondary transplant studies)
“In vivo studies were also conducted to assess the activity and safety of mBMCs transduced with BB305 following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice.”
Species: DART
Not conducted (no adverse findings in mouse reproductive tissues)
“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 mBMCs transduced with BB305 LVV”
Species: carcinogenicity
Not conducted (acceptable based on product type)
“No traditional carcinogenicity studies were conducted with lovo-cel which is acceptable based on the product type.”
Surrogate used in
Yes: murine bone marrow cells as surrogate cell product; SCD transgenic mouse POC used a related βA-T87Q vector
“In vivo POC studies were also conducted using transgenic mouse models of SCD, where murine bone marrow cells (mBMCs) were transduced with the βA-T87Q LVV, a related vector encoding the same transgene, and showed expression of βA-T87Q and correction of the sickling phenotype through 3 months post-transplantation.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Scheduled Sacrifice Time Points 6 months post-transplant”
Pivotal GLP studies
Non-GLP single-dose IV studies: primary transplant in beta-thal mice (4 months) and secondary transplant in C57BL/6 mice (6 months)
“In vivo studies were also conducted to assess the activity and safety of mBMCs transduced with BB305 following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice.”
Route in tox
Intravenous (after irradiation or busulfan myeloablation)
“Route of Administration IV injection”
Skipped studiesopen answer page →
Genotoxicity
Insertional mutagenesis assessed: in vitro immortalization (IVIM) assay and integration site analyses; low risk
“Per the applicant, based on these data, the risk of insertional mutagenesis following BB305 transduction is low.”
Carcinogenicity
Not conducted (acceptable based on product type)
“No traditional carcinogenicity studies were conducted with lovo-cel which is acceptable based on the product type.”
Instead of carcinogenicity
In vitro immortalization assay showing low mutagenic potential of BB305 LVV versus positive control vectors, with integration site analysis
“The risk of insertional mutagenesis of BB305 LVV as evaluated using an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced mBMCs showed low mutagenic potential of BB305 LVV compared to positive control vectors , which are known to cause insertional transformation. Integration site analysis of CD34+ HSCs obtained from healthy donors showed no enrichment for LVV integration in or near known oncogenes.”
DRG histopathology
Not applicable: ex vivo HSC product, no vector administered to patients
Reproductive & developmental
Not conducted (no reproductive tissue findings in mouse studies; busulfan risk addressed in label)
“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 mBMCs transduced with BB305 LVV”
Safety pharmacology
Not conducted
“No safety pharmacology studies with lovo-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 in transduced mouse marrow cells: low mutagenic potential vs positive control vectors
“The risk of insertional mutagenesis of BB305 LVV as evaluated using an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced mBMCs showed low mutagenic potential of BB305 LVV compared to positive control vectors”
Genotox: in vivo
Integration site analysis of transduced mouse marrow from transplant studies: no evidence of insertional mutagenesis
“There was no evidence of insertional mutagenesis.”
Carcinogenicity model
No carcinogenicity study; secondary-transplant mouse study: T-cell lymphoma/leukemia within radiation-associated background (15.7-25.3%), considered incidental
“The observed incidence of T-cell lymphoma and/or leukemia was within the reported range (15.7-25.3%) for radiation-associated lymphoma in C57BL/6 mice (E. Will et al. (2007) Mol Ther 15:782-91) and was considered incidental.”
Carcinogenicity timing
Not required (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. 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 lovo-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 Lyfgenia 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: Applicant designated single tested dose (11x10^6 cells/kg) NOAEL; no test article-related deaths or adverse findings through 6 months; lymphomas background (FDA pharmacology/toxicology review, p. 3)
NOAEL / key findings
Applicant designated single tested dose (11x10^6 cells/kg) NOAEL; no test article-related deaths or adverse findings through 6 months; lymphomas background
“In the secondary transplantation study, no deaths or adverse findings attributed to the BB305 LVV-transduced cells occurred through 6 months post-transplantation of 6×106 cells/mouse.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
No traditional PK; cell distribution assessed by VCN in bone marrow and peripheral blood
“Cell distribution was assessed by the applicant in the target tissues, BM, and peripheral blood, by VCN measurements.”
Modality-specific risk
Insertional oncogenesis from LVV integration; T-cell lymphomas in serial transplant mice judged incidental (low VCN in tumors)
“A mean VCN of <1 was detected in the analyzed thymus and BM tissues, suggesting that the tumors found in the animals were not linked to high vector copy numbers.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
Boxed warning: Hematologic malignancy
- Hematologic Malignancy
- Delayed Platelet Engraftment
- Neutrophil Engraftment Failure
- Insertional Oncogenesis
- Hypersensitivity Reactions
- Anti-retroviral Use
- Hydroxyurea Use
- Iron Chelation
- Interference with PCR-based Testing
CytopeniasSecondary malignancyThrombocytopeniaHypersensitivity & infusion 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 Lyfgenia 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: Applicant designated single tested dose (11x10^6 cells/kg) NOAEL; no test article-related deaths or adverse findings through 6 months; lymphomas background (FDA pharmacology/toxicology review, p. 3)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; single-transplant mouse studies, longest followed 6 months post-transplant (secondary transplantation)
“In the secondary transplantation study, no deaths or adverse findings attributed to the BB305 LVV-transduced cells occurred through 6 months post-transplantation of 6×106 cells/mouse.”
Pivotal GLP studies
Non-GLP single-dose IV studies: primary transplant in beta-thal mice (4 months) and secondary transplant in C57BL/6 mice (6 months)
“In vivo studies were also conducted to assess the activity and safety of mBMCs transduced with BB305 following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice.”
DART package
Species: DART
Not conducted (no adverse findings in mouse reproductive tissues)
“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 mBMCs transduced with BB305 LVV”
Reproductive & developmental
Not conducted (no reproductive tissue findings in mouse studies; busulfan risk addressed in label)
“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 mBMCs transduced with BB305 LVV”
PPND / ePPND: when
Not conducted; not warranted given product characteristics and safety profile
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (acceptable based on product type)
“No traditional carcinogenicity studies were conducted with lovo-cel which is acceptable based on the product type.”
Carcinogenicity model
No carcinogenicity study; secondary-transplant mouse study: T-cell lymphoma/leukemia within radiation-associated background (15.7-25.3%), considered incidental
“The observed incidence of T-cell lymphoma and/or leukemia was within the reported range (15.7-25.3%) for radiation-associated lymphoma in C57BL/6 mice (E. Will et al. (2007) Mol Ther 15:782-91) and was considered incidental.”
Carcinogenicity timing
Not required (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. 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
Applicant designated single tested dose (11x10^6 cells/kg) NOAEL; no test article-related deaths or adverse findings through 6 months; lymphomas background
“In the secondary transplantation study, no deaths or adverse findings attributed to the BB305 LVV-transduced cells occurred through 6 months post-transplantation of 6×106 cells/mouse.”
Efficacy evidenceopen answer page →
Efficacy evidence
Transgenic SCD mice given marrow cells transduced with a related βA-T87Q vector: βA-T87Q expression and correction of sickling
“In vivo POC studies were also conducted using transgenic mouse models of SCD, where murine bone marrow cells (mBMCs) were transduced with the βA-T87Q LVV, a related vector encoding the same transgene, and showed expression of βA-T87Q and correction of the sickling phenotype through 3 months post-transplantation.”
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: no nonclinical deficiencies; no further nonclinical data requested
“There are no nonclinical deficiencies identified in this submission. There are no outstanding requests for additional nonclinical data for evaluation of LYFGENIA™.”
Test articleopen answer page →
Test article vs clinical lot
Murine bone marrow cells transduced with BB305 used in the primary and secondary transplantation studies, not patient CD34+ cells
“In vivo studies were also conducted to assess the activity and safety of mBMCs transduced with BB305 following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice.”
Vector and route
Non-replicating BB305 lentiviral vector in autologous cells; suspension for intravenous infusion after thawing
“transduced with a non-replicating lentiviral vector (LVV), referred to as BB305, containing the human βA-T87Q-globin transgene sequence. LYFGENIA is supplied frozen in 20 mL bags as a suspension for intravenous infusion after thawing.”
First approval
2023 (FDA)
“Summary Basis for Regulatory Action Date: December 08, 2023 From: Graeme Price, PhD, Chair of Review Committee”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No traditional carcinogenicity studies; insertional mutagenesis assessed by in vitro immortalization assay and integration site analysis
Why: Acceptable based on the product type · Other reason
“Carcinogenicity Studies: No traditional carcinogenicity studies were conducted with lovo-cel which is acceptable based on the product type.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: No adverse findings in reproductive tissues of mice; not warranted given product characteristics and safety profile · Weight of evidence · Other reason
“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 mBMCs transduced with BB305 LVV”
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. These studies are not warranted based on the product characteristics and safety profile.”
Efficacy modelVerdict not stated
Proof-of-concept in SCD mice used a related vector (βA-T87Q LVV) encoding the same transgene, not BB305
Why: Related vector encodes the same transgene
“In vivo POC studies were also conducted using transgenic mouse models of SCD, where murine bone marrow cells (mBMCs) were transduced with the βA-T87Q LVV, a related vector encoding the same transgene, and showed expression of βA-T87Q and correction of the sickling phenotype through 3 months post-transplantation.”
Similar precedents
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