Lenmeldy
atidarsagene autotemcel
Species
Mouse
Longest study
52 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 (As2-/- MLD model, murine ARSA-LV HSPCs) for pivotal GLP; immunodeficient mice for human-cell biodistribution
“The in vivo safety of single IV administration of ARSA LVV-transduced mHSPCs at 1x106 cells/mouse (40-50x106 cells/kg) in irradiated As2-/- mice was evaluated in a pivotal GLP study for up to 12 months post-transplant.”
Why that species
As2-/- mouse used as MLD disease model; recapitulates some pathology but milder phenotype than patients
“The applicant has used the As2-/- mouse as a disease model for MLD in children.”
Surrogate molecule
Yes: murine Lin- HSPCs from As2-/- mice transduced with ARSA LVV (plus healthy human HSPCs) used instead of patient cells
“Therefore, lineage negative (Lin-) mHSPCs (derived from the BM of As2-/- mice) and healthy hHSPCs (derived from umbilical cord blood or BM) transduced with ARSA LVV were used for the majority of the nonclinical studies.”
Species: general tox
Mouse only (irradiated As2-/- MLD mice given ARSA-LV murine HSPCs; pivotal GLP study up to 12 months)
“The in vivo safety of single IV administration of ARSA LVV-transduced mHSPCs at 1x106 cells/mouse (40-50x106 cells/kg) in irradiated As2-/- mice was evaluated in a pivotal GLP study for up to 12 months post-transplant.”
Species: DART
Not conducted (ex vivo transduction with replication-incompetent LV; germline risk very limited)
“No dedicated reproductive and developmental studies are undertaken. As the cells are transduced ex vivo with a replication-incompetent lentiviral vector, the risk for transduction of the gametes and consequently the risk from germline transduction can be regarded as very limited and rather theoretical.”
Species: carcinogenicity
Not conducted (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
Surrogate used in
Yes: murine Lin- HSPCs as homologue of human CD34+ cells, transduced with LV carrying human PGK and ARSA
“For the proof-of-principle studies, the applicant has used murine Lin- HSPCs as homologue for human CD34+ cells, although the LV vector did contain human PGK and ARSA.”
Study lengthopen answer page →
Longest pivotal study
52 weeks
“Scheduled Sacrifice Time Points 52 weeks post-dose”
Pivotal GLP studies
GLP toxicology/tumorigenicity study, As2-/- mice, single IV ARSA-LV or mock HSPCs, 52 weeks post-dose
“Toxicology and tumorigenicity study in ARSA KO mice treated with ARSA-/- HSPCs transduced with ARSA.LV Vector”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Conducted: integration site analysis, in vitro immortalization assay, tumor-prone Cdkn2a-/- mouse; no insertional transformation
“Genotoxicity risk was assessed in vitro using hHSPCs derived from healthy donors and MLD patients and showed no effects of LVV transduction or ARSA overexpression on the proliferation or differentiation of hHSPCs.”
Carcinogenicity
Not conducted (not warranted); tumorigenicity assessed within GLP mouse study
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200.”
Reproductive & developmental
Not conducted (ex vivo transduction; germline transduction risk very limited)
“No dedicated reproductive and developmental studies are undertaken.”
Safety pharmacology
Not conducted; no CNS, cardiovascular or respiratory toxicity seen in animal studies
“No dedicated safety pharmacology studies have been performed with human or murine HSPCs transduced with ARSA-LV.”
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 same-backbone GFP-LV: no insertional mutagenesis
“No evidence of insertional mutagenesis of the LVV backbone in an in vitro immortalization (IVIM) assay and no increase in tumorigenesis in vivo in a tumor-prone mouse model were demonstrated using a LVV expressing GFP, which shares the same LVV backbone as that of ARSA LVV.”
Genotox: in vivo
Tumor-prone mouse model with same-backbone GFP-LV: no increase in tumorigenesis
“No evidence of insertional mutagenesis of the LVV backbone in an in vitro immortalization (IVIM) assay and no increase in tumorigenesis in vivo in a tumor-prone mouse model were demonstrated using a LVV expressing GFP, which shares the same LVV backbone as that of ARSA LVV.”
Carcinogenicity model
No carcinogenicity study; 12-month GLP tumorigenicity study in As2-/- mice: 2 hepatocellular neoplasms (1 ARSA-LV, 1 mock-LV)
“During the observation period of 12 months after transplantation, only 2 hepatocellular neoplasms were found (1 in ARSA-LV group, 1 in mock-LV group).”
Carcinogenicity timing
Not required (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
hERG / QT
Not conducted (no dedicated safety pharmacology studies)
“No dedicated safety pharmacology studies have been performed with human or murine HSPCs transduced with ARSA-LV.”
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 Lenmeldy 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 formal NOAEL; no test-article toxicity or malignancy at 1x10^6 cells/mouse (40-50x10^6 cells/kg); findings from As2-/- phenotype and irradiation (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
No formal NOAEL; no test-article toxicity or malignancy at 1x10^6 cells/mouse (40-50x10^6 cells/kg); findings from As2-/- phenotype and irradiation
“No test article-related mortality, toxicity or hematologic malignancy was observed, with study findings primarily attributed to the As2-/- phenotype, irradiation, and incidental age-related findings.”
Risksopen answer page →
Immune & cytokine safety
No anti-ARSA antibodies or adverse neurobehavioral effects in mice; anti-ARSA antibodies in 15% of patients clinically
“No development of anti-ARSA antibodies or adverse neurobehavioral effects were observed in As2-/- mice transplanted with ARSA LVV-transduced mHSPCs.”
Biodistribution & persistence
Engrafts BM, spleen, thymus, liver; lower levels in brain; integrated LVV persists stably; shedding risk low
“In addition to the bone marrow, spleen, thymus, and liver, transduced human cells were also detected at lower levels in the mouse brain, demonstrating migration of the transduced cells into target organs.”
Modality-specific risk
Insertional mutagenesis/oncogenesis of LVV; none seen in tumor-prone mouse (SIN vector); conditioning-related toxicity
“Libmeldy-related LV showed no considerable insertional transformation potential in the tumour-prone mice, which is most likely due to the absence of active LTRs (i.e. LV is self-inactivating).”
Anti-drug antibodies: animals
No anti-human ARSA antibodies detected in As2-/- mice (Week 52)
“No anti-human ARSA antibodies were detected.”
Anti-drug antibodies: patients
Anti-ARSA antibodies in 6 of 39 patients (15%); no indication of decreased ARSA activity in five PSLI children with antibodies
“Anti-ARSA antibodies (AAA) were detected in 6 out 39 subjects (15%). There is no indication of decreased ARSA activity in five children with PSLI who developed AAA”
Label warnings
- Thrombosis and Thromboembolic Events
- Encephalitis
- Serious Infection
- Veno-occlusive Disease
- Delayed Platelet Engraftment
- Neutrophil Engraftment Failure
- Insertional Oncogenesis
- Hypersensitivity Reactions
- Anti-retroviral Use
- Interference with Serology Testing
Thrombosis & embolismInfectionsThrombocytopeniaCytopeniasSecondary 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 Lenmeldy 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 formal NOAEL; no test-article toxicity or malignancy at 1x10^6 cells/mouse (40-50x10^6 cells/kg); findings from As2-/- phenotype and irradiation (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration); single-dose toxicity assessed within long-term toxicity studies
“No single dose and repeat dose toxicity studies were performed. Single dose toxicity was taken along in the long-term toxicity studies.”
Pivotal GLP studies
GLP toxicology/tumorigenicity study, As2-/- mice, single IV ARSA-LV or mock HSPCs, 52 weeks post-dose
“Toxicology and tumorigenicity study in ARSA KO mice treated with ARSA-/- HSPCs transduced with ARSA.LV Vector”
DART package
Species: DART
Not conducted (ex vivo transduction with replication-incompetent LV; germline risk very limited)
“No dedicated reproductive and developmental studies are undertaken. As the cells are transduced ex vivo with a replication-incompetent lentiviral vector, the risk for transduction of the gametes and consequently the risk from germline transduction can be regarded as very limited and rather theoretical.”
Reproductive & developmental
Not conducted (ex vivo transduction; germline transduction risk very limited)
“No dedicated reproductive and developmental studies are undertaken.”
PPND / ePPND: when
Not conducted; not warranted given product characteristics and safety profile
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity model
No carcinogenicity study; 12-month GLP tumorigenicity study in As2-/- mice: 2 hepatocellular neoplasms (1 ARSA-LV, 1 mock-LV)
“During the observation period of 12 months after transplantation, only 2 hepatocellular neoplasms were found (1 in ARSA-LV group, 1 in mock-LV group).”
Carcinogenicity timing
Not required (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. 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 formal NOAEL; no test-article toxicity or malignancy at 1x10^6 cells/mouse (40-50x10^6 cells/kg); findings from As2-/- phenotype and irradiation
“No test article-related mortality, toxicity or hematologic malignancy was observed, with study findings primarily attributed to the As2-/- phenotype, irradiation, and incidental age-related findings.”
Efficacy evidenceopen answer page →
Efficacy evidence
As2-/- MLD mice given ARSA-LV murine HSPCs: improved motor conduction, rotarod coordination and neuropathology vs GFP-LV controls
“Improvement in motor conduction abnormalities, motor coordination by rotarod testing, and neuropathology were observed compared to mice receiving GFP LVV-transduced mHSPCs when evaluated between 4-12 months post-transplantation.”
Why that model
ARSA-deficient As2-/- mouse available as MLD disease model, though with milder, non-lethal phenotype
“The applicant has used the As2-/- mouse as a disease model for MLD in children. The applicant stated that neuropathological changes and symptoms observed in these mice are comparable to those patients, although symptoms are milder and disease is not life-threatening (i.e. normal life span).”
Reviewer's view of the efficacy data
EMA: As2-/- mouse model gives proof of principle but no quantitative extrapolation (effective dose, VCN/ARSA thresholds, duration)
“In conclusion, while the used animal model may be able to provide proof of principle, more quantitative extrapolation of treatment effects (e.g. effective dose, thresholds for VCN levels or ARSA activity needed for disease correction, duration and course of ARSA expression) is not possible based on this animal model”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Ex vivo transduction with replication-incompetent vector; no bystander transduction or vector mobilisation observed in animals · Low-risk modality · Weight of evidence
“As the transduction of the cells occurs ex vivo, the risk for transduction of the gametes and consequently the risk from germline transduction is limited and rather theoretical.”
“The absence of dedicated studies addressing the reproductive and developmental toxicity can thus be agreed upon.”
CarcinogenicityAcceptedBeyond the letter
No standard carcinogenicity studies; tumorigenicity assessed in mouse transplantation studies and integration analyses
Why: Product characteristics and safety profile · Weight of evidence
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
GenotoxicityVerdict not stated
Insertional mutagenesis (immortalization assay, tumor-prone mice) tested with a GFP-expressing vector sharing the ARSA vector backbone
Why: GFP vector shares the same lentiviral backbone · Class precedent
“No evidence of insertional mutagenesis of the LVV backbone in an in vitro immortalization (IVIM) assay and no increase in tumorigenesis in vivo in a tumor-prone mouse model were demonstrated using a LVV expressing GFP, which shares the same LVV backbone as that of ARSA LVV.”
OtherVerdict not stated
Toxicity studies used murine HSPCs with total-body irradiation conditioning instead of clinical busulfan
Why: Total-body irradiation better tolerated than busulfan in mice
“Because TBI was better tolerated, the applicant used this regimen for pre-conditioning in the long-term toxicity studies. Clinically, busulfan instead of irradiation is used as a pre-conditioning regimen.”
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