Waskyra
etuvetidigene autotemcel
Sources:EMA assessment report ↗US prescribing information ↗FDA summary basis for approval ↗FDA pharmacology/toxicology review ↗
Species
Mouse
Longest study
64 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: WAS knockout (C57BL/6 and SV129) mice with murine surrogate cells; Rag2-/-IL2rg-/- mice for human-cell fate
“Two different WAS disease models were used to evaluate in vivo safety of transduced HSPCs: a WAS knockout (WKO) mouse on a C57BL/6 background”
Why that species
Autologous human cells cannot be used in animals; murine Lin- HSPCs functionally equivalent to human CD34+; Rag2-/-IL2rg-/- avoids immunogenicity
“The impossibility of using autologous human cells in animal models limits the scope of possible nonclinical studies.”
Surrogate molecule
Yes: mouse Lin- HSPCs transduced with w1.6W or clinical w1.6W_mut6 vector as surrogate test article
“In both models, the test article was comprised of a mouse surrogate test article”
Species: general tox
Mouse only: WAS knockout mice on C57BL/6 (sublethal irradiation) and SV129 (lethal irradiation) backgrounds
“Thus, two different WAS disease models were used to evaluate in vivo safety of transduced HSPCs: a WAS knockout (WKO) mouse on a C57BL/6 background, which required sublethal irradiation conditioning for transduced cell engraftment and a WKO mouse on SV129 background that required lethal irradiation conditioning.”
Species: DART
Not conducted (patient population, nature of gene therapy, conditioning with developmental toxicants)
“The absence of standard developmental and reproductive toxicity studies with Telethon003 is acceptable in view of the patient population, nature of the gene therapy, and preconditioning regimen with developmental toxicants.”
Species: carcinogenicity
Not conducted (not suitable for this product type)
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type.”
Surrogate used in
Yes: murine Lin- HSPCs transduced with w1.6W or clinical w1.6W_mut6 vector as test article in WKO mouse models
“In both models, the test article was a lineage-deficient (Lin-) HSPCs transduced with either the w1.6W or the w1.6W_mut6 (clinical) vector.”
Study lengthopen answer page →
Longest pivotal study
64 weeks
“Overall, these studies demonstrated no increased tumorigenic potential over a period of up to 16 months when WAS LVV-transduced HSPCs were transplanted into WAS deficient mice.”
Pivotal GLP studies
No standalone GLP pivotal tox study; two non-pivotal WKO mouse studies (sublethal/lethal irradiation) plus serial transplant, 12-16 months
“No standalone, GLP in vivo pivotal toxicology study has been performed.”
Route in tox
Intravenous
“injected intravenously with Telethon003 (0.3 x 106 cells per animal)”
Skipped studiesopen answer page →
Genotoxicity
Conventional mutagenicity not conducted; IVIM assay, vector insertion site analysis and VITA performed, no genotoxic potential
“No mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have been performed with WASKYRA”
Carcinogenicity
Not conducted (not suited to product); tumorigenicity assessed in mouse toxicity and serial transplant studies up to 16 months
“While, standard carcinogenicity studies are usually not required due to the nature of the advanced medicinal product”
Instead of carcinogenicity
In vitro immortalization assay and integration site analysis showed no tumorigenicity and no preferential integration near proto-oncogenes
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type. The nonclinical data provided by the applicant showed no evidence of tumorigenicity using the in vitro immortalization (IVIM) assay (U Modlich, 2009) and for the in vivo studies performed with no preferential integration near proto-oncogenes as evaluated via ISA.”
DRG histopathology
Not applicable: ex vivo HSC product, no vector administered to patients
Reproductive & developmental
Not conducted; no vector in testes, no treatment-related effect on reproductive organs in mouse surrogate study
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA.”
Safety pharmacology
Not conducted (WASP expressed under WAS promoter, accidental expression in heart unlikely)
“No standalone safety pharmacology studies have been conducted.”
Genotox: Ames
Not conducted (conventional mutagenicity studies not required for gene therapy)
“Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted, which is in accordance with scientific and regulatory recommendations related to gene therapies.”
Genotox: in vitro mammalian
In vitro immortalization (IVIM) assay in wild-type mouse Lin- HSPCs: WAS LVV negative; SFFV gammaretroviral vectors positive
“In the IVIM test, Lin- HSPCs were used from untreated wild type C57BL6/J mice which lack a pre-existing transforming lesion. The positive control vector and all gammaretroviral vectors with the SFFV enhancer– promoter induced re-plating in every experiment. Only the LVV with the WAS promoter and WAS transgene was negative in the assay.”
Genotox: in vivo
In vivo integration site analysis in Rag2-/-γc-/- mice: no enrichment near cancer genes (6.3% vs 16.1% random)
“After 8 weeks from transduced cell infusion in Rag2−/−/γc−/− mice, there was no in vivo enrichment of the frequency of insertion sites in close proximity to genes involved in cancer (6.3% in both HD and WAS patients versus 16.1% in random in silico insertions dataset).”
Carcinogenicity model
Not conducted; tumorigenicity assessed by IVIM assay and in vivo integration site analysis, no evidence of tumorigenicity
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type. The nonclinical data provided by the applicant showed no evidence of tumorigenicity using the in vitro immortalization (IVIM) assay (U Modlich, 2009)”
Carcinogenicity timing
Not required (not warranted for this product)
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA. These studies are not warranted based on the drug product characteristics and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA.”
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 Waskyra 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; no increased mortality, tumorigenicity or toxicity related to transduced HSPCs; lymphomas were of host origin (EMA assessment report, p. 35)
NOAEL / key findings
No NOAEL; no increased mortality, tumorigenicity or toxicity related to transduced HSPCs; lymphomas were of host origin
“results do not reveal any increased mortality, tumorigenicity, or other forms of toxicity related to the transduction of mouse SV129 WKO Lin- HSPCs with w1.6W LVV.”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotox studies; no anti-WASP antibodies in 27 treated patients
“No anti-WASP antibodies have been detected in any of the 27 participants treated with WASKYRA”
Biodistribution & persistence
Distribution limited to hematopoietic tissues; no vector in brain or testes, no bystander transduction or germline transmission
“No human or LVV sequences were detected in non-hematopoietic tissues (brain and testes)”
Modality-specific risk
Insertional mutagenesis/oncogenesis of integrating LVV; mitigated by SIN design and low VCN; 15-year follow-up required
“However, the risk of insertional mutagenicity with the integrative viral vector is an established feature, albeit mitigated in that case by the SIN virus and low VCN.”
Anti-drug antibodies: animals
Not assessed: no immune response anticipated, dedicated antigenicity/immunotoxicity studies not warranted
“WAS-LV-transduced HSPCs are not anticipated to induce an immune response. Therefore, dedicated antigenicity and immunotoxicity non-clinical studies are not warranted.”
Anti-drug antibodies: patients
No anti-WASP antibodies in any of 27 treated patients
“No anti-WASP antibodies have been detected in any of the 27 participants treated with WASKYRA, and no events indicative of immunogenicity have been reported.”
Label warnings
- Hypersensitivity and Infusion Related Reactions
- Engraftment failure
- Cytopenias
- Serious Infections
- Transmission of an infectious agent
- Hepatic veno-occlusive disease
- Risk of oncogenesis
- Interference with HIV testing
- Blood, organ, tissue and cell donation
Hypersensitivity & infusion reactionsCytopeniasInfectionsHepatotoxicitySecondary 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 Waskyra 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; no increased mortality, tumorigenicity or toxicity related to transduced HSPCs; lymphomas were of host origin (EMA assessment report, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration with engraftment)
“No repeat-dose toxicity studies have been presented by the applicant, which is acceptable considering that the product is intended to be administered to patients as a single administration, with subsequent engraftment into the patient.”
Pivotal GLP studies
No standalone GLP pivotal tox study; two non-pivotal WKO mouse studies (sublethal/lethal irradiation) plus serial transplant, 12-16 months
“No standalone, GLP in vivo pivotal toxicology study has been performed.”
DART package
Species: DART
Not conducted (patient population, nature of gene therapy, conditioning with developmental toxicants)
“The absence of standard developmental and reproductive toxicity studies with Telethon003 is acceptable in view of the patient population, nature of the gene therapy, and preconditioning regimen with developmental toxicants.”
Reproductive & developmental
Not conducted; no vector in testes, no treatment-related effect on reproductive organs in mouse surrogate study
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA.”
PPND / ePPND: when
Not conducted: DART not warranted based on product characteristics and safety profile
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA. These studies are not warranted based on the drug product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not suitable for this product type)
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type.”
Carcinogenicity model
Not conducted; tumorigenicity assessed by IVIM assay and in vivo integration site analysis, no evidence of tumorigenicity
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type. The nonclinical data provided by the applicant showed no evidence of tumorigenicity using the in vitro immortalization (IVIM) assay (U Modlich, 2009)”
Carcinogenicity timing
Not required (not warranted for this product)
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA. These studies are not warranted based on the drug 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; no increased mortality, tumorigenicity or toxicity related to transduced HSPCs; lymphomas were of host origin
“results do not reveal any increased mortality, tumorigenicity, or other forms of toxicity related to the transduction of mouse SV129 WKO Lin- HSPCs with w1.6W LVV.”
Efficacy evidenceopen answer page →
Efficacy evidence
WAS-deficient mice transplanted with WAS LVV-transduced murine Lin- BM cells: increased B cells, platelets, granulocytes; improved T, B and DC function
“In vivo pharmacology studies conducted using surrogate lineage negative (Lin-) BM cells transduced with WAS LVV transplanted into WAS-deficient mice demonstrated increased B cell, platelet, and granulocyte cell counts and improved T cell, B cell and DC function.”
Why that model
Autologous human cells cannot be used in animal models, limiting nonclinical studies
“The impossibility of using autologous human cells in animal models limits the scope of possible nonclinical studies.”
Reviewer's view of the efficacy data
Models considered acceptable as surrogate of Waskyra-transduced HSPCs
“The pharmacology, toxicology and genotoxicity of Waskyra were evaluated in vitro and in vivo. The models used were considered acceptable as surrogate of HPSC transduced with Waskyra.”
Test articleopen answer page →
Test article vs clinical lot
Mouse surrogate: lineage-deficient HSPCs transduced with either the w1.6W or the clinical w1.6W_mut6 vector. Bridging: The clinical w1.6W_mut6 vector was used alongside the earlier w1.6W vector in both mouse models
“In both models, the test article was comprised of a mouse surrogate test article: lineagedeficient (Lin-) HSPCs transduced with either the w1.6W or the w1.6W_mut6 (clinical) vector.”
Vector and route
Mobilized autologous CD34+ HSPCs transduced by a LVV encoding WAS cDNA; cell suspension for IV infusion
“Etuvetidigene autotemcel is a cell suspension for IV infusion. Its active drug substance consists of mobilized autologous CD34+ HSPCs isolated from WAS patients transduced by a LVV encoding the WAS complementary deoxyribonucleic acid (cDNA) sequence for expression of WASP in hematopoietic cell lineages”
First approval
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
Pharmacology and toxicology done with murine surrogate HSPCs transduced with the WAS vector in mice, not the human product
Why: Autologous human cells cannot be used in animal models · No relevant species
“The impossibility of using autologous human cells in animal models limits the scope of possible nonclinical studies.”
“The models used were considered acceptable as surrogate of HPSC transduced with Waskyra.”
CarcinogenicityAccepted
No standard carcinogenicity studies; tumorigenicity assessed in the mouse biosafety study and secondary transplantation
Why: Standard studies not suited to gene therapy; consistent with gene therapy recommendations · Within the guideline · Weight of evidence
“Carcinogenicity While, standard carcinogenicity studies are usually not required due to the nature of the advanced medicinal product, the tumorigenic potential was investigated in the general toxicology biosafety study and in transplantation of WAS LVV-transduced BM cells from SV129-WKO mice into secondary recipients.”
“Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted, which is in accordance with scientific and regulatory recommendations related to gene therapies.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Patient population, nature of the gene therapy and conditioning with developmental toxicants · Low-risk modality · Other reason
“Developmental and reproductive toxicity The absence of standard developmental and reproductive toxicity studies with Telethon003 is acceptable in view of the patient population, nature of the gene therapy, and preconditioning regimen with developmental toxicants.”
Similar precedents
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