Skysona
elivaldogene autotemcel
Species
Mouse
Longest study
13 wk (derived)
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse only: myeloablated immunodeficient NSG/NSGS mice given human CD34+ HSCs
“pivotal combined in vivo pharmacology, single-dose toxicity, genotoxicity and biodistribution studies in immunodeficient (NSG and NSGS) mice”
Why that species
Human cells rejected by immunocompetent animals, so immune-incompetent mice used; species barrier limits translatability
“they will be rejected. Therefore immune”
Surrogate molecule
No surrogate vector; clinical Lenti-D vector in human healthy-donor CD34+ HSCs (not patient cells) xenografted into mice
“Lenti-D donors lentiviral vector transduced human CD34+ HSCs from healthy”
Species: general tox
Immunodeficient NSG and NSGS mice only (single-dose, human CD34+ cell xenograft)
“The non-clinical safety programme conducted with Lenti-D LVV transduced human CD34+ HCSs consists of two single-dose toxicology studies performed in NSG and NSGS immune-incompetent mice.”
Species: DART
Not conducted (acceptable given product characteristics and safety profile)
“Reproductive and developmental toxicity studies were not performed for eli-cel which is acceptable based on the product characteristics and safety profile.”
Species: carcinogenicity
Not conducted
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Surrogate used in
Yes: ALDP-deficient AMN patient CD34+ HSCs used as surrogate product in in vitro pharmacology
“These ALDP-deficient AMN CD34+ HSCs were used as a surrogate product in the in vitro pharmacology studies to demonstrate vector integration, ALDP production, and correction of VLCFA metabolism.”
Study lengthopen answer page →
Longest pivotal study
13 (derived from the dosing and observation schedule)
“A 92-day GLP toxicology study in myeloablated mice evaluated a single administration of 1x106 Lenti-D transduced healthy human CD34+ HSCs/mouse.”
Pivotal GLP studies
Single 92-day GLP IV toxicity/biodistribution study (NC-12-007) in myeloablated NSG mice, 1x10^6 cells/mouse; no repeat-dose studies
“A 92-day GLP toxicology study in myeloablated mice evaluated a single administration of 1x106 Lenti-D transduced healthy human CD34+ HSCs/mouse.”
Route in tox
Intravenous
“Route of Administration Intravenous”
Skipped studiesopen answer page →
Genotoxicity
Standard genotox not relevant; insertional mutagenesis assessed by in vitro immortalization assay and integration site analysis
“Lenti-D is an autologous human cellular product, therefore, standard genotoxicity studies are not considered relevant.”
Carcinogenicity
Not conducted (traditional studies unsuitable for product); ISA on engrafted marrow instead
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Instead of carcinogenicity
Integration site analysis on pre-transplant human CD34+ HSCs and post-transplant engrafted mouse bone marrow instead of traditional carcinogenicity studies
“Traditional carcinogenicity studies were not conducted for eli-cel. However, integration site analysis (ISA) was performed on Lenti-D transduced pre-transplant human CD34+ HSCs and post-transplant engrafted bone marrow cells (BMCs) from animals in the GLP toxicology study harvested at 29 and 92 days.”
DRG histopathology
Not applicable: ex vivo HSC product, no vector administered to patients
Reproductive & developmental
Not conducted; no findings in reproductive tissues in mouse GLP study
“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”
Safety pharmacology
Not conducted; no overt CNS, CV or respiratory toxicity in two animal studies
“No dedicated safety pharmacology studies have been carried out.”
Genotox: Ames
Not conducted (standard genotoxicity not relevant for autologous cell product)
“Lenti-D is an autologous human cellular product, therefore, standard genotoxicity studies are not considered relevant.”
Genotox: in vitro mammalian
In vitro immortalization (IVIM) assay in murine Lin- bone marrow cells: reduced immortalization potential vs positive control vectors
“An in vitro immortalization (IVIM) assay was conducted with mouse lineage-depleted (hematopoietic non-lineage committed; Lin-) BMCs (the murine equivalent of human CD34+ HSCs) transduced with Lenti-D. There was a reduced potential for immortalization induced by insertional mutagenesis of the clinical vector, Lenti-D, compared to positive control vectors.”
Genotox: in vivo
Integration site analysis (pre-transplant HSCs and engrafted mouse bone marrow): expected SIN-lentiviral profile, no transcriptional start site preference
“Lenti-D transduced HSCs demonstrated the expected integration profile for self-inactivating lentiviral vectors, with preferred integration in gene-coding regions across the whole genome, no preference for integration in transcriptional start sites, and no bias for the 5’ or 3’ end of genes.”
Carcinogenicity model
Not conducted (traditional studies not suitable for this product type)
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Carcinogenicity timing
Not required; omission acceptable given nature of product
“No repeat-dose toxicology, dedicated carcinogenicity, juvenile or developmental and reproductive toxicology studies were performed, and their omission is acceptable considering the nature of the product.”
hERG / QT
Not conducted; no safety pharmacology studies
“Safety pharmacology studies were not conducted for this product.”
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 Skysona 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: True NOAEL not determined; ~5x10^7 CD34+ cells/kg (max feasible, 10x minimum clinical dose); early deaths in both test and control groups (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
True NOAEL not determined; ~5x10^7 CD34+ cells/kg (max feasible, 10x minimum clinical dose); early deaths in both test and control groups
“Although a true no observed adverse effect level (NOAEL) could not be determined, the dose level administered in this study, approximately 5x107 CD34+ cells/kg, represents the maximum feasible dose”
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
Human and vector sequences in all tissues tested through 3 months; highest in bone marrow, then lung, liver, spleen; lowest in brain, intestine, muscle
“the highest concentration (copies/µg) was observed in bone-marrow were signals above the upper LoQ were observed.”
Modality-specific risk
Insertional mutagenesis/oncogenesis from lentiviral integration; clinical hematologic malignancy concern; IVIM and ISA used
“There was a reduced potential for immortalization induced by insertional mutagenesis of the clinical vector, Lenti-D, compared to positive control vectors.”
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
- Serious Infections
- Prolonged Cytopenias
- Delayed Platelet Engraftment
- Risk of Neutrophil Engraftment Failure
- Hypersensitivity Reactions
- Anti-retroviral Use
- Laboratory Test Interference
CytopeniasSecondary malignancyInfectionsThrombocytopeniaHypersensitivity & 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 Skysona 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: True NOAEL not determined; ~5x10^7 CD34+ cells/kg (max feasible, 10x minimum clinical dose); early deaths in both test and control groups (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single autologous IV administration)
“As Lenti-D Drug Product is intended for a single autologous IV administration, not performing any repeat-dose toxicity studies is acceptable.”
Pivotal GLP studies
Single 92-day GLP IV toxicity/biodistribution study (NC-12-007) in myeloablated NSG mice, 1x10^6 cells/mouse; no repeat-dose studies
“A 92-day GLP toxicology study in myeloablated mice evaluated a single administration of 1x106 Lenti-D transduced healthy human CD34+ HSCs/mouse.”
DART package
Species: DART
Not conducted (acceptable given product characteristics and safety profile)
“Reproductive and developmental toxicity studies were not performed for eli-cel which is acceptable based on the product characteristics and safety profile.”
Reproductive & developmental
Not conducted; no findings in reproductive tissues in mouse GLP study
“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”
PPND / ePPND: when
Not conducted; acceptable given product characteristics and safety profile
“Reproductive and developmental toxicity studies were not performed for eli-cel which is acceptable based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Carcinogenicity model
Not conducted (traditional studies not suitable for this product type)
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Carcinogenicity timing
Not required; omission acceptable given nature of product
“No repeat-dose toxicology, dedicated carcinogenicity, juvenile or developmental and reproductive toxicology studies were performed, and their omission is acceptable considering the nature of the product.”
Safety marginopen answer page →
Safety margin at NOAEL
Maximum feasible mouse dose (cells/kg) ~10-fold the minimum recommended human dose; NOAEL not determined
“Although a no observed effect level (NOAEL) could not be determined, a dose level of 1x106 CD34+ cells/animal or 5x107 CD34+ cells/kg provides an approximately 10-fold safety margin to the recommended minimum dose level to be administered in humans (5x106 CD34+ cells/kg).”
NOAEL / key findings
True NOAEL not determined; ~5x10^7 CD34+ cells/kg (max feasible, 10x minimum clinical dose); early deaths in both test and control groups
“Although a true no observed adverse effect level (NOAEL) could not be determined, the dose level administered in this study, approximately 5x107 CD34+ cells/kg, represents the maximum feasible dose”
Efficacy evidenceopen answer page →
Efficacy evidence
Healthy-donor Lenti-D HSCs in myeloablated immunodeficient mice: bone marrow and brain engraftment with ABCD1 expression and ALDP production
“In vivo assessment of Lenti-D-transduced healthy donor derived CD34+ HSCs transplanted in myeloablated immunodeficient mice demonstrated bone marrow and brain engraftment that was associated with stable ABCD1 transgene expression and ALDP production for the 3-month study duration.”
Why that model
No animal model of CALD; ABCD1 knockout mice resemble AMN, lacking cerebral inflammation and demyelination
“There are no known animal models of CALD that recapitulate the human disease. Murine ABCD1/ALDP knockout mice (ALD mice) lack ALDP and have altered VLCFA metabolism, but the disease phenotype resembles AMN rather than ALD and does not display the cerebral inflammation and cerebral demyelination observed in human cerebral ALD (CALD).”
Reviewer's view of the efficacy data
EMA: not a regular proof of concept, but with brain engraftment acceptable preclinical support for the treatment concept
“However, in the assessment this is not considered as a regular PoC. Nevertheless, taken together with the indicated brain engraftment, these both observations provide acceptable preclinical support for the treatment concept.”
Test articleopen answer page →
Test article vs clinical lot
Healthy-donor CD34+ HSCs transduced with the same Lenti-D LVV used to produce the clinical product, not patient cells. Bridging: All cells were transduced with the same LVV, Lenti-D, that is used to produce eli-cel
“Therefore, CD34+ HSCs from healthy donors (with normal ALDP expression) were used for the in vivo pharmacology/toxicology studies. All cells were transduced with the same LVV, Lenti-D, that is used to produce eli-cel”
Vector and route
Lenti-D LVV-transduced autologous HSCs; single IV infusion
“Thus, the Lenti-D LVV is not administered to patients; it is used to transduce the patients’ own autologous HSCs ex vivo during the manufacture of the drug substance. Skysona is intended for autologous use only, as a single IV infusion of 2-30 × 106 CD34+ cells/mL dispersion for infusion,(the minimum recommended dose of Skysona is 5 × 106 CD34+ cells/kg)”
First approval
2022 (FDA)
“DATE REVIEW COMPLETED: August 20, 2022 PRODUCT: SKYSONA (elivaldogene autotemcel)”
Flexibilityopen answer page →
Flexibility accepted
SpeciesCriticised but acceptedBeyond the letter
Safety tested only in single-dose studies in immunodeficient myeloablated mice given healthy-donor transduced cells
Why: Immunodeficient mice justified as an HSC engraftment model; animal models are poor predictors of cell therapy safety · No relevant species · Other reason
“The safety data from immune-deficient mice are considered less relevant in predicting the human situation. When it comes to cell therapies, it is well established that animal models are poor predictors of safety in humans.”
“Although the value of using immune-incompetent mice to predict safety issues for a human cell therapy is questionable, the strains have been used as a model for HSC engraftment and their use can from that point be justified.”
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity study; insertional mutagenesis addressed by in vitro immortalisation assay and integration site analysis (single donor, single vector lot)
Why: ISA shortcomings covered by clinical ISA monitoring every 6 months to 5 years and 15-year leukemia/lymphoma follow-up · Weight of evidence · Human data
“Traditional carcinogenicity studies were not conducted for eli-cel. However, integration site analysis (ISA) was performed on Lenti-D transduced pre-transplant human CD34+ HSCs and post-transplant engrafted bone marrow cells (BMCs) from animals in the GLP toxicology study harvested at 29 and 92 days.”
“However, these shortcomings are not considered enough for demanding additional analysis and could be considered covered by the clinical monitoring, were subjects in the clinical studies are monitored by ISA every 6 months up to 5 years after treatment and patients are to be monitored annually for leukemia/lymphoma for 15 years post treatment.”
DARTAcceptedBeyond the letter
No reproductive, developmental or juvenile toxicity studies
Why: Product type; no findings in reproductive tissues in the mouse toxicology study · Low-risk modality · Weight of evidence
“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”
“Reproductive and developmental toxicity studies were not performed for eli-cel which is acceptable based on the product characteristics and safety profile.”
BiodistributionAcceptedBeyond the letter
No germline transmission studies
Why: Ex vivo transduction, replication-incompetent vector, no free vector in product; busulfan conditioning often causes infertility · Low-risk modality · Other reason
“Given that the cells are transduced ex vivo with a replication-incompetent vector and no residual free viral particles are present in the Lenti-D Drug Product, the risk for germ line transmission is considered regarded very limited and rather theoretical.”
“Also, patients will be preconditioned with the reprotoxic busulfan, often resulting in infertility. The omission of specific germ line transmission studies is therefore acceptable.”
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