Kebilidi
eladocagene exuparvovec
Sources:EMA assessment report ↗FDA summary basis for approval ↗FDA clinical review (nonclinical section) ↗US prescribing information ↗
Species
MonkeyRat
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Conducted Stated
Speciesopen answer page →
Species
Rat (pivotal GLP); cynomolgus monkey for biodistribution/excipient studies
“The nonclinical safety program conducted to characterize the toxicity and biodistribution of eladocagene exuparvovec comprised of two studies, a 30-day study, and a 6 month study, both in rats.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For biologics, ICH S6(R1) asks for species in which the product is pharmacologically active (target binding and activity), usually a cynomolgus monkey.
“A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).”
✓ VerifiedICH 2011: ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived…, p. 7Source ↗
Surrogate molecule
No surrogate; clinical vector in rat; NHP used rAAV2-hAADC and rAAV2-eGFP reporter vector
“The recombinant adeno-associated virus, serotype 2 (rAAV2) vector was identical to that used for eladocagene exuparvovec and this study also evaluated limited toxicological parameters.”
Species: general tox
Rat (pivotal single-dose studies) and non-human primate
“Single-dose toxicology studies were conducted in rats and nonhuman primates (NHPs) using direct bilateral intraputaminal infusion.”
Species: DART
Not conducted (agreed with CHMP)
“No specific developmental and reproductive toxicology studies were conducted by the applicant with eladocagene exuparvovec, in agreement with CHMP.”
Species: carcinogenicity
Not conducted (not warranted given product characteristics and patient population)
“No nonclinical studies were conducted to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of eladocagene exuparvovec-tneq as such studies were not warranted based on the product characteristics and target patient population.”
Surrogate used in
No surrogate molecule; NHP formulation study used an identical rAAV2 vector carrying a GFP reporter
“The recombinant adeno-associated virus, serotype 2 (rAAV2) vector was identical to that used for eladocagene exuparvovec and this study also evaluated limited toxicological parameters.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“There were no significant adverse findings noted in a 6-month toxicology study in rats administered dose levels ranging from 7.5x108 – 7.5x109 vg/animal.”
Pivotal GLP studies
Rat single-dose intraputaminal 30-day and 6-month GLP tox/BD; NHP 30-day poloxamer study; NHP 4-week route BD study
“Two single-dose studies were conducted to assess toxicity at 30-days and 6 months.”
Route in tox
Bilateral intraputaminal infusion (also substantia nigra in rat; ICV/IT in NHP BD study)
“In the 6-month study a single eladocagene exuparvovec administration via bilateral IPI at doses up to 7.5×109 vg was generally well tolerated with no obvious signs of toxicity.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (agreed with CHMP; low integration risk in post-mitotic neurons)
“It was previously agreed with CHMP that genotoxicity, carcinogenicity and evaluation of insertional mutagenesis studies were not required (EMEA/CHMP/SAWP/236092/2018).”
Carcinogenicity
Not conducted (product characteristics and patient population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted.”
Reproductive & developmental
Not conducted (local brain delivery, no systemic exposure or gonadal distribution)
“Given the local administration of eladocagene exuparvovec to the brain and lack of systemic exposure, and the absence of biodistribution to the gonads, the risk for germline transmission is low.”
Safety pharmacology
CNS (FOB) endpoints incorporated into 6-month GLP rat tox study; no stand-alone studies
“Stand-alone safety pharmacology studies were not conducted with eladocagene exuparvovec. An evaluation of CNS effects was included in the 6-month GLP toxicology study.”
Genotox: Ames
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been performed with KEBILIDI.”
Genotox: in vitro mammalian
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been performed with KEBILIDI.”
Genotox: in vivo
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been performed with KEBILIDI.”
Carcinogenicity model
Not conducted; weight-of-evidence (episomal AAV2, no tumors in rat chronic studies) indicates low integration/tumorigenicity risk in post-mitotic neurons
“The applicant has provided a discussion on the risk of insertional mutagenesis and carcinogenic potential. Based on the weight of evidence discussed there appears to be a low risk for genomic integration or tumorigenicity in postmitotic neuronal cells.”
Carcinogenicity timing
Not required; not warranted given product characteristics and target patient population
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted. These studies were not warranted based on the product characteristics and target patient population.”
hERG / QT
Not conducted (no safety pharmacology studies)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted.”
First doseopen answer page →
First-in-human starting dose
Prior adult PD rAAV2-hAADC clinical doses (up to 3x10^11 vg) scaled by brain mass; 1.8x10^11 vg (~60%)
“The applicant justified this dose on the basis that clinical studies in adult PD using rAAV2-hAADC reported that doses up to 3x 1011 vg of rAAV2-hAADC in a volume of 4×50 μl were well tolerated following bilateral, intraputaminal infusions during a single operative session.”
NOAEL / key findings
Rat NOAEL 7.5x10^9 vg (highest dose; ~21x margin by brain weight); no significant adverse findings
“Since there were no toxicologically significant findings at the high dose, the no observed adverse effect level (NOAEL) was set at the high dose (7.5x109 vg).”
Risksopen answer page →
Immune & cytokine safety
Dose-dependent anti-AAV2 capsid ADA in rats; no effect on biodistribution or expression; anti-AADC not assessed
“The formation of anti-drug antibodies against the AAV2 vector capsid was dose dependent with the highest incidence observed in Group 4 high-dose animals at Days 30 and 180.”
Biodistribution & persistence
Mostly CNS, highest in putamen; vector persists to D180 with decline; no blood/CSF shedding in rat
“Persistence of vector DNA was most notable in the putamen, cerebrum, cerebellum, and spinal cord at all time points, with the highest levels in the putamen.”
Modality-specific risk
Off-target spread/ectopic dopamine-serotonin expression, poloxamer 188 brain safety, insertional mutagenesis
“That being said, one cannot dismiss the possibility that the transgene will spread to adjacent brain regions (e.g. globus pallidus, caudate, amygdala) at least in some individuals.”
Anti-drug antibodies: animals
Rats: dose-dependent anti-AAV2 capsid ADA, highest at high dose (Days 30 and 180); no effect on biodistribution or expression; anti-AADC not assessed
“The formation of anti-drug antibodies against the AAV2 vector capsid was dose dependent with the highest incidence observed in Group 4 high-dose animals at Days 30 and 180.”
Anti-drug antibodies: patients
All patients (N=13) had rising anti-AAV2 total binding and neutralizing antibodies from Week 3, still elevated at Week 48
“In all patients (N=13), titers of total binding antibody and neutralizing antibody increased from Week 3 and remained elevated, as measured at Week 48 (N=9).”
Label warnings
- Procedural Complications
- Dyskinesia
Skin reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; the vector (rAAV2-hAADC) was first tested in humans in Parkinson's disease patients by bilateral intraputaminal dosing
“rAAV2-hAADC was subsequently tested in the first-in-human clinical trials of patients with Parkinson’s disease at dose levels of 9×1010 and 3×1011 vg via bilateral intra-putaminal dosing (Christine 2009, Muramatsu 2010).”
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
Prior adult PD rAAV2-hAADC clinical doses (up to 3x10^11 vg) scaled by brain mass; 1.8x10^11 vg (~60%)
“The applicant justified this dose on the basis that clinical studies in adult PD using rAAV2-hAADC reported that doses up to 3x 1011 vg of rAAV2-hAADC in a volume of 4×50 μl were well tolerated following bilateral, intraputaminal infusions during a single operative session.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration; persistent expression through 6 months in rodents gives chronic exposure)
“Eladocagene exuparvovec is a single dose gene therapy with persistent gene expression through 6 months in rodents (Leidos 8366537, AADC-003) which provides chronic exposure and, therefore, no repeat-dose studies were conducted.”
Pivotal GLP studies
Rat single-dose intraputaminal 30-day and 6-month GLP tox/BD; NHP 30-day poloxamer study; NHP 4-week route BD study
“Two single-dose studies were conducted to assess toxicity at 30-days and 6 months.”
DART package
Species: DART
Not conducted (agreed with CHMP)
“No specific developmental and reproductive toxicology studies were conducted by the applicant with eladocagene exuparvovec, in agreement with CHMP.”
Reproductive & developmental
Not conducted (local brain delivery, no systemic exposure or gonadal distribution)
“Given the local administration of eladocagene exuparvovec to the brain and lack of systemic exposure, and the absence of biodistribution to the gonads, the risk for germline transmission is low.”
PPND / ePPND: when
Not conducted; not warranted given product characteristics and target patient population
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted. These studies were not warranted based on the product characteristics and target patient population.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted given product characteristics and patient population)
“No nonclinical studies were conducted to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of eladocagene exuparvovec-tneq as such studies were not warranted based on the product characteristics and target patient population.”
Carcinogenicity model
Not conducted; weight-of-evidence (episomal AAV2, no tumors in rat chronic studies) indicates low integration/tumorigenicity risk in post-mitotic neurons
“The applicant has provided a discussion on the risk of insertional mutagenesis and carcinogenic potential. Based on the weight of evidence discussed there appears to be a low risk for genomic integration or tumorigenicity in postmitotic neuronal cells.”
Carcinogenicity timing
Not required; not warranted given product characteristics and target patient population
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted. These studies were not warranted based on the product characteristics and target patient population.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat highest dose (NOAEL) gives a safety margin of 21 over the clinical dose, scaled by brain weight
“Based on the study results, the highest dose administered (7.5×109 vg) in the study provides a safety margin of 21 over the human dose used in clinical studies, as calculated by the applicant.”
NOAEL / key findings
Rat NOAEL 7.5x10^9 vg (highest dose; ~21x margin by brain weight); no significant adverse findings
“Since there were no toxicologically significant findings at the high dose, the no observed adverse effect level (NOAEL) was set at the high dose (7.5x109 vg).”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro studies in human cells (AADC expression and biological activity) only
“The nonclinical pharmacology program for eladocagene exuparvovec consists of in vitro studies in human cells to characterize the expression and biological activity of eladocagene exuparvovec.”
Why that model
Mouse model of AADC deficiency was generated only after clinical development began; Parkinson's models used as surrogate pathophysiology
“Subsequent to the applicant commencing clinical studies, Lee et al., generated a mouse model of AADC deficiency (Lee et al., 2013, 2014).”
Reviewer's view of the efficacy data
EMA: neuronal transduction not shown in vitro; accepted given clinical PET evidence of putaminal dopamine production
“The applicant acknowledges that an in vitro demonstration of rAAV2-hAADC transduction of neuronal cells has not been carried out, however positron emission tomography imaging from subjects dosed with eladocagene exuparvovec shows that dopamine is produced in the putamen”
Flexibilityopen answer page →
Flexibility accepted
Efficacy modelAcceptedBeyond the letter
No in vivo pharmacology studies with the product; in vitro human cell data plus published literature only
Why: Published literature used as supportive information · Other reason
“No in vivo pharmacology studies were carried out in support of this application, and this is acceptable. The applicant refers to studies published in the literature as supportive information.”
CarcinogenicityAcceptedBeyond the letter
No genotoxicity, carcinogenicity or insertional mutagenesis studies; weight-of-evidence discussion instead
Why: Weight of evidence indicates low risk of genomic integration or tumorigenicity in post-mitotic neuronal cells · Weight of evidence · Low-risk modality
“It was previously agreed with CHMP that genotoxicity, carcinogenicity and evaluation of insertional mutagenesis studies were not required (EMEA/CHMP/SAWP/236092/2018).”
“Based on the weight of evidence discussed there appears to be a low risk for genomic integration or tumorigenicity in post-mitotic neuronal cells.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicology studies
Why: Local brain administration, no systemic exposure and no gonadal biodistribution · Pharmacology or kinetics
“No specific developmental and reproductive toxicology studies were conducted by the applicant with eladocagene exuparvovec, in agreement with CHMP. Given the local administration of eladocagene exuparvovec to the brain and lack of systemic exposure, and the absence of biodistribution to the gonads, the risk for germline transmission is low.”
Juvenile toxAcceptedBeyond the letter
Second planned juvenile monkey biodistribution and toxicity study waived after the route-of-administration study
Why: Superior putamen expression with intraputaminal route at 10-fold lower dose than ICV or IT routes · Pharmacology or kinetics
“Based on the data obtained in the initial RoA study demonstrating superior expression in the target putamen region with iPut administration despite using a 10-fold lower dose as compared to ICV and IT administration, a waiver (EMEA-002435-PIP01-18-M02 [eladocagene exuparvovec]) for the second study was submitted to PDCO and accepted 16 December 2020.”
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