Lupkynis
voclosporin
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The rat and monkey were determined to be the most appropriate toxicological species, given the emetic effect observed in dogs.”
Why that species
Rat: higher exposure and sensitivity; monkey: metabolic profile closest to human; dog excluded due to emesis
“agrees based on the higher systemic exposure (and consequently, higher sensitivity) observed in the rat and the more similar metabolic profile of the monkey compared to humans. The reviewer agrees the emetic effect in the dog would lead to drug exposure inconsistencies and problems with data interpretation.”
Surrogate molecule
Yes: most of the toxicology program used mix-ISA247 (isomer mixture), bridged to voclosporin
“As most studies were performed using mix-ISA247, a bridging programme was performed with voclosporin which included a 13-week study in the rat.”
Species: general tox
Rat (26-week) and monkey (39-week)
“This was demonstrated in some of the studies that used cyclosporine A as a comparator including the pivotal 26-week study in rats and 39- week study in monkeys.”
Species: DART
Rat and rabbit (developmental toxicity); rat (pre/postnatal, mix-ISA247)
“There were no test article related malformations or variations seen in fetuses from the developmental toxicity studies with rats or rabbits. In a prenatal and postnatal development study with mix-ISA247 in rats, dystocia (observed as prolonged parturition) was observed at 25 mg/kg/day.”
Species: carcinogenicity
Rat and mouse (2-year)
“Two-year studies were conducted in rats and mice.”
Surrogate used in
No species-specific surrogate; most studies used the isomer mixture mix-ISA247, bridged to voclosporin
“As most studies were performed using mix-ISA247, a bridging programme was performed with voclosporin which included a 13-week study in the rat.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“This was demonstrated in some of the studies that used cyclosporine A as a comparator including the pivotal 26-week study in rats and 39- week study in monkeys.”
Pivotal GLP studies
26-week rat and 39-week monkey studies
“This was demonstrated in some of the studies that used cyclosporine A as a comparator including the pivotal 26-week study in rats and 39- week study in monkeys.”
Route in tox
Oral gavage
“Repeat-dose toxicity studies have been performed in rat and cynomolgus monkey using oral (gavage) administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, CHO chromosomal aberration and rat in vivo micronucleus assays
“Mix-ISA247 (approximately 50: 50 cis-trans mixture) was negative for genetic toxicity in the in vitro bacteria reverse mutation assay (Ames) test, a chromosomal aberration test with CHO cells, and an in vivo micronucleus assay in rats after single oral doses up to 2000 mg/kg.”
Carcinogenicity
2-year rat: no neoplasms; 2-year mouse: drug-related malignant lymphomas at 30 mg/kg/day
“Two-year studies were conducted in rats and mice. In the rat study, there were no voclosporin-related neoplasms in either males or females. In the mouse study, females had a significant increase in voclosporin-related malignant lymphomas at the high dose of 30 mg/kg/day”
Reproductive & developmental
Rat EFD: increased resorptions, reduced litter size and viable pups at 25 mg/kg/day
“Mix-ISA247 caused a decrease in litter size and numbers of viable pups and an increase in resorptions (both early and late) at 25 mg/kg/day in the embryofetal development study in rats.”
Safety pharmacology
QTc increased in monkeys at 200 mg/kg; QTc signal in hERG and Purkinje fiber assays
“Cardiovascular studies in conscious cynomolgus monkeys found a that voclosporin, mix-ISA247 or cis-enhance ISA247 at a high dose of 200 mg/kg increased the QTc interval. There was also a signal for QTc prolongation from the hERG assay and Purkinje fiber electrophysiology assay.”
Genotox: Ames
Negative (voclosporin and mix-ISA247)
“Voclosporin was negative for mutagenic potential in the in vitro bacteria reverse mutation assay (Ames) test.”
Genotox: in vitro mammalian
CHO cell chromosomal aberration: negative
“Voclosporin was not mutagenic in a bacterial reverse mutation assay (Ames) or in a vitro chromosomal aberration assay using CHO cells.”
Genotox: in vivo
Rat bone marrow micronucleus (mix-ISA247): negative
“An isomer mix (Mix-ISA247), used in early development, showed no genotoxic potential in an in vivo micronucleus assay with bone marrow smears.”
Carcinogenicity model
Mouse and rat, planned 2-year; both terminated early due to decreased survival
“Two long term studies with voclosporin were performed in mice and rats. Planned to be 2-year studies, both had to be early terminated due to decreased survival.”
Carcinogenicity timing
2-year rat and mouse studies completed before the marketing application
“Two-year studies were conducted in rats and mice.”
hERG / QT
hERG IC50 43 µM (voclosporin), much greater than expected human exposure
“The hERG assay showed IC50 values of 23, 72, and 43 µM for mix-ISA247, cis-ISA247, and voclosporin, respectively.”
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 Lupkynis 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Immunosuppression plus class effects: renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity (FDA multi-discipline review, p. 367)
NOAEL / key findings
Immunosuppression plus class effects: renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity
“The adverse findings observed were either expected due to drug-related immunosuppression (e.g., thymic medullary atrophy, absence of germinal centers, lymphomas, decreased lymphocyte counts) or to the known drug class specific adverse effects (e.g., renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity).”
Risksopen answer page →
Immune & cytokine safety
Immunosuppression: thymic medullary atrophy, absent germinal centers, lymphomas, decreased lymphocytes
“In general, the adverse findings with the different proportions of cis:trans isomers of voclosporin were due to drug-related immunosuppression (e.g., thymic medullary atrophy, absence of germinal centers, lymphomas, decreased lymphocyte counts)”
Biodistribution & persistence
Low distribution to eye; negligible melanin binding
“Drug-derived radioactivity distributed to the eye (target tissue) following oral administration of 14C-voclosporin, although at low levels. The distribution profile of drug-derived radioactivity was similar in pigmented and non-pigmented rats, suggesting negligible binding of the drug and/or its metabolites to melanin.”
Modality-specific risk
Safety margins below 10x, with cyclosporine-like calcineurin-inhibitor toxicity
“Therefore, the safety margins are lower than the optimal 10x. However, the toxicological profile of voclosporin was similar to that of cyclosporine”
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: Malignancies and serious infections
- Lymphoma and Other Malignancies
- Serious Infections
- Nephrotoxicity
- Hypertension
- Neurotoxicity
- Hyperkalemia
- QTc Prolongation
- Hypersensitivity Reactions
- Immunizations
- Pure Red Cell Aplasia
InfectionsSecondary malignancyNephrotoxicityCardiovascularNeurotoxicityMetabolic & endocrineHypersensitivity & 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 Lupkynis 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Immunosuppression plus class effects: renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity (FDA multi-discipline review, p. 367)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (oral) with 28-day recovery
“A 39-Week Oral Toxicity Study in Cynomolgus Monkey Followed by a 28 Day Recovery Period (Study # ISA02-01)”
Pivotal GLP studies
26-week rat and 39-week monkey studies
“This was demonstrated in some of the studies that used cyclosporine A as a comparator including the pivotal 26-week study in rats and 39- week study in monkeys.”
DART package
Species: DART
Rat and rabbit (developmental toxicity); rat (pre/postnatal, mix-ISA247)
“There were no test article related malformations or variations seen in fetuses from the developmental toxicity studies with rats or rabbits. In a prenatal and postnatal development study with mix-ISA247 in rats, dystocia (observed as prolonged parturition) was observed at 25 mg/kg/day.”
Reproductive & developmental
Rat EFD: increased resorptions, reduced litter size and viable pups at 25 mg/kg/day
“Mix-ISA247 caused a decrease in litter size and numbers of viable pups and an increase in resorptions (both early and late) at 25 mg/kg/day in the embryofetal development study in rats.”
PPND / ePPND: when
PPND in rat (mix-ISA247) completed before the marketing application
“In a prenatal and postnatal development study with mix-ISA247 in rats, dystocia (observed as prolonged parturition) was observed at 25 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (2-year)
“Two-year studies were conducted in rats and mice.”
Carcinogenicity model
Mouse and rat, planned 2-year; both terminated early due to decreased survival
“Two long term studies with voclosporin were performed in mice and rats. Planned to be 2-year studies, both had to be early terminated due to decreased survival.”
Carcinogenicity timing
2-year rat and mouse studies completed before the marketing application
“Two-year studies were conducted in rats and mice.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL exposure margins lower than the optimal 10x; toxicology similar to cyclosporine
“Therefore, the safety margins are lower than the optimal 10x. However, the toxicological profile of voclosporin was similar to that of cyclosporine”
NOAEL / key findings
Immunosuppression plus class effects: renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity
“The adverse findings observed were either expected due to drug-related immunosuppression (e.g., thymic medullary atrophy, absence of germinal centers, lymphomas, decreased lymphocyte counts) or to the known drug class specific adverse effects (e.g., renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity).”
Efficacy evidenceopen answer page →
Efficacy evidence
Animal models of autoimmune uveitis, arthritis and organ transplantation; calcineurin inhibition in monkeys
“The pharmacological activity of voclosporin has been demonstrated both in vitro and in vivo using calcineurin inhibition and lymphocyte proliferation as markers of pharmacological effect and using different animal models for autoimmune uveitis, arthritis and organ transplants.”
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
CHMP: calcineurin potency 1.5-fold above cyclosporine in vitro and higher in vivo; limited secondary pharmacology acceptable
“Pharmacology studies showed that voclosporin inhibited calcineurin with a 1.5-fold higher potency compared to cyclosporine in vitro and also that voclosporin had a higher potency in vivo in animal models. Secondary pharmacodynamics has not been well characterised, but this is considered acceptable”
Flexibilityopen answer page →
Flexibility accepted
OtherVerdict not stated
Most toxicology studies used a cis/trans isomer mixture (mix-ISA247) rather than the clinical product, with a limited bridging programme
Why: Bridging programme with voclosporin: 13-week rat study, rabbit embryo-fetal study and Ames test
“Voclosporin consists of 2 geometric isomers, a trans-isomer and a cis-isomer, and most studies in the programme have evaluated a mixture of the two isomers (mix-ISA247; 45-50% trans-, 50-55% cis-), whereas a few newer studies have evaluated the clinical product. A bridging programme with the two formulations has been performed which consisted of a 13-week oral voclosporin study in rats, an EFD study in rabbits and an Ames’ test.”
GenotoxicityAcceptedBeyond the letter
Genotoxicity battery run with the isomer mixture, underdosing the trans-isomer (about 55% of ICH-recommended doses)
Why: Weight of evidence supports lack of genotoxic potential; additional studies not necessary · Weight of evidence
“Note that the doses used in these studies assessed approximately 55% of the ICH recommended doses for the trans-isomer (for example if the Ames assay maximal dose is 5000 µg, only about 2500 µg, rather than 4500 µg of the trans-isomer (if voclosporin was assayed) would be assayed for this dose.”
“While the level of trans-voclosporin might have been underdosed in the original genetic toxicity studies, the weight of evidence supports the lack of genotoxic potential and additional studies are not necessary.”
Safety marginAcceptedBeyond the letter
NOAEL exposure margins in pivotal rat and monkey studies below the optimal 10x
Why: Toxicity profile similar to cyclosporine; substantial clinical experience with calcineurin inhibitors allows monitoring and risk minimisation · Class precedent · Human data
“Therefore, the safety margins are lower than the optimal 10x. However, the toxicological profile of voclosporin was similar to that of cyclosporine and the findings observed were either expected due to the pharmacological action of the drug (e.g., thymic medullary atrophy, absence of germinal centers, lymphomas) and/or to the known class specific adverse effects”
“There is substantial clinical experience from the use of cyclosporine and other calcineurin inhibitors to allow for the proper monitoring of adverse findings and strategies to minimize risk (e.g., frequent dose adjustments).”
Safety marginVerdict not stated
No exposure margin at the developmental NOAEL in the rabbit embryo-fetal study with mix-ISA247 (TK below quantification)
“At this dose, all TK values were BLQ why there are no margins to clinical exposure. Of note, the MoE to the dose associated with increased early and late resorptions is only 1.9.”
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