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.”
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.”
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”