Joenja
leniolisib
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 Applicant has conducted subchronic and chronic toxicology studies with leniolisib in both rats and cynomolgus monkeys.”
Why that species
Metabolic profiles in nonclinical species similar to human; no major human metabolites
“Characterization and structural elucidation of metabolites in plasma, urine or bile from nonclinical species have demonstrated the similarities in the metabolic profiles between these species and humans. It is noted that no major human metabolites were identified in completed clinical studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Rats (20/sex/group) were exposed to 0, 15, 40, and 120 mg/kg/day of leniolisib for 26 weeks via oral gavage with additional animals included in the control and HD groups for a 4-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“general toxicity studies with leniolisib were conducted in rats and monkeys with dosing durations up to 6 months in rodents and 9 months in non-rodents.”
Pivotal GLP studies
26-week (6-month) rat and 39-week (9-month) monkey repeat-dose studies
“general toxicity studies with leniolisib were conducted in rats and monkeys with dosing durations up to 6 months in rodents and 9 months in non-rodents.”
Route in tox
Oral gavage
“Monkeys (n=3/sex/group) were dosed once daily at 0, 30, 100, or 300 mg/kg/day via oral gavage for 14 days.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration, in vitro TK6 micronucleus and in vivo rat micronucleus assays
“Leniolisib was not genotoxic in the in vitro Ames assay, in vitro chromosomal aberration assay in human lymphocytes, or micronucleus assays in TK6 cells ( in vitro ) and rats ( in vivo ).”
Carcinogenicity
6-month Tg.rasH2 mouse: not carcinogenic up to 80 mg/kg/day
“Leniolisib was not carcinogenic in the 6-month carcinogenicity study in Tg.rasH2 transgenic mice at doses up to 80 mg/kg/day.”
Reproductive & developmental
Rat and rabbit EFD: embryofetal toxicity including malformations at 2-6x MRHD (AUC)
“In animal reproduction studies, oral administration of leniolisib to pregnant rats and rabbits during the period of organogenesis at exposures approximately 2-6 times the MRHD on an AUC basis, produced embryofetal toxicity including malformations ( see Data ).”
Safety pharmacology
hERG IC50 11.9 μM; QTc prolongation in two monkey telemetry studies at 150 mg/kg
“Leniolisib was found to inhibit hERG channel currents in hERG-transfected HEK cells with an IC50 of 11.9 μM. Consistent with this finding, single dose leniolisib (150 mg/kg, oral) administration induced QTcI (QT interval, individual correction) prolongation in two separate monkey telemetry studies.”
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 Joenja 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: Immune suppression and skin lesions (rats, monkeys), germ cell depletion (rats), GI inflammation and QTc prolongation (monkeys) (FDA multi-discipline review, p. 36)
NOAEL / key findings
Immune suppression and skin lesions (rats, monkeys), germ cell depletion (rats), GI inflammation and QTc prolongation (monkeys)
“Leniolisib-related toxicities included immune suppression (rats & monkeys), skin lesions (rats & monkeys), germ cell depletion (rats), GI tract inflammation (monkeys), and QTc prolongation (monkeys).”
Risksopen answer page →
Immune & cytokine safety
Lymphoid atrophy (lymph node, thymus, GALT) and immunosuppression-related skin lesions/infections in rats
“Treatment-related atrophy of the mesenteric lymph node, thymus, and GALT/Peyer’s patches were observed in male and female rats at all doses and attributed to immune suppression based on the pharmacology of leniolisib.”
Biodistribution & persistence
Moderate tissue distribution with high skin affinity; highest in bile, hair follicle, liver, intestinal wall, kidney and melanin-containing structures
“In radioactive studies, leniolisib was moderately distributed into tissues (Vss of 1.06 L/kg in rats and 0.657 L/kg in monkeys) with a high skin affinity. After a single oral dose of 10 mg/kg to male rats, the highest exposures were found in the bile, hair follicle, liver, intestinal wall, kidney as well as in melanin-containing structures.”
Modality-specific risk
Embryofetal toxicity (eye malformations), immunosuppression and QTc prolongation
“Leniolisib-related external, visceral, and skeletal malformations were observed in fetuses in the HD group. Most notably, malformations of the eye were observed in fetuses from 6/20 litters.”