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.”
Species: general tox
Rat and cynomolgus monkey
“The Applicant has conducted subchronic and chronic toxicology studies with leniolisib in both rats and cynomolgus monkeys.”
Species: DART
Rat and rabbit (embryo-fetal development)
“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.”
Species: carcinogenicity
Tg-RasH2 mouse (6-month) and rat (2-year), ongoing at approval
“The 6-month transgenic (Tg-RasH2) mouse carcinogenicity study and 2-year carcinogenicity study with rats are ongoing under Special Protocol Assessments with ECAC concurrence.”
Surrogate used in
No surrogate used; leniolisib tested directly in rats and monkeys
“The Applicant has conducted subchronic and chronic toxicology studies with leniolisib in both rats and cynomolgus monkeys.”
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.”
Genotox: Ames
Negative up to 5,000 μg/plate
“In the bacterial reverse mutation assay, there was no evidence of mutagenicity of leniolisib at up to 5,000 μg/plate.”
Genotox: in vitro mammalian
Chromosomal aberration (human lymphocytes) and TK6 micronucleus: negative
“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 ).”
Genotox: in vivo
Rat micronucleus: negative up to 700 mg/kg/day
“In an in vivo micronucleus assay with rats, there were no statistically significant effects of leniolisib treatment on the number of micronucleated polychromatic erythrocytes at doses up to 700 mg/kg/day.”
Carcinogenicity model
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.”
Carcinogenicity timing
6-month Tg-rasH2 mouse and 2-year rat studies ongoing at approval; final reports due as postmarketing requirements
“The 6-month transgenic (Tg-RasH2) mouse carcinogenicity study and 2-year carcinogenicity study with rats are ongoing under Special Protocol Assessments with ECAC concurrence. The final study reports will be submitted as post-marketing requirements.”
hERG / QT
hERG IC50 11.9 μM; QTcI 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.”
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
Label warnings
- Embryo-Fetal Toxicity
- Vaccinations
- Risk of Hypersensitivity Reactions, Including Anaphylaxis
Embryo-fetal toxicityHypersensitivity & infusion reactions
US prescribing information, 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week monkey (oral gavage) with 4-week recovery
“Leniolisib has been administrated in monkeys by oral gavage for 2 weeks, 13 weeks and 39 weeks with 4-week recovery period.”
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.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“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.”
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 ).”
PPND / ePPND: when
PPND in rat: postmarketing requirement; study completion 12/2022, final report due 04/2023, not in the marketing application
“Requirement Conduct a pre- and post- natal development study in rats. Table 50. PMR-3 Milestones Schedule, Pre- and Postnatal Development Study in Rats Milestone Status Study completion date 12/2022 Final report submission date 04/2023”
Carcinogenicity
Species: carcinogenicity
Tg-RasH2 mouse (6-month) and rat (2-year), ongoing at approval
“The 6-month transgenic (Tg-RasH2) mouse carcinogenicity study and 2-year carcinogenicity study with rats are ongoing under Special Protocol Assessments with ECAC concurrence.”
Carcinogenicity model
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.”
Carcinogenicity timing
6-month Tg-rasH2 mouse and 2-year rat studies ongoing at approval; final reports due as postmarketing requirements
“The 6-month transgenic (Tg-RasH2) mouse carcinogenicity study and 2-year carcinogenicity study with rats are ongoing under Special Protocol Assessments with ECAC concurrence. The final study reports will be submitted as post-marketing requirements.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL margins 0.8x (rat, 15 mg/kg/day) and 1.0x (monkey, 20 mg/kg/day)
“The safety margins in toxicity studies were 0.8 (15mg/kg/day) and 1.0 (20 mg/kg/day) at the NOAEL in rat and monkeys.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Pik3cd E1020K/+ mouse model of APDS; rat TDAR and induced inflammation models
“Leniolisib was evaluated in two mechanistic and one relevant disease model of PI3Kδ activation.”
Why that model
No validated APDS animal disease model; sponsor used SRBC antibody response (rat) and ozone lung inflammation (mouse)
“Currently, there is no validated APDS disease model in animals. The Sponsor explored antibody response to sheep red blood cells (SRBC) in rats and ozone-induced neutrophil infiltration in mouse bronchoalveolar lavage (BAL).”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo pharmacodynamic studies show efficacy, specificity and selectivity for p110δ
“Primary and secondary pharmacodynamic studies performed in vitro and in vivo on leniolisib show efficacy, specificity and selectivity in regard to the p110δ subunit.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Carcinogenicity studies (6-month Tg-rasH2 mouse, 2-year rat) ongoing at approval; final reports deferred to postmarketing
Why: Unmet medical need for APDS · Rare disease / unmet need
“Carcinogenicity studies with leniolisib have not been conducted. The 6-month transgenic (Tg-RasH2) mouse carcinogenicity study and 2-year carcinogenicity study with rats are ongoing under Special Protocol Assessments with ECAC concurrence.”
“Based on the unmet medical need for the APDS indication, the carcinogenicity and pre/ postnatal development assessments will be completed as PMRs.”
DARTAccepted with a conditionBeyond the letter
No pre- and postnatal development study before approval; rat PPND study required postmarketing
Why: Unmet medical need for APDS · Rare disease / unmet need
“A pre- and postnatal development study with leniolisib has not been conducted. A pre- and postnatal development study with rats will be submitted as a post-marketing requirement.”
“Based on the unmet medical need for the APDS indication, the carcinogenicity and pre/ postnatal development assessments will be completed as PMRs.”
DARTVerdict not stated
Fertility and early embryonic development assessed in a subset of rats after a juvenile toxicology study (combined design)
“The Fertility and Early Embryonic Development (FEED) study was conducted in a subset (20/sex/group) of rats immediately after the conclusion of a juvenile toxicology study in which rats were treated with 0, 10, 30, or 90 mg/kg/day leniolisib once daily by oral gavage from PND 7 – 77.”
Safety marginVerdict not stated
NOAEL margins 0.8 (rat) and 1.0 (monkey); animal NOAEL exposure similar to human therapeutic exposure
“The safety margins in toxicity studies were 0.8 (15mg/kg/day) and 1.0 (20 mg/kg/day) at the NOAEL in rat and monkeys.”
Efficacy modelVerdict not stated
No validated APDS animal model; pharmacology shown in rat SRBC antibody response and mouse ozone lung inflammation models
“Currently, there is no validated APDS disease model in animals. The Sponsor explored antibody response to sheep red blood cells (SRBC) in rats and ozone-induced neutrophil infiltration in mouse bronchoalveolar lavage (BAL).”
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