Litfulo
ritlecitinib
Species
RatDog
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 dog
“In the pivotal 26- and 39-week oral repeat dose toxicity (RDT) studies in rats and dogs, respectively, ritlecitinib displayed reversible effects consistent with its intended pharmacology”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“In the pivotal 26- and 39-week oral repeat dose toxicity (RDT) studies in rats and dogs, respectively, ritlecitinib displayed reversible effects consistent with its intended pharmacology”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“Oral repeat dose toxicity studies in rats (up to 26 weeks in duration); oral repeat dose toxicity studies in dogs (up to 39 weeks in duration)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“a fertility and early embryonic development study in rats; embryofetal development studies in rats and rabbits; a pre- and postnatal development study in rats.”
Species: carcinogenicity
Rat (2-year) and transgenic mouse (6-month)
“a 6-month oral carcinogenicity study in transgenic mice; a 2-year oral carcinogenicity study in rats”
Surrogate used in
No surrogate used; ritlecitinib itself tested, including in the alopecia areata mouse model
“The effect of ritlecitinib at a dosage of 30mg/kg/day, intravenously administered via an osmotic pump, on disease onset (4 weeks treatment) and disease progression/revision (12 weeks treatment) was investigated in C3H/HeJ skin-grafted mice.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“In the pivotal 26- and 39-week oral repeat dose toxicity (RDT) studies in rats and dogs, respectively, ritlecitinib displayed reversible effects consistent with its intended pharmacology”
Pivotal GLP studies
26-week rat and 39-week dog oral repeat-dose studies
“In the pivotal 26- and 39-week oral repeat dose toxicity (RDT) studies in rats and dogs, respectively, ritlecitinib displayed reversible effects consistent with its intended pharmacology”
Route in tox
Oral
“In the pivotal 26- and 39-week oral repeat dose toxicity (RDT) studies in rats and dogs, respectively, ritlecitinib displayed reversible effects consistent with its intended pharmacology”
Skipped studiesopen answer page →
Genotoxicity
Aneugenic in in vitro TK6 micronucleus assay; Ames negative
“Ritlecitinib was aneugenic in vitro, as determined by an in vitro micronucleus assay in TK6 cells and follow-up in vitro mechanism experiments. However, ritlecitinib was not mutagenic in a reverse mutation assay in bacterial cells.”
Carcinogenicity
2-year rat: thymomas (females) and thyroid follicular tumors (males) at 100 mg/kg/day; no tumors at ≤30 mg/kg/day
“In a 2-year rat carcinogenicity study, ritlecitinib increased the incidence of combined benign and malignant thymomas in female rats, and thyroid follicular adenomas and combined follicular adenomas and carcinomas in male rats at 100 mg/kg/day (29 times the MRHD based on AUC comparison). No ritlecitinib-related tumors were noted at doses up to 30 mg/kg/day (6.3 times the MRHD based on AUC comparison).”
Reproductive & developmental
Rat EFD: lower fetal weight and skeletal malformations at ≥175 mg/kg/day (49x MRHD AUC)
“In an embryo-fetal development study in pregnant rats, oral administration of ritlecitinib from gestation days 6 to 17 decreased fetal body weights and caused fetal skeletal malformations (malformed vertebrae and ribs) and variations (delayed ossification) at doses ≥175 mg/kg/day (49 times the MRHD based on AUC comparison).”
Safety pharmacology
No hERG inhibition (IC50 >300 µM); no acute CNS or respiratory effects in rats up to 400 mg/kg
“At clinically relevant concentrations in vitro, ritlecitinib did not inhibit hERG currents (IC50 >300 µM). A single oral dose of ritlecitinib did not produce acute CNS or respiratory effects in male rats (doses: 0, 75, 175, and 400 mg/kg; NOEL: 400 mg/kg).”
Genotox: Ames
Negative
“Ritlecitinib was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay).”
Genotox: in vitro mammalian
Positive in vitro micronucleus in TK6 cells; aneugenic mechanism, not clinically relevant
“Ritlecitinib was positive in an in vitro micronucleus assay in TK6 cells. However, mechanistic studies determined that ritlecitinib is aneugenic and does not present a clinically relevant genotoxic concern.”
Genotox: in vivo
Negative rat bone marrow micronucleus up to 400 mg/kg/day
“Additionally, in an in vivo rat bone marrow micronucleus assay, ritlecitinib was not aneugenic or clastogenic at doses up to 400 mg/kg/day.”
Carcinogenicity model
2-year rat: thymomas (females) and thyroid follicular tumors (males) at 100 mg/kg/day (29x MRHD AUC)
“In a 2-year rat carcinogenicity study, ritlecitinib increased the incidence of combined benign and malignant thymomas in female rats, and thyroid follicular adenomas and combined follicular adenomas and carcinomas in male rats at 100 mg/kg/day (29 times the MRHD based on AUC comparison).”
Carcinogenicity timing
6-month rasH2 mouse and 2-year rat completed before the marketing application
“The potential for carcinogenicity was assessed in a 6-month study in transgenic rasH2 (tg/wt) mice and a 2-year study in rats in accordance with ICH Guidelines M3(R2), 2009.”
hERG / QT
No hERG inhibition at clinically relevant concentrations (IC50 >300 µM)
“At clinically relevant concentrations in vitro, ritlecitinib did not inhibit hERG currents (IC50 >300 µM).”
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 Litfulo 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: NOAEL 5 mg/kg/day: brainstem findings at ≥20 mg/kg/day; immunosuppression and hearing effects at high dose (FDA multi-discipline review, p. 39)
NOAEL / key findings
NOAEL 5 mg/kg/day: brainstem findings at ≥20 mg/kg/day; immunosuppression and hearing effects at high dose
“The NOAEL was 5 mg/kg/day based on microscopic findings in the brainstem at doses ≥20 mg/kg/day and adverse immunosuppressive effects and effects on hearing at the HD.”
Risksopen answer page →
Immune & cytokine safety
Adverse immunosuppression (skin mites, lung inflammation) at 40 mg/kg/day in the 39-week dog study
“In the first 39-week oral RDT study in dogs with 3-month recovery (doses: 0, 5, 20, and 40 mg/kg/day), no ritlecitinib-related effects were noted on mortality, ECG, or ophthalmology. At the HD, ritlecitinib-related immunosuppression was adverse because of skin mites and lung inflammation.”
Biodistribution & persistence
Poor blood-brain barrier penetration in rat (brain:plasma ~0.04); melanin-related accumulation in uveal tract
“However, the low brain: plasma AUC ratio at ~0.04 demonstrates that penetration of the blood-brain barrier is inefficient in the rat. The high AUC and long excretion T1/2 in the uveal tract suggest melanin-related accumulation.”
Modality-specific risk
Axonal dystrophy in dogs, considered an off-target effect
“Based on a series of nonclinical studies investigating the potential mechanism, ritlecitinib-related axonal dystrophy appears to be an off-target effect, rather than mediated through inhibition of JAK3 or TEC kinase family members.”
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: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), and THROMBOSIS
- Serious Infections
- Mortality
- Malignancy and Lymphoproliferative Disorders
- Major Adverse Cardiovascular Events (MACE)
- Thromboembolic Events
- Hypersensitivity
- Hypoglycemia in Patients with Diabetes
- Laboratory Abnormalities
- Vaccinations
Thrombosis & embolismInfectionsCardiovascularSecondary malignancyHypersensitivity & infusion reactionsMetabolic & endocrine
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 Litfulo 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: NOAEL 5 mg/kg/day: brainstem findings at ≥20 mg/kg/day; immunosuppression and hearing effects at high dose (FDA multi-discipline review, p. 39)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral) with 6-month recovery (the later of the 39-week dog studies)
“In the second 39-week oral RDT study in dogs with 6-month recovery (doses: 0, 10, 20, 10 [BID, 6 hours apart] and 40 mg/kg/day), ritlecitinib exposure was similar between sexes and increased dose-proportionally”
Pivotal GLP studies
26-week rat and 39-week dog oral repeat-dose studies
“In the pivotal 26- and 39-week oral repeat dose toxicity (RDT) studies in rats and dogs, respectively, ritlecitinib displayed reversible effects consistent with its intended pharmacology”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“a fertility and early embryonic development study in rats; embryofetal development studies in rats and rabbits; a pre- and postnatal development study in rats.”
Reproductive & developmental
Rat EFD: lower fetal weight and skeletal malformations at ≥175 mg/kg/day (49x MRHD AUC)
“In an embryo-fetal development study in pregnant rats, oral administration of ritlecitinib from gestation days 6 to 17 decreased fetal body weights and caused fetal skeletal malformations (malformed vertebrae and ribs) and variations (delayed ossification) at doses ≥175 mg/kg/day (49 times the MRHD based on AUC comparison).”
PPND / ePPND: when
PPND in rat completed before the marketing application
“Developmental and reproductive studies were completed in rats and rabbits. These included a fertility and early embryonic development study in male and female rats, DRF and pivotal EFD studies in pregnant rats and rabbits, and a pre- and postnatal development study in rats.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and transgenic mouse (6-month)
“a 6-month oral carcinogenicity study in transgenic mice; a 2-year oral carcinogenicity study in rats”
Carcinogenicity model
2-year rat: thymomas (females) and thyroid follicular tumors (males) at 100 mg/kg/day (29x MRHD AUC)
“In a 2-year rat carcinogenicity study, ritlecitinib increased the incidence of combined benign and malignant thymomas in female rats, and thyroid follicular adenomas and combined follicular adenomas and carcinomas in male rats at 100 mg/kg/day (29 times the MRHD based on AUC comparison).”
Carcinogenicity timing
6-month rasH2 mouse and 2-year rat completed before the marketing application
“The potential for carcinogenicity was assessed in a 6-month study in transgenic rasH2 (tg/wt) mice and a 2-year study in rats in accordance with ICH Guidelines M3(R2), 2009.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog study 20099163 at 10 mg/kg/day: 7.4-fold human AUC (6.0-fold Cmax); axonal dystrophy still seen at this dose
“According to the applicant, the margins between the clinical exposure and the exposures in the lowest dose group at which ritlecitinib-related axonal dystrophies were observed (rostral cerebellar vermis at 10 mg/kg/day, study 20099163) are only 6.0-fold in terms of Cmax and 7.4-fold in terms of AUC24.”
NOAEL / key findings
NOAEL 5 mg/kg/day: brainstem findings at ≥20 mg/kg/day; immunosuppression and hearing effects at high dose
“The NOAEL was 5 mg/kg/day based on microscopic findings in the brainstem at doses ≥20 mg/kg/day and adverse immunosuppressive effects and effects on hearing at the HD.”
Efficacy evidenceopen answer page →
Efficacy evidence
C3H/HeJ skin-grafted alopecia areata mice: IV ritlecitinib prevented AA onset and hair loss
“Intravenously administered ritlecitinib at 30mg/kg prevented the onset of AA by effectively reducing AA-associated skin inflammation (e.g. supported by data from immunofluorescence and flow cytrometric analysis) and avoiding hair loss in C3H/HeJ skin grafted mice.”
Why that model
AA mouse study only intended to show JAK3 inhibition improves AA; no oral-route exposure or withdrawal data
“the applicant justified that exposure data of ritlecitinib after oral administration (the proposed route of administration in human) in AA mice and data on symptoms, markers of neuroinflammation and molecular data upon ritlecitinib withdrawal were not available as the study in AA mice was performed solely with the intention to demonstrate that JAK3 inhibition would improve symptoms of AA.”
Reviewer's view of the efficacy data
CHMP: disease models for other indications only supportive; submitted studies acceptable
“Therefore, experiments performed by the applicant in animal models of diseases for different indications are considered as supportive only. Studies and assays submitted by the applicant are acknowledged and considered acceptable to the CHMP.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAccepted with a conditionBeyond the letter
Dog axonal dystrophy margin only 6.0-fold (Cmax) and 7.4-fold (AUC); lowest affected dog dose 10 mg/kg/day
Why: SmPC warning and nonclinical summary added; safety concern followed up post-approval
“According to the applicant, the margins between the clinical exposure and the exposures in the lowest dose group at which ritlecitinib-related axonal dystrophies were observed (rostral cerebellar vermis at 10 mg/kg/day, study 20099163) are only 6.0-fold in terms of Cmax and 7.4-fold in terms of AUC24.”
“Therefore, upon CHMP’s request, a warning was added in section 4.4 of the SmPC, and a summary of the axonal dystrophy findings in dogs was included in the section 5.3 of the SmPC. Furthermore, given the limited availability of long-term clinical safety data, this safety concern will be followed-up post-approval (see clinical safety and RMP sections below).”
GenotoxicityAcceptedBeyond the letter
Aneugenic in vitro (TK6 micronucleus); negative in vivo rat micronucleus
Why: Threshold effect seen only at supra-therapeutic exposures; in vivo micronucleus negative · Weight of evidence · Pharmacology or kinetics
“While ritlecitinib was unequivocally an in vitro aneugen, the in vivo relevance of this finding is considered to be low, especially as aneugenicity is generally considered to be a threshold effect and as in vitro aneugenicity was only observed at exceedingly high supra-therapeutic exposures.”
“This notion was supported by the in vivo micronucleus rat study 14GR132, in which no increases in micronucleated cells were observed in test-article groups at relevant exposures.”
Safety pharmacologyCriticised but acceptedBeyond the letter
Dog cardiovascular safety study with very small sample size (three evaluable dogs); supportive only
Why: Cardiovascular effects not expected given selectivity towards JAK3 · Pharmacology or kinetics
“However, the very small sample size of 4 beagle dogs, actually 3 in the GLP-compliant study, since the data of one dog could not be evaluated, poses an issue with the informative value of the results.”
“Although the results of these cardiovascular safety studies in beagle dogs can be regarded as supportive information only, possible CV effects are not expected with ritlecitinib due to selectivity towards JAK3.”
GLPAccepted
Non-GLP exploratory Ames tests used for mutagenicity evaluation of impurities
Why: Assays in line with appropriate guidance; ICH M7(R1) allows use without full GLP compliance · Within the guideline
“As the submitted exploratory Ames tests were nonetheless in line with appropriate guidance (e.g. highest tested concentrations 5 mg/plate, cytotoxicity and solubility assessments, 5 relevant strains, adequate positive controls etc.), the non-GLP assays submitted in the dossier are considered sufficient for mutagenicity evaluation of (potential) impurities.”
“The ICH M7(R1) specifies that bacterial mutagenicity assays are expected to be performed in compliance with Good Laboratory Practices (GLP) regulations and that lack of full GLP compliance does not necessarily mean that the data cannot be used to support clinical trials and marketing authorisations.”
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