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”
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).”
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.”