Leqselvi
deuruxolitinib
Sources:FDA multi-discipline review ↗
Species
RatDog
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Pivotal repeat-dose toxicity studies were conducted in rats and dogs.”
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 nonclinical studies, CTP-543 and C-21543 were used as code names for deuruxolitinib.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week dog)
“Study title / number: 52-Week oral gavage toxicity and toxicokinetic study of CTP-543 in Beagle dogs with an 8-week recovery”
Pivotal GLP studies
26-week rat and 52-week dog oral studies
“26-week rat study Oral 37.5 1640 0.8 52-week dog study Oral 3 2850 1.4”
Route in tox
Oral (gavage)
“Pivotal repeat-dose oral toxicity studies were conducted in rats and dogs.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat bone marrow micronucleus; positive in vitro micronucleus (likely aneugenic)
“In genotoxicity studies, deuruxolitinib was negative in the Ames test, an in vitro chromosome aberration assay, and an in vivo rat bone marrow micronucleus assay. It was positive in an in vitro micronucleus assay.”
Carcinogenicity
6-month rasH2 mouse and 2-year rat oral studies: not carcinogenic
“Deuruxolitinib was not carcinogenic in a 6-month oral transgenic mouse carcinogenicity study or a 2-year oral rat carcinogenicity study.”
Reproductive & developmental
Rat EFD: lower fetal weight and skeletal malformations at 60 mg/kg/day without significant maternal toxicity
“In an embryo-fetal toxicity study in rats, lower fetal weight and increased skeletal malformations were noted at 60 mg/kg/day, with no significant maternal toxicity observed.”
Safety pharmacology
Dog CV study: 10 mg/kg caused mild transient BP decrease, heart rate increase and QT interval decrease
“a single oral dose of 10 mg/kg deuruxolitinib induced mild transient decreases in blood pressure, which correlated with mild transient increases in heart rate and decreases in QT interval.”
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 Leqselvi 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: NOAELs 37.5 mg/kg/day (26-week rat) and 3 mg/kg/day (52-week dog), ~0.8x and 1.4x human AUC (FDA multi-discipline review, p. 217)
NOAEL / key findings
NOAELs 37.5 mg/kg/day (26-week rat) and 3 mg/kg/day (52-week dog), ~0.8x and 1.4x human AUC
“26-week rat study Oral 37.5 1640 0.8 52-week dog study Oral 3 2850 1.4”
Risksopen answer page →
Immune & cytokine safety
Reduced WBC and lymphocytes; lymphoid depletion in spleen, thymus, lymph nodes and GALT
“The target organs were identified as lymphoid organs in both species, with major study findings including reduced circulating white blood cells and lymphocytes and decreased lymphocytes/cellularity in various lymphoid tissues (including spleen, thymus, lymph nodes, and gut-associated lymphoid tissue).”
Biodistribution & persistence
Excreted in rat milk; milk/plasma ratios ~7 to 20 over 8 hours
“Milk/plasma concentration ratios were approximately 7, 13, 19, and 20 at 1 hr, 2 hr, 4 hr, and 8 hr postdose, respectively.”
Modality-specific risk
Exaggerated JAK pharmacology: lymphoid organ toxicity with reduced white cells and lymphocytes
“The major safety signals identified in these studies were consistent with deuruxolitinib’s pharmacological activity. The target organs were identified as lymphoid organs in both species, with major study findings including reduced circulating white blood cells and lymphocytes”