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.”
Species: general tox
Rat and dog (oral)
“Pivotal repeat-dose oral toxicity studies were conducted in rats and dogs.”
Species: DART
Rat and rabbit (embryo-fetal development)
“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. In an embryo-fetal toxicity study in rabbits, lower fetal weight and increased postimplantation loss were noted at 60 mg/kg/day.”
Species: carcinogenicity
Sprague Dawley rat (2-year) and Tg.rasH2 mouse (6-month)
“Deuruxolitinib was not carcinogenic when administered orally to Sprague Dawley rats once daily for 2 years or to Tg.rasH2 mice once daily for 6 months.”
Surrogate used in
No surrogate used; deuruxolitinib (CTP-543) itself 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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
In vitro chromosome aberration negative; in vitro micronucleus positive (potential aneugenic effect)
“It was positive in an in vitro micronucleus assay. The positive response could be due to a potential aneugenic effect.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“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.”
Carcinogenicity model
2-year oral rat; 6-month oral Tg.rasH2 mouse; not carcinogenic
“Deuruxolitinib was not carcinogenic when administered orally to Sprague Dawley rats once daily for 2 years or to Tg.rasH2 mice once daily for 6 months.”
Carcinogenicity timing
6-month Tg.rasH2 mouse and 2-year rat completed before the marketing application
“Deuruxolitinib was not carcinogenic in a 6-month oral transgenic mouse carcinogenicity study or a 2-year oral rat carcinogenicity study.”
hERG / QT
hERG IC50-based margin at least 3900x free exposure at 8 mg BID; no QTc prolongation
“Also, the corresponding safety margin for free deuruxolitinib based on the in vitro hERG assay deuruxolitinib IC50 ƌĞƐƵůƚ ŽĨ ϭϱϯ ʅD, is at least 3900 times higher than the systemic exposure of 8-mg BID dose.”
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”
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 assessed (small molecule, not expected to be immunogenic)
“Deuruxolitinib is a small molecule that is not expected to be associated with immunogenicity. Therefore, the Applicant did not assess the potential for antibody formation.”
Label warnings
Boxed warning: Serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis
- Serious Infections
- Mortality
- Malignancy and Lymphoproliferative Disorders
- Major Adverse Cardiovascular Events (MACE)
- Thrombosis
- Increased Risk of LEQSELVI-Associated Serious Adverse Reactions in CYP2C9 Poor Metabolizers or with Concomitant Use of Moderate or Strong CYP2C9 Inhibitors
- Gastrointestinal Perforations
- Hypoglycemia in Patients with Diabetes
- Lipid Elevations, Anemia, Neutropenia, and Lymphopenia
- Immunizations
Thrombosis & embolismInfectionsCardiovascularSecondary malignancyGastrointestinalMetabolic & endocrineCytopenias
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week dog (oral gavage) with 8-week recovery
“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”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“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. In an embryo-fetal toxicity study in rabbits, lower fetal weight and increased postimplantation loss were noted at 60 mg/kg/day.”
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.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre- and postnatal developmental study in rats, decreased pup survival, decreased F1 animal body weight, and adverse effects on reproductive outcome in the F1 females were noted at 75 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Sprague Dawley rat (2-year) and Tg.rasH2 mouse (6-month)
“Deuruxolitinib was not carcinogenic when administered orally to Sprague Dawley rats once daily for 2 years or to Tg.rasH2 mice once daily for 6 months.”
Carcinogenicity model
2-year oral rat; 6-month oral Tg.rasH2 mouse; not carcinogenic
“Deuruxolitinib was not carcinogenic when administered orally to Sprague Dawley rats once daily for 2 years or to Tg.rasH2 mice once daily for 6 months.”
Carcinogenicity timing
6-month Tg.rasH2 mouse and 2-year rat completed before the marketing application
“Deuruxolitinib was not carcinogenic in a 6-month oral transgenic mouse carcinogenicity study or a 2-year oral rat carcinogenicity study.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL ~0.8x (26-week rat) and ~1.4x (52-week dog) human AUC at MRHD
“26-week rat study Oral 37.5 1640 0.8 52-week dog study Oral 3 2850 1.4”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro kinase assays and IL-6-stimulated STAT3 inhibition, benchmarked against ruxolitinib
“Deuruxolitinib exhibited similar pharmacology properties compared with ruxolitinib, including the selectivity and potency of JAK inhibition and the inhibition of interleukin-6 (IL-6)-stimulated STAT3 activation.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: pharmacology similar to approved ruxolitinib (deuterated isotopolog)
“Deuruxolitinib is a deuterated isotopolog of ruxolitinib, an approved JAK inhibitor. It is structurally similar to ruxolitinib with the only differences of eight deuterium atoms substituting hydrogen.”
Flexibilityopen answer page →
Flexibility accepted
Juvenile toxAccepted with a conditionBeyond the letter
Juvenile rat toxicity study deferred to a postmarketing requirement
“PMR 4655-1 Conduct a juvenile toxicity study to evaluate the potential toxicity of deuruxolitinib, including the potential effects on growth, development, and reproduction, when administered orally to juvenile rats.”
“However, PeRC ultimately agreed that the JTS could be conducted as a deferred study with an accelerated timeline.”
GenotoxicityAcceptedBeyond the letter
Positive in vitro micronucleus assay, possibly aneugenic; other genotoxicity assays negative
Why: Positive response possibly aneugenic; no significant overall genotoxicity concern · Weight of evidence
“It was positive in an in vitro micronucleus assay. The positive response could be due to a potential aneugenic effect.”
“Overall, there is no significant concern for deuruxolitinib’s genotoxicity.”
Similar precedents
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