Klisyri
tirbanibulin
Species
RatDogPig
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog (oral); minipig and rat (topical)
“Tirbanibulin was evaluated in repeat-dose general toxicity studies involving topical administration to the skin of rats and minipigs for up to 4 weeks, as well as in studies that involved oral dosing of rats and dogs for up to 4 weeks.”
Why that species
Minipig considered the best available nonclinical model for topical application to skin
“This study involves exposure to the to-be-marketed formulation once daily for five days via the clinical route of exposure, utilizing the best available nonclinical model for topical application to skin.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a general toxicity study conducted with rats, the animals were orally dosed with tirbanibulin at dosages of 0, 2.5, 5, and 10 mg/kg/day in males and 0, 1.25, 2.5, and 4 mg/kg/day in females (administered in two equal daily doses).”
Species: general tox
Rat and minipig (topical); rat and dog (oral), up to 4 weeks
“Tirbanibulin was evaluated in repeat-dose general toxicity studies involving topical administration to the skin of rats and minipigs for up to 4 weeks, as well as in studies that involved oral dosing of rats and dogs for up to 4 weeks.”
Species: DART
Rat and rabbit (oral dosing)
“Tirbanibulin was evaluated in a battery of reproductive toxicology studies involving oral dosing of rats and rabbits, as summarized below.”
Species: carcinogenicity
Not conducted (short-term use, no chronic exposure)
“Not applicable, as the proposed use does not involve chronic exposure.”
Surrogate used in
No surrogate used; tirbanibulin tested directly by topical and oral routes
“Tirbanibulin was evaluated in repeat-dose general toxicity studies involving topical administration to the skin of rats and minipigs for up to 4 weeks, as well as in studies that involved oral dosing of rats and dogs for up to 4 weeks.”
Study lengthopen answer page →
Longest pivotal study
4 (28-day oral rat and dog)
“Tirbanibulin was evaluated in repeat-dose general toxicity studies involving topical administration to the skin of rats and minipigs for up to 4 weeks, as well as in studies that involved oral dosing of rats and dogs for up to 4 weeks.”
Pivotal GLP studies
Topical rat and minipig and oral rat and dog repeat-dose studies, up to 4 weeks
“Tirbanibulin was evaluated in repeat-dose general toxicity studies involving topical administration to the skin of rats and minipigs for up to 4 weeks, as well as in studies that involved oral dosing of rats and dogs for up to 4 weeks.”
Route in tox
Topical (dermal) and oral gavage
“Tirbanibulin has been evaluated in a battery of nonclinical studies that included evaluation of ADME, pharmacology, safety pharmacology, repeat-dose toxicity (via both the oral and topical routes), genetic toxicology, reproductive toxicology, and evaluation for potential to induce ocular irritation or sensitization.”
Skipped studiesopen answer page →
Genotoxicity
Genotoxic: Ames negative; positive in CHO chromosome aberration, mouse lymphoma and rat micronucleus assays
“Tirbanibulin was negative in an in vitro bacterial reverse mutation (Ames) assay. Tirbanibulin was positive in an in vitro chromosomal aberration assay with Chinese hamster ovary (CHO) cells, an in vitro mouse lymphoma assay with L5178/TK +/- cells, and an in vivo micronucleus assay in rats.”
Carcinogenicity
Not conducted (short-term use, no chronic exposure)
“Not applicable, as the proposed use does not involve chronic exposure.”
Reproductive & developmental
Rat EFD: fetal deaths and malformations at ≥1.25 mg/kg/day
“Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day,”
Safety pharmacology
Irwin and hERG negative; no CV effects in dogs at clinically relevant exposure; no ECG effects in 4-week dog
“The Irwin and hERG assay were negative. No cardiovascular effects were observed in dogs following intravenous dosing at clinically relevant levels of systemic exposure.”
Genotox: Ames
Negative
“Tirbanibulin was negative in a bacterial reverse mutation (Ames) assay”
Genotox: in vitro mammalian
Positive: CHO chromosomal aberration and mouse lymphoma (L5178Y TK+/-) assays
“Tirbanibulin was positive in an in vitro chromosomal aberration assay with Chinese hamster ovary (CHO) cells, an in vitro mouse lymphoma assay with L5178/TK +/- cells, and an in vivo micronucleus assay in rats.”
Genotox: in vivo
Rat bone marrow micronucleus: positive (clastogenic)
“Tirbanibulin was clastogenic in an in vivo rodent (micronucleus) assay, as indicated by increased incidence of MPE.”
Carcinogenicity model
Not conducted: proposed use does not involve chronic exposure
“Not applicable, as the proposed use does not involve chronic exposure.”
Carcinogenicity timing
Not required: proposed topical use does not involve chronic exposure
“Not applicable, as the proposed use does not involve chronic exposure.”
hERG / QT
hERG assay negative
“The Irwin and hERG assay were negative.”
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 Klisyri 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: Rat 4-week oral: thymus, testes, epididymis and bone marrow lesions, tending to reverse (FDA multi-discipline review, p. 34)
NOAEL / key findings
Rat 4-week oral: thymus, testes, epididymis and bone marrow lesions, tending to reverse
“included findings in the thymus (lymphocyte deletion), testes (germ cell degeneration and depletion, sperm granuloma), epididymis (cellular debris, oligospermia), and bone marrow (hypocellularity). These effects tended to reverse during the recovery period.”
Risksopen answer page →
Immune & cytokine safety
Some skin sensitisation potential in guinea pig Buehler assay
“Tirbanibulin ointment exhibited some evidence of potential to induce sensitization when topically applied to the skin of guinea pigs in a Buehler assay.”
Biodistribution & persistence
Rat oral QWBA: highest in plasma, liver, stomach, intestines, adrenals, kidneys and thyroid
“Activity achieved highest levels in plasma, liver, stomach, intestines, adrenals, kidneys, and thyroid.”
Modality-specific risk
Genotoxicity, addressed by labeling and short-term use
“Although tirbanibulin is a genetic toxicant, this matter may be appropriately addressed through labeling. The product is intended for short-term use only, which partially assuages concerns about genotoxicity.”
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
- Ophthalmic Adverse Reactions
- Local Skin Reactions
Skin 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 Klisyri 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: Rat 4-week oral: thymus, testes, epididymis and bone marrow lesions, tending to reverse (FDA multi-discipline review, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week oral rat and dog studies, each with 2-week recovery (topical rat and minipig studies also up to 4 weeks)
“4-Week Oral Gavage Toxicity and Toxicokinetic Study with KX2-391 in Rats with a 2-Week Recovery Sprague-Dawley rats, study No. 7709- 102. Study title: 4-Week Oral Gavage Toxicity and Toxicokinetic Study with KX2-391 in Dogs with a 2-Week Recovery, study No. 7709-103.”
Pivotal GLP studies
Topical rat and minipig and oral rat and dog repeat-dose studies, up to 4 weeks
“Tirbanibulin was evaluated in repeat-dose general toxicity studies involving topical administration to the skin of rats and minipigs for up to 4 weeks, as well as in studies that involved oral dosing of rats and dogs for up to 4 weeks.”
DART package
Species: DART
Rat and rabbit (oral dosing)
“Tirbanibulin was evaluated in a battery of reproductive toxicology studies involving oral dosing of rats and rabbits, as summarized below.”
Reproductive & developmental
Rat EFD: fetal deaths and malformations at ≥1.25 mg/kg/day
“Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day,”
PPND / ePPND: when
PPND in rat (oral) completed and reviewed in the marketing application
“Tirbanibulin was evaluated for effects on prenatal and postnatal development, including maternal function, in a study that involved administration by oral gavage to female rats from day 6 of gestation until day 20 of lactation”
Carcinogenicity
Species: carcinogenicity
Not conducted (short-term use, no chronic exposure)
“Not applicable, as the proposed use does not involve chronic exposure.”
Carcinogenicity model
Not conducted: proposed use does not involve chronic exposure
“Not applicable, as the proposed use does not involve chronic exposure.”
Carcinogenicity timing
Not required: proposed topical use does not involve chronic exposure
“Not applicable, as the proposed use does not involve chronic exposure.”
Safety marginopen answer page →
Safety margin at NOAEL
5-day topical minipig NOAEL (highest dose tested): 9x (females) and 20x (males) clinical AUC
“5-Day Topical Minipig RDT NOAEL (2 mL/kg/day of 1.0% tirbanibulin ointment) Males Females 100 46 20 9”
NOAEL / key findings
Rat 4-week oral: thymus, testes, epididymis and bone marrow lesions, tending to reverse
“included findings in the thymus (lymphocyte deletion), testes (germ cell degeneration and depletion, sperm granuloma), epididymis (cellular debris, oligospermia), and bone marrow (hypocellularity). These effects tended to reverse during the recovery period.”
Efficacy evidenceopen answer page →
Efficacy evidence
Cultured keratinocytes in vitro: proliferation reduced 50% at 40 nM
“In vitro, the concentration of tirbanibulin at which proliferation of cultured keratinocytes is reduced by 50% is 40 nM.”
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: nonclinical database acceptably addresses all nonclinical issues
“The available nonclinical database acceptably addresses all nonclinical issues associated with NDA 213189.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAccepted with a conditionBeyond the letter
Positive genotoxicity (clastogenic in vitro and in vivo, weakly mutagenic in mouse lymphoma) accepted for a topical product
Why: Short-term use only; marketed actinic keratosis alternative fluorouracil is also a genetic toxicant; addressed through labeling · Class precedent · Other reason
“Although tirbanibulin is a genetic toxicant, this matter may be appropriately addressed through labeling. The product is intended for short-term use only, which partially assuages concerns about genotoxicity.”
“Also, it should be considered that a currently marketed product that is labeled for topical treatment of actinic keratoses, Efudex (a clinical alternative) contains fluorouracil, which is a genetic toxicant. No nonclinical post-marketing requirements are necessary.”
CarcinogenicityAccepted
No carcinogenicity studies
Why: Proposed use does not involve chronic exposure · Within the guideline
“Not applicable, as the proposed use does not involve chronic exposure.”
Similar precedents
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