Vtama
tapinarof
Species
RatPig
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 minipig
“Tapinarof (GSK2894512; WBI-1001) has been evaluated in single- and repeat-dose dermal toxicity studies of up to 13 weeks in mice and rats, 28 days in rabbits, and up to 39 weeks in minipigs. Tapinarof was also evaluated in repeat-dose subcutaneous toxicity studies of up to 26 weeks in rats.”
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
“Twice daily dermal administration of tapinarof cream at doses of 0 (vehicle), 0.5, 1.0 and 3.0% (Formulation F; 0, 10, 20, and 60 mg/kg/day) were applied onto 10% of total BSA of minipigs (3/sex/group) with no occlusion for 39 weeks.”
Species: general tox
Minipig (dermal, up to 39 weeks) and rat (subcutaneous, up to 26 weeks); also dermal mouse, rat and rabbit
“Tapinarof (GSK2894512; WBI-1001) has been evaluated in single- and repeat-dose dermal toxicity studies of up to 13 weeks in mice and rats, 28 days in rabbits, and up to 39 weeks in minipigs. Tapinarof was also evaluated in repeat-dose subcutaneous toxicity studies of up to 26 weeks in rats.”
Species: DART
Rat and rabbit, subcutaneous (fertility, embryofetal, pre/postnatal development)
“The effect of tapinarof on reproductive toxicity, including fertility, embryofetal development, and prenatal and postnatal development was investigated in rats or rabbits following subcutaneous administration:”
Species: carcinogenicity
Mouse (topical, 98-102 weeks) and rat (subcutaneous, 83 weeks in females)
“No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug-related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at doses up to 1 mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons).”
Surrogate used in
No surrogate used; tapinarof tested directly
“Tapinarof (GSK2894512; WBI-1001) has been evaluated in single- and repeat-dose dermal toxicity studies of up to 13 weeks in mice and rats, 28 days in rabbits, and up to 39 weeks in minipigs. Tapinarof was also evaluated in repeat-dose subcutaneous toxicity studies of up to 26 weeks in rats.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month minipig)
“Twice daily dermal administration of tapinarof cream at doses of 0 (vehicle), 0.5, 1.0 and 3.0% (Formulation F; 0, 10, 20, and 60 mg/kg/day) were applied onto 10% of total BSA of minipigs (3/sex/group) with no occlusion for 39 weeks.”
Pivotal GLP studies
26-week subcutaneous rat and 39-week dermal minipig studies
“Tapinarof (GSK2894512; WBI-1001) has been evaluated in single- and repeat-dose dermal toxicity studies of up to 13 weeks in mice and rats, 28 days in rabbits, and up to 39 weeks in minipigs. Tapinarof was also evaluated in repeat-dose subcutaneous toxicity studies of up to 26 weeks in rats.”
Route in tox
Dermal (minipig) and subcutaneous (rat)
“Tapinarof (GSK2894512; WBI-1001) has been evaluated in single- and repeat-dose dermal toxicity studies of up to 13 weeks in mice and rats, 28 days in rabbits, and up to 39 weeks in minipigs. Tapinarof was also evaluated in repeat-dose subcutaneous toxicity studies of up to 26 weeks in rats.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration, mouse lymphoma and mouse and rat micronucleus assays
“Tapinarof was not mutagenic or clastogenic in the Ames bacterial reverse mutation assay, the in vitro mammalian chromosome aberration test, and the in vitro mouse lymphoma assay. Tapinarof was not genotoxic in two in vivo micronucleus assays in mice and rats.”
Carcinogenicity
Dermal mouse (98-102 weeks) and subcutaneous rat (females, 83 weeks): no drug-related neoplasms
“No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug-related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at doses up to 1 mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons).”
Reproductive & developmental
Rat PPND: decreased pup survival and viability at ≥6 mg/kg/day; NOAEL 1 mg/kg/day
“There were test article-related decreases in F1 pup survival and viability at ≥6 mg/kg/day that resulted in reduced litter sizes and decreased pup weights. The NOAEL was 1 mg/kg/day for tapinarof effects on prenatal and postnatal development of the offspring in rats.”
Safety pharmacology
Concentration-dependent hERG inhibition (IC50 4.02 μM)
“Tapinarof inhibited hERG channel tail current in a concentration-dependent manner. The IC25, IC50 and IC75 values were estimated to be 1.72, 4.02, and 9.37 μM, respectively.”
Genotox: Ames
Negative
“Tapinarof was not mutagenic or clastogenic in the Ames bacterial reverse mutation assay, the in vitro mammalian chromosome aberration test, and the in vitro mouse lymphoma assay. Tapinarof was not genotoxic in two in vivo micronucleus assays in mice and rats.”
Genotox: in vitro mammalian
Negative: chromosome aberration test and mouse lymphoma assay
“Tapinarof was not mutagenic or clastogenic in the Ames bacterial reverse mutation assay, the in vitro mammalian chromosome aberration test, and the in vitro mouse lymphoma assay. Tapinarof was not genotoxic in two in vivo micronucleus assays in mice and rats.”
Genotox: in vivo
Negative: micronucleus assays in mice and rats
“Tapinarof was not mutagenic or clastogenic in the Ames bacterial reverse mutation assay, the in vitro mammalian chromosome aberration test, and the in vitro mouse lymphoma assay. Tapinarof was not genotoxic in two in vivo micronucleus assays in mice and rats.”
Carcinogenicity model
Subcutaneous Wistar-Han rat: negative in females; male portion of inadequate duration
“The subcutaneous carcinogenicity study in Wistar-Han rats is negative for drug-related neoplasms in female rats but the male portion of the study, while it did not show any statistical increase in tumors, was of an inadequate duration.”
Carcinogenicity timing
Dermal mouse and subcutaneous rat long-term studies completed before the marketing application
“Long-term carcinogenicity studies were conducted in mice (daily topical administration at doses of 0.5, 1.5 and 3% tapinarof cream) and in rats (subcutaneous administration at doses of 0.1, 0.3, and 1 mg/kg/day tapinarof).”
hERG / QT
Concentration-dependent hERG inhibition, IC50 4.02 μM
“Tapinarof inhibited hERG channel tail current in a concentration-dependent manner. The IC25, IC50 and IC75 values were estimated to be 1.72, 4.02, and 9.37 μM, respectively.”
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 Vtama 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: Target organs skin, liver, kidney and thymus, with secondary clinical pathology findings (FDA multi-discipline review, p. 30)
NOAEL / key findings
Target organs skin, liver, kidney and thymus, with secondary clinical pathology findings
“The major test article-related findings observed in repeat-dose dermal and subcutaneous studies were related to the skin, liver, kidney, and thymus with associated secondary clinical pathology findings.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion with decreased thymus weights in rats at 10 and 40 mg/kg/day subcutaneously
“Additionally, lymphoid depletion was seen in males and females at doses of 10 or 40 mg/kg/day and correlated with thymus weight decreases.”
Biodistribution & persistence
Rapid, wide tissue distribution in pigmented rat QWBA, all tissues quantifiable by 1 hour
“In male pigmented rats following a single SC administration of [14C]-tapinarof at 2 mg/kg, radioactivity was rapidly and widely distributed throughout the body with all tissues containing quantifiable radioactivity concentrations by 1-hour post-dose.”
Modality-specific risk
Juvenile toxicity: renal pelvic dilatation and thymic changes in juvenile rats
“At ≥ 10/15 mg/kg/day, there were adverse microscopic changes in the form of renal pelvic dilatation in both sexes; test article-related changes also included decreased thymus weight, and decreased cellularity in the thymus and changes of thymic T cell maturation populations.”
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.
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 Vtama 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: Target organs skin, liver, kidney and thymus, with secondary clinical pathology findings (FDA multi-discipline review, p. 30)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week (9-month) GLP dermal study in Göttingen minipigs with 1-month recovery
“Toxicity Study by Dermal Administration to Göttingen Minipigs for 9 Months Followed by a 1-Month Off-Dose Period”
Pivotal GLP studies
26-week subcutaneous rat and 39-week dermal minipig studies
“Tapinarof (GSK2894512; WBI-1001) has been evaluated in single- and repeat-dose dermal toxicity studies of up to 13 weeks in mice and rats, 28 days in rabbits, and up to 39 weeks in minipigs. Tapinarof was also evaluated in repeat-dose subcutaneous toxicity studies of up to 26 weeks in rats.”
DART package
Species: DART
Rat and rabbit, subcutaneous (fertility, embryofetal, pre/postnatal development)
“The effect of tapinarof on reproductive toxicity, including fertility, embryofetal development, and prenatal and postnatal development was investigated in rats or rabbits following subcutaneous administration:”
Reproductive & developmental
Rat PPND: decreased pup survival and viability at ≥6 mg/kg/day; NOAEL 1 mg/kg/day
“There were test article-related decreases in F1 pup survival and viability at ≥6 mg/kg/day that resulted in reduced litter sizes and decreased pup weights. The NOAEL was 1 mg/kg/day for tapinarof effects on prenatal and postnatal development of the offspring in rats.”
PPND / ePPND: when
Subcutaneous PPND in rat completed before the marketing application
“GSK2894512A: Subcutaneous Pre- and Postnatal Development Study in Rats / 2018N368233”
Carcinogenicity
Species: carcinogenicity
Mouse (topical, 98-102 weeks) and rat (subcutaneous, 83 weeks in females)
“No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug-related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at doses up to 1 mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons).”
Carcinogenicity model
Subcutaneous Wistar-Han rat: negative in females; male portion of inadequate duration
“The subcutaneous carcinogenicity study in Wistar-Han rats is negative for drug-related neoplasms in female rats but the male portion of the study, while it did not show any statistical increase in tumors, was of an inadequate duration.”
Carcinogenicity timing
Dermal mouse and subcutaneous rat long-term studies completed before the marketing application
“Long-term carcinogenicity studies were conducted in mice (daily topical administration at doses of 0.5, 1.5 and 3% tapinarof cream) and in rats (subcutaneous administration at doses of 0.1, 0.3, and 1 mg/kg/day tapinarof).”
Safety marginopen answer page →
Safety margin at NOAEL
General toxicity NOAELs: modest (dermal) to large (subcutaneous) margins over topical human exposure
“For the no-observed-adverse-effect-level (NOAEL) determined in the general toxicity studies with tapinarof, there are modest (dermal studies) to large (subcutaneous studies) safety margins when systemic tapinarof exposure is compared between animals and humans topically treated with tapinarof cream, 1%.”
NOAEL / key findings
Target organs skin, liver, kidney and thymus, with secondary clinical pathology findings
“The major test article-related findings observed in repeat-dose dermal and subcutaneous studies were related to the skin, liver, kidney, and thymus with associated secondary clinical pathology findings.”
Efficacy evidenceopen answer page →
Efficacy evidence
Imiquimod mouse psoriasis model: reduced epidermal thickness and IL-17a/IL-17f/IL-19/IL-1β/IL-23a mRNA
“In animal models, the anti-inflammatory activity of tapinarof has been demonstrated in the imiquimod mouse model of psoriasis. It led to reductions in epidermal thickness and mRNA expression of key pro-inflammatory cytokines (IL-17a, IL-17f, IL-19, IL-1β, and IL-23a).”
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 data supported label mechanism statements, but several were of unclear relevance and removed
“Although the applicant provided nonclinical data to factually support statements made in section 12.1, several portions are of unclear relevance to the mechanism of action and should be removed.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityQuestioned
Male arm of the subcutaneous rat carcinogenicity study of inadequate duration; only female rat data adequate
“The study is negative for drug-related neoplasms in female rats. The male portion of the study, while it did not show any statistical increase in tumors, was of an inadequate duration.”
DARTAcceptedBeyond the letter
No separate male fertility study; male fertility assessed by spermatogenesis staging in a 4-week subcutaneous rat study
Why: Male fertility assessed in the 4-week subcutaneous rat study · Weight of evidence
“Although there was no separate male fertility study in this drug development program, it is not considered an approvability issue. Assessment of tapinarof effects on male fertility was conducted in the 4-week subcutaneous rat study.”
Impurity or metaboliteAcceptedBeyond the letter
Two Ames-positive impurities allowed above the 1.5 µg/day TTC
Why: Topical route gives very limited systemic exposure; two negative carcinogenicity studies with tapinarof · Pharmacology or kinetics · Weight of evidence
“From a pharmacology/toxicology perspective, the applicant’s proposal of setting the acceptable limit of these two impurities at times higher than TTC of 1.5 µg/day appears reasonable, because (1) the clinical route of administration for tapinarof is topical, which provides very limited amount of systemic exposure of these impurities; (2) two carcinogenicity studies have been conducted with tapinarof and no drug-related neoplasms was noted;”
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