VTAMA Cream Ref.[107244] Active ingredients: Tapinarof

Pharmacodynamics of VTAMA cream are unknown.

Cardiac Electrophysiology

At the approved recommended dosage, VTAMA does not prolong the QTc interval to any clinically relevant extent.

Absorption

No accumulation was observed with repeat topical application. Plasma concentration of tapinarof was below the quantifiable limits (BQL) of the assay (lower limit of quantification was 50 pg/mL) in 68% of the pharmacokinetic samples. On Day 1, mean ± SD values of C_max and AUC_0-last were 0.90 ± 1.4 ng/mL and 4.1 ± 6.3 ng.h/mL, respectively, following a mean daily dose of 5.23 g applied to a mean body surface area involvement of 27.2% (range 21 to 46%) in 21 subjects with moderate to severe plaque psoriasis. On Day 29, the mean ± SD C_max and AUC_0-last were 0.12 ± 0.15 ng/mL and 0.61 ± 0.65 ng.h/mL, respectively.

Distribution

Human plasma protein binding of tapinarof is approximately 99% in vitro.

Elimination

Metabolism

Tapinarof is metabolized in the liver by multiple pathways including oxidation, glucuronidation, and sulfation in vitro.

Drug Interaction Studies

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Tapinarof is not an inhibitor of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CRP2D6 or CYP3A4/5. Tapinarof is not an inducer of CYP1A2, CYP2B6 or CYP3A4.

Transporter Systems: Tapinarof is not an inhibitor of BCRP, MATE1, MATE-2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, or P-gp. Tapinarof is not a substrate for BCRP, OATP1B1, OATP1B3, or P-gp.

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). 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).

Tapinarof revealed no evidence of mutagenicity or clastogenicity in an Ames assay, an in vitro mammalian chromosomal aberration assay, an in vitro mouse lymphoma assay and two in vivo micronucleus assays in mice and rats.

Tapinarof did not impair female fertility at subcutaneous doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparisons).

Two multicenter, randomized, double-blind, vehicle-controlled trials were conducted to evaluate the safety and efficacy of VTAMA cream for the treatment of adults with plaque psoriasis (PSOARING 1 [NCT03956355] and PSOARING 2 [NCT03983980].

Baseline disease severity was graded using the 5-point Physician’s Global Assessment (PGA). The majority of subjects had “Moderate” disease (82%), while 10% had “Mild” disease, and 8% had “Severe” disease at baseline. The extent of disease involvement assessed by mean body surface area (BSA), excluding the scalp, palms, and soles, was 8% (range 3 to 20%). Subjects ranged in age from 18 to 75 years, with a median age of 51 years. Overall, 57% of the subjects were male and 85% were White.

The primary efficacy endpoint in both studies was the proportion of subjects who achieved treatment success, defined as a PGA score of “Clear” (0) or “Almost Clear” (1) and at least a 2-grade improvement from baseline. Efficacy results from the two trials are summarized in Table 2.

Table 2. Clinical Response at Week 12 in PSOARING 1 and PSOARING 2 in Adults with Plaque Psoriasis (Intent-to-Treat; Multiple Imputation):

^a Treatment success was defined as a PGA score of “Clear” or “Almost Clear” and a least a 2-grade improvement from baseline.

Following 12 weeks of treatment, 73 subjects randomized to VTAMA achieved complete disease clearance (PGA 0) and had VTAMA withdrawn. These subjects were followed for up to 40 additional weeks with a median time to first worsening (PGA ≥2 [“Mild”]) of 114 days (95% CI: 85, 142).