1.1 Plaque Psoriasis

VTAMA ®cream is indicated for the topical treatment of plaque psoriasis in adults.

1.2 Atopic Dermatitis

VTAMA cream is indicated for the topical treatment of atopic dermatitis in adults and pediatric patients 2 years of age and older.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Plaque Psoriasis Clinical Trials

In two randomized, double-blind, multicenter, vehicle-controlled clinical trials (PSOARING 1 and PSOARING 2), 1025 adults with plaque psoriasis were treated with VTAMA cream or vehicle cream once daily for up to 12 weeks.

Subjects ranged in age from 18 to 75 years, with an overall median age of 51 years. The majority of subjects were white (85%) and male (57%); and 85% were non-Hispanic or Latino.

Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with VTAMA Cream, and for which the rate exceeded the rate for vehicle.

Two (0.3%) subjects using VTAMA cream developed urticaria. Adverse reactions leading to treatment discontinuation in >1% of subjects who received VTAMA cream were contact dermatitis (2.9%) and folliculitis (2.8%).

In an open label safety trial (PSOARING 3), 763 subjects were treated for up to an additional 40 weeks after completing PSOARING 1 or PSOARING 2. In addition to the adverse reactions reported in the 12-week PSOARING 1 and PSOARING 2 clinical trials, the following adverse reactions were reported: urticaria (1.0%) and drug eruption (0.7%).

Atopic Dermatitis Clinical Trials

In two randomized, double-blind, multicenter, vehicle-controlled clinical trials (ADORING 1 and ADORING 2), 811 adult and pediatric subjects 2 years of age and older with atopic dermatitis were treated with VTAMA cream or received vehicle cream once daily for up to 8 weeks.

Subjects ranged in age from 2 to 81 years, with an overall median age of 11 years. The majority (51%) of subjects were White, 31% were Black, 12% were Asian; 54% were female; and 78% of subjects identified as non-Hispanic or Latino.

Table 2 presents adverse reactions that occurred in at least 1% of subjects treated with VTAMA cream, and for which the rate exceeded the rate for vehicle.

Application site reactions were reported in 19 (3.5%) subjects treated with VTAMA cream and 9 (3.3%) subjects receiving vehicle.

The adverse reactions observed in pediatric subjects 2 years of age and older were generally consistent with those observed in adults with atopic dermatitis. Adverse reactions occurring more frequently in pediatric subjects compared to adults were upper respiratory tract infection (16.3% in subjects ages 2-6 years of age and 11.2% in subjects ages 7-17 years of age vs. 9.5% in subjects 18 years and older) and ear infection (5.7% in subjects ages 2-6 years of age and 1.4% in subjects ages 7-11 years of age vs. 0% in subjects 12 years and older).

In an open label safety trial (ADORING 3), 728 subjects (124 adult and 604 pediatric subjects 2 years of age and older) were treated for up to 48 weeks. This included 624 subjects completing either ADORING 1 or ADORING 2, 28 subjects completing the maximal usage trial, and 76 subjects treated only in ADORING 3. The safety profile with long term use was generally consistent with the safety profile observed at Week 8.

8.1 Pregnancy

Risk Summary

The available data on VTAMA cream use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of tapinarof to pregnant rats and rabbits during the period of organogenesis resulted in no significant adverse effects at doses 268 and 16 times, respectively, the maximum recommended human dose (MRHD) ( see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryofetal development study in rats, tapinarof was administered by subcutaneous injection to pregnant animals at doses of 1.2, 6.9 and 34 mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations. Tapinarof increased the incidence of skeletal variations (incomplete ossification of nasal bones) at the dose of 34 mg/kg/day (268 times the MRHD based on AUC comparisons).

In an embryofetal development study in rabbits, tapinarof was administered by subcutaneous injection to pregnant animals twice daily at doses of 0.3, 1, and 3 mg/kg/day during the period of organogenesis. Maternal toxicity as evidenced by decreased maternal body weight gain and associated increased post-implantation loss (embryolethality) was observed at 3 mg/kg/day. In addition, fetal skeletal variations were observed at 3 mg/kg/day. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to 1 mg/kg/day (16 times the MRHD based on AUC comparison) or fetal malformations at doses up to 3 mg/kg/day (30 times the MRHD based on AUC comparison).

In a second embryofetal development study in rabbits, tapinarof was administered by continuous subcutaneous infusion to pregnant animals at doses of 1, 2 and 3 mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to 3 mg/kg/day (20 times the MRHD based on AUC comparison).

In a prenatal and postnatal development study, tapinarof was administered by subcutaneous injection to pregnant rats at doses of 1, 6 and 30 mg/kg/day beginning on gestation day 6 through lactation day 20. Maternal toxicity associated with decreases in body weight gain and food consumption was noted at 30 mg/kg/day (268 times the MRHD based on AUC comparisons). Tapinarof decreased fetal survival and viability that resulted in reduced litter sizes and decreased fetal weights at doses greater than or equal to 6 mg/kg/day (45 times the MRHD based on AUC comparisons). No tapinarof-related effects on fetal survival and viability were noted at a dose of 1 mg/kg/day (6 times the MRHD based on AUC comparisons). No tapinarof-related effects on postnatal development, neurobehavioral or reproductive performance of offspring were noted at doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparison).

8.2 Lactation

Risk Summary

No data are available regarding the presence of tapinarof in human milk or the effects of tapinarof on the breastfed infant, or on milk production. Tapinarof was detected in rat offspring following subcutaneous administration to pregnant female rats which suggests that tapinarof was transferred into the milk of lactating rats ( see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VTAMA cream and any potential adverse effects on the breastfed infant from VTAMA cream or from the underlying maternal condition.

Data

In a prenatal and postnatal development study, tapinarof was administered by subcutaneous injection to pregnant rats at doses of 1, 6, and 30 mg/kg/day from gestation day 6 through lactation day 20. Tapinarof was quantifiable in offspring plasma samples on postnatal day 10 at doses of 6 and 30 mg/kg/day, suggesting that tapinarof is present in animal milk.

8.4 Pediatric Use

Plaque Psoriasis

The safety and efficacy of VTAMA cream have not been established in pediatric subjects with psoriasis under 18 years of age.

Atopic Dermatitis

The safety and efficacy of VTAMA cream for the topical treatment of atopic dermatitis have been established in pediatric patients 2 years of age and older. Use of VTAMA cream for this indication is supported by evidence from two adequate and well-controlled trials (ADORING 1 and ADORING 2), which included 654 pediatric subjects 2 years of age and older (436 of whom received VTAMA cream) with moderate to severe atopic dermatitis. Adverse reactions occurring more frequently in pediatric subjects compared to adults were upper respiratory tract infection and ear infection [ see Adverse Reactions ( 6.1), Clinical Pharmacology ( 12.3) and Clinical Studies ( 14.2)] .

The safety and efficacy of VTAMA cream for the topical treatment of atopic dermatitis have not been established in pediatric patients younger than 2 years of age.

Juvenile Animal Toxicity Data

In a juvenile animal toxicity study, tapinarof was administered by subcutaneous injection to juvenile rats at doses of 1, 10 and 20 mg/kg/day from postnatal day (PND) 7 to 21 and at doses of 1.5, 15, and 30 mg/kg/day from PND 22 to 77. The dose escalation conducted at PND 22 was implemented to maintain consistent systemic exposure across the duration of the dosing period. Renal pelvic dilatation was observed at doses greater than or equal to 15 mg/kg/day (165 times the MRHD based on AUC comparisons). No adverse effects in juvenile animals were noted at 1.5 mg/kg/day (11 times the MRHD based on AUC comparisons).

8.5 Geriatric Use

Plaque Psoriasis

Of the 683 subjects exposed to VTAMA cream in the PSOARING 1 or PSOARING 2 clinical trials, 99 (14.5%) were 65 years of age and older, including 8 (1.2%) subjects who were 75 years of age and older. No overall differences in efficacy, safety, or tolerability were observed between elderly subjects and younger adult subjects in clinical trials.

Atopic Dermatitis

Of the 541 subjects exposed to VTAMA cream in the ADORING 1 or ADORING 2 clinical trials, 20 (3.7%) were 65 years of age and older, including 4 (0.7%) subjects who were 75 years of age and older. No overall differences in efficacy, safety, or tolerability were observed between subjects 65 years of age and older and younger adult subjects.

12.1 Mechanism of Action

Tapinarof is an aryl hydrocarbon receptor (AhR) agonist. The specific mechanisms by which VTAMA cream exerts its therapeutic action in psoriasis patients are unknown.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

The plasma concentrations of tapinarof were higher in pediatric subjects 2 years of age and older with atopic dermatitis when compared to adult subjects with plaque psoriasis.

Absorption

Adults with Plaque Psoriasis

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 maxand AUC 0-lastwere 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 maxand AUC 0-lastwere 0.12 ± 0.15 ng/mL and 0.61 ± 0.65 ng.h/mL, respectively.

Pediatric Subjects with Atopic Dermatitis

The PK of VTAMA cream were investigated in 36 pediatric subjects 2 years of age and older with moderate to severe atopic dermatitis and a mean ± SD BSA involvement of 43% ± 15% (range 26% to 90%). In this study, subjects applied approximately 3.2 g/day for 27 days.
Plasma concentrations were BQL in 25% of PK samples on Day 1 and 76% of PK samples on Day 28. On Day 1, the mean ± SD C maxand AUC 0-lastwere 2.4 ± 3.9 ng/mL and 4.7 ± 5.6 ng.h/mL, respectively in the overall pediatric population with atopic dermatitis. The mean ± SD C maxand AUC 0-laston Day 1 in pediatric subjects with atopic dermatitis stratified by age is shown in Table 3.

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

14.1 Plaque Psoriasis

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]). These trials were conducted in a total of 1025 subjects randomized 2:1 to VTAMA cream or vehicle cream applied once daily for 12 weeks to any lesion regardless of anatomic location.

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 4.

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).

14.2 Atopic Dermatitis

Two multicenter, randomized, double-blind, vehicle-controlled trials were conducted to evaluate the safety and efficacy of VTAMA cream for the treatment of adult and pediatric subjects 2 years of age and older with atopic dermatitis (ADORING 1 [NCT05014568] and ADORING 2 [NCT05032859]). These trials were conducted in a total of 813 subjects (80% of subjects were 2 to 17 years of age) randomized 2:1 to VTAMA cream or vehicle cream applied once daily for 8 weeks to any lesion regardless of anatomic location.

Baseline disease severity was graded using the 5-point validated Investigator’s Global Assessment (vIGA-AD™). The majority of subjects had “Moderate” disease (87%), while 13% had “Severe” disease at baseline. The extent of disease involvement assessed by mean affected BSA, excluding the scalp, was 16.8% (range 5 to 44%). The mean baseline Eczema Area and Severity Index (EASI) score was 12.9 (range 4.4 to 36.0). The mean baseline Peak Pruritus Numeric Rating Scale (PP-NRS) score for subjects 12 years of age and older was 6.4 on a scale of 0-10. Subjects ranged in age from 2 to 81 years, with a median age of 11 years. Overall, 54% of the subjects were female, 51% were White, 31% were Black, and 12% were Asian. For ethnicity, 78% of subjects identified as non-Hispanic or Latino.

The primary efficacy endpoint in both trials was the proportion of subjects who achieved treatment success, defined as a vIGA-AD score of “Clear” (0) or “Almost Clear” (1) and at least a 2-grade improvement from baseline. Efficacy was also assessed using a ≥ 4-point improvement in PP-NRS score in subjects 12 years of age and older. Efficacy results from the two trials are summarized in Table 5.

Of the 431 subjects randomized to VTAMA who completed 8 weeks of treatment in ADORING 1 and ADORING 2 and elected to continue follow-up, 51 subjects achieved complete disease clearance (vIGA-AD = 0) and had VTAMA withdrawn. These subjects were followed for up to 48 additional weeks with a median time to first worsening (vIGA-AD ≥ 2 [“Mild”]) of 57 days (95% CI: 30, 79).