ADQUEY Ointment Ref.[116221] Active ingredients: Difamilast

The pharmacodynamics of ADQUEY ointment in the treatment of atopic dermatitis is not known.

Cardiac Electrophysiology

ADQUEY ointment is not expected to cause clinically significant QTc interval prolongation at the recommended dosages.

Absorption

The pharmacokinetics (PK) of ADQUEY were investigated in 31 pediatric subjects 2 years of age and older with moderate to severe atopic dermatitis and a mean ± SD body surface area (BSA) involvement of 44 ± 13% (range 25% to 80%). In this trial, subjects applied an average of approximately 4.3 g of ADQUEY ointment, 1% (dose range was 1.7 to 11.7 g per application) twice daily for 2 weeks.

Plasma concentrations were quantifiable in all the subjects. On Day 15, the mean ± SD maximum plasma concentration (C_max) and area under the concentration time curve from 0 to 8 hours post dose (AUC_0-8) for difamilast were 16.9 ± 21.9 ng/mL and 86.2 ± 79.6 ng*h/mL, respectively. Systemic concentrations of difamilast were at steady state by Day 15, with no evidence of accumulation.

The PK of ADQUEY were investigated in 31 adult subjects with mild to moderate atopic dermatitis and a mean ± SD BSA involvement of 6 ± 3% (range 3% to 19%). Subjects applied an average of approximately 0.9 g of ADQUEY ointment, 1% (dose range was 0.1 to 3.8 g per application) twice daily for 4 weeks. On Day 29, the mean ± SD C_max and AUC_0-12 for difamilast were 0.76 ± 1.16 ng/mL and 6.10 ± 8.85 ng*h/mL, respectively.

Distribution

Difamilast serum protein binding is 99% and is not concentration-dependent, in vitro.

Elimination

Metabolism

Difamilast is substantially metabolized to form three major metabolites in the plasma via CYP3A4-mediated O-deethylation (Metabolite 1), CYP1A2-mediated hydroxylation (Metabolite 2), and enzymatic hydrolysis (Metabolite 3).

Excretion

After both single dosing and twice daily administration of difamilast ointment 1% in healthy Japanese subjects for 2 weeks, difamilast and Metabolite 1 were undetectable in urine. The urinary excretion ratios of all the other metabolites were less than 0.1% of the administered dose.

Specific Populations

No dedicated clinical trials have been conducted to assess the impact of intrinsic factors on the PK of difamilast. Based on cross-study analyses, no substantial differences in the PK of difamilast were observed based on age (2-70 years), sex, race, mild or moderate renal impairment, or mild or moderate hepatic impairment. The effect of severe renal impairment (eGFR <30 mL/min), or severe (Child-Pugh Class C) hepatic impairment on difamilast PK is unknown.

Pediatric Patients

The plasma difamilast trough concentration corrected by dose in pediatric patients was 1.3 to 1.9 times higher than that in adults (on Day 1 and Day 15, respectively).

Drug Interaction Studies

Clinical Studies

No clinical drug interaction trials have been conducted with topical difamilast.

In Vitro Studies

CYP450 Enzymes: Difamilast is a substrate of CYP3A4 and CYP1A2. Difamilast is not expected to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 at clinically relevant concentrations. Induction of CYP1A2, CYP2B6, CYP2C9, and CYP3A4 by difamilast is expected to be low at clinically relevant concentrations.

Transporter Systems: Difamilast is a substrate of breast cancer resistance protein (BCRP),but is not a substrate of P-glycoprotein (P-gp), OATP1B1, or OATP1B3. Difamilast is not expected to inhibit P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2- K at clinically relevant concentrations.

In a 2-year dermal carcinogenicity study in rats, no test article-related neoplastic findings were observed in male or female rats that received difamilast at dermal doses up to 3% ointment applied at 0.008 ml/cm² (4 times the MRHD based on AUC comparison).

In a 2-year dermal carcinogenicity study in mice, no test article-related neoplastic findings were observed in male or female mice that received difamilast at dermal doses up to 3% ointment applied at 0.008 ml/cm² (4 times the MRHD based on AUC comparison).

Difamilast was not genotoxic in an in vitro bacterial reverse mutation (Ames) test, an in vitro mammalian cell mutation test in mouse lymphoma cells, or an in vivo rat bone marrow micronucleus test.

In a fertility and early embryonic development study in rats, irregular estrus cycles, sperm abnormalities, increased preimplantation loss, and decreased copulation and fertility indexes were observed at a subcutaneous dose of 100 mg/kg/day difamilast (116 times the MRHD for males and 263 times the MRHD for females, respectively, based on AUC comparison). No treatment-related adverse effects on fertility or early embryonic development were observed at 10 mg/kg/day for males and females (20 times the MRHD for males and 30 times the MRHD for females, respectively, based on AUC comparison).

The efficacy of ADQUEY for the treatment of mild to moderate atopic dermatitis was assessed in three multicenter, randomized, double-blind, parallel-group, vehicle-controlled trials (Trial 1 [NCT02068352], Trial 2 [NCT03908970], and Trial 3 [NCT03911401]) that treated a total of 612 subjects. Trial 1 enrolled adult and pediatric subjects 10 years of age and older in the United States, Australia, and Poland. Trial 2 enrolled adult and pediatric subjects 15 years of age and older in Japan, and Trial 3 enrolled pediatric subjects 2 to 14 years of age in Japan. In these trials, subjects were randomized 1:1 to receive ADQUEY or vehicle ointment, applied topically to the entire treatment area twice daily for at least 4 weeks.

The trials enrolled subjects with an Investigator's Global Assessment (IGA) score of 2 (mild) or 3 (moderate) atopic dermatitis and affected body surface area (BSA) (excluding the face, neck, and head [Trial 1]; excluding the scalp [Trials 2 and 3]) of ≥5% and ≤40%. The IGA included an overall assessment of atopic dermatitis (erythema, induration/papulation, and oozing/crusting) on a severity scale of 0 to 4.

At baseline, 29%, 15%, and 15% of the subjects had an IGA of mild, and 71%, 85%, and 85% had an IGA of moderate in Trials 1, 2, and 3, respectively. Concomitant treatment for atopic dermatitis was prohibited.

In Trial 1, 56% of the subjects were female, 73% were White, 20% were Black or African American, and 4% were Asian; for ethnicity, 18% of the subjects identified as Hispanic or Latino. In Trials 2 and 3, the majority of the subjects were male (54% in Trial 2 and 58% in Trial 3), 100% were Asian, and 100% identified as Not Hispanic or Latino. The median age of enrolled subjects at baseline was 30 years (range 10 to 67 years), 30 years (range 15 to 65 years), and 7 years (range 2 to 14 years) in Trials 1, 2, and 3, respectively.

The primary efficacy endpoint for all trials was the proportion of subjects who achieved IGA success, defined as an IGA grade of clear (0) or almost clear (1) and with a 2-grade or greater improvement from baseline, at Week 4.

The efficacy results at Week 4 are shown in Table 2.

Table 2. Efficacy Results at Week 4 in Adult and Pediatric Subjects 2 Years of Age and Older with Mild to Moderate Atopic Dermatitis in Trials 1, 2, and 3:

^† IGA success is defined as an IGA score of 0 or 1 and with ≥ 2-grade improvement from baseline.
^‡ Trial 1 enrolled subjects from the United States, Australia, and Poland.
Subjects with missing IGA scores were imputed as failures.