A phase 1 study found that RPT193 monotherapy led to greater improvements in clinical efficacy than treatment with a placebo.
In a phase 1 study (NCT04271514), RPT193, an oral C-C motif chemokine receptor 4 (CCR4), exhibited greater improvements in clinical efficacy endpoints among patients with atopic dermatitis (AD) versus a placebo.
Investigators sought to explore the safety and tolerability of the oral CCR4 antagonist in patients with AD for its ability to inhibit the migration and downstream activation of T-helper Type 2 (Th2) cells, given the role of Th2 upregulation in the pathogenesis of AD. To the knowledge of study authors Bissonnette et al, this study is the first to demonstrate clinical improvement and a modulated cutaneous transcriptomic profile in any inflammatory skin disease.
Study participants included adults between the ages of 18 and 55 years old with a body mass index (BMI) between 18 and 30. Patients were divided into 1 of 3 cohorts: a single ascending dose (SAD) and food effect cohort involving healthy participants, a multiple ascending dose (MAD) cohort involving healthy participants, and a multiple dose cohort including patients with AD.
Patients included in the AD cohort were required to meet key inclusion criteria, including expanded age qualifications (ages 18 to 65 years), a BMI equal to or greater than 18 and less than 40, AD affecting 10% or greater of the body's surface area, and Eczema Area and Severity Index (EASI) score of 12 or greater, and a visual Investigator's Global Assessment (vIGA) score of 3 or greater.
Among members of the AD cohort, 21 participants were assigned to receive a once-daily dose of 400 mg RPT193, and 10 participants were assigned to received a placebo.
In the SAD cohort, 32 randomized healthy subjects and 8 subjects receiving open-label RPT193 5 or 20 mg completed the study. In the MAD cohort, 31 out of 32 subjects completed the study, with one subject in the RPT193 200 mg QD group withdrawing voluntarily. In the AD cohort, 30 out of 31 subjects completed the study, with one subject each from the RPT193 and placebo groups discontinuing for reasons such as withdrawal by subject and other reasons, respectively.
Across all cohorts, treatment-emergent adverse events (TEAEs) in healthy subjects and subjects with AD were mostly mild or moderate, with no severe TEAEs reported. Headache was the most common TEAE, and the majority of events were not considered related to the study treatment.
In the AD cohort, 35.5% of subjects receiving RPT193 400 mg and 20% of subjects in the placebo group experienced at least one TEAE, all of which were mild or moderate in severity. No serious adverse events or TEAEs leading to study discontinuation were reported in the AD cohort.
Patients receiving RPT193 400 mg QD exhibited numerically greater improvements in EASI, body surface area, vIGA, and SCORing Atopic Dermatitis (SCORAD) compared to the placebo group throughout the 28-day treatment period. At Day 29, the percent improvement from baseline in mean EASI score was 36.3% in the RPT193 group, with a proportion of subjects achieving EASI-50 at 42.9%, compared to 17.0% and 10.0%, respectively, in the placebo group.
Post-hoc analysis at day 43 revealed statistically significant differences in several efficacy endpoints, including changes from baseline in mean EASI, proportion of subjects achieving EASI-50, BSA, and SCORAD total scores, indicating sustained efficacy beyond the treatment period.
"These data showed that the oral CCR4 antagonist RPT193 was well tolerated and induced clinical improvement and renormalization of the skin transcriptome in subjects with moderate to severe AD," study authors wrote. "CCR4 antagonists merit further investigation in AD and other diseases where the Th2 axis plays a key role."
Bissonnette R, DuBois J, Facheris P, et al. Clinical and molecular effects of oral CCR4 antagonist RPT193 in atopic dermatitis: A phase 1 study. Allergy. Published online November 20, 2023. doi:10.1111/all.15949