AD Pipeline Watch: Oral Zelnecirnon Shows Early Promise in AD

11/27/2023

Based on the efficacy and safety data observed in the Phase 1b study, RAPT initiated a dose-ranging Phase 2b study in patients with moderate-to-severe AD.

Zelnecirnon performed well in a Phase 1a/1b clinical trial of atopic dermatitis (AD), RAPT Therapeutics reports.

Zelnecirnon is a small molecule oral therapy designed to selectively inhibit the migration of Th2 cells into inflamed tissues by blocking CCR4, a receptor highly expressed on Th2 cells

The Phase 1a portion of the trial was a standard single and multiple dose-escalation study in 72 healthy volunteers. The Phase 1b portion of the trial was a randomized, double-blind, placebo-controlled study examining zelnecirnon as monotherapy in 31 patients with moderate-to-severe AD.

The findings showed that once-daily zelnecirnon treatment was generally well tolerated, with no serious adverse events reported, and all reported treatment-emergent adverse events were mild-to-moderate in nature across both patients with atopic dermatitis and healthy volunteers.

In the Phase 1b trial, after four weeks of treatment, patients with moderate-to-severe AD who received zelnecirnon showed a 36.3% change from baseline in the Eczema Area and Severity Index (EASI) score, a standard measure of disease severity, compared to 17.0% in the placebo group. Notably, in the two-week period following the end of treatment, the zelnecirnon group showed continued deepening of the response and a statistically significant difference compared to placebo with a 53.2% change from baseline in EASI at the six-week time point compared to 9.6% in the placebo group. Further, significant changes in the transcriptional profile were seen in skin biopsies of zelnecirnon-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with clinical efficacy measures.

The deepening of the response may be related to zelnecirnon’s mechanism of action, which is upstream of other agents targeting cytokines or signaling pathways.  

 “These data strongly support the potential of zelnecirnon as a safe, once-daily, oral treatment for patients with atopic dermatitis which could be an attractive therapeutic alternative ahead of injectable drugs,” says Brian Wong, MD, PhD, President and CEO of RAPT Therapeutics, in a news release. “We look forward to reporting top-line data from our Phase 2b trial in atopic dermatitis in mid-2024 and continuing to progress enrollment in our Phase 2a trial in asthma.”

More on the Phase 1b study

In the Phase 1b study, 21 patients with moderate-to-severe atopic dermatitis were treated with 400 mg of zelnecirnon, administered orally once a day for four weeks, while 10 patients received placebo. The zelnecirnon group showed clear improvement in key efficacy measures compared to placebo at the end of the four-week treatment period, including percent change from baseline in the Eczema Area and Severity Index (EASI) score, validated Investigator Global Assessment (vIGA) and pruritis Numerical Rating Scale (NRS):

  • Patients treated with zelnecirnon achieved a 36.3% change from baseline in EASI score compared with 17.0% in patients in the placebo group
  • 42.9% of patients treated with zelnecirnon achieved a 50% change from baseline in EASI score (EASI-50) compared with 10.0% in the placebo group
  • 4.8% of patients treated with zelnecirnon achieved a vIGA score of 0/1 and at least a two-point improvement over baseline compared with 0.0% in the placebo group; and
  • 45.0% of patients treated with zelnecirnon achieved at least a four-point reduction in the pruritus NRS score, compared with 22.2% in the placebo group

Patients were also evaluated for exploratory endpoints at six weeks (two weeks after the end of treatment). At six weeks, the patients treated with zelnecirnon showed further deepening of the response in EASI score and vIGA:

  • Patients treated with zelnecirnon achieved a 53.2% change from baseline in EASI score compared with 9.6% in patients in the placebo group
  • 61.9% of patients treated with zelnecirnon achieved EASI-50 compared with 20.0% in the placebo group; and
  • 14.3% of patients treated with zelnecirnon achieved a vIGA score of 0/1 and at least a two-point improvement over baseline compared with 0.0% in the placebo group

Based on exploratory statistical analyses, the difference between zelnecirnon and placebo on the percent change in EASI score and EASI-50 was statistically significant at Day 43. No other endpoints or timepoints achieved statistical significance.

Zelnecirnon was well tolerated in the Phase 1b study. No serious adverse events were reported, and all adverse events reported were mild or moderate in intensity. The overall safety profile of zelnecirnon in the Phase 1b study and from the Phase 1a study in healthy volunteers, suggests zelnecirnon is a well-tolerated oral drug that would not require any laboratory safety monitoring.

The study is published in Allergy.

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