A Double-Blind, Randomized, Placebo- and Positive-Controlled Phase III Trial of 1% Benvitimod Cream in Mild-to-Moderate Plaque Psoriasis

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A Double-Blind, Randomized, Placebo- and Positive-Controlled Phase III Trial of 1% Benvitimod Cream in Mild-to-Moderate Plaque Psoriasis

Introduction

Psoriasis, a chronic inflammatory skin disease, affects over 80% of patients as plaque psoriasis. Current topical treatments, such as corticosteroids and vitamin D analogs, face limitations due to long-term safety concerns. Benvitimod (3,5-dihydroxy-4-isopropylstilbene), a synthetic small molecule derived from Photorhabdus luminescens metabolites, has shown promise in preclinical and early clinical trials. This phase III study evaluates the efficacy and safety of 1% benvitimod cream compared to calcipotriol ointment and placebo in mild-to-moderate plaque psoriasis.

Study Design and Methodology

This multicenter, double-blind, randomized trial (ChiCTR-TRC-13003259) enrolled 686 patients (18–65 years) across 23 Chinese centers from February 2013 to June 2014. Patients with ≤10% body surface area involvement and a static Physician’s Global Assessment (sPGA) score ≥2 were randomized in a 2:1:1 ratio to receive:

  • 1% benvitimod cream (n=344)
  • 0.005% calcipotriol ointment (positive control, n=169)
  • Placebo (vehicle cream, n=173)

Treatments were applied twice daily for 12 weeks, excluding sensitive areas (face, scalp, groin). After 12 weeks, patients achieving sPGA 0/1 (clear/minimal) entered an 8-week follow-up. Those without recurrence by week 20 proceeded to a 52-week long-term follow-up, with retreatment using benvitimod upon relapse.

Primary endpoints included:

  1. Proportion achieving ≥75% reduction in Psoriasis Area and Severity Index (PASI 75) at week 12.
  2. Proportion achieving sPGA 0/1 at week 12.

Secondary endpoints included PASI 50 (≥50% improvement) and PASI 90 (≥90% improvement). Safety assessments monitored adverse events (AEs), laboratory parameters, and recurrence rates.

Statistical analysis used the full analysis set with last observation carried forward for missing data. Superiority of benvitimod over placebo and non-inferiority to calcipotriol were tested using two-sided 95% confidence intervals (CIs).

Results

Primary Efficacy Outcomes

  • PASI 75 Response:

    • Benvitimod: 50.4% (173/344) achieved PASI 75, significantly higher than calcipotriol (38.5%, 65/169; P<0.05) and placebo (13.9%, 24/173; P<0.05). The difference vs. placebo was 36.5% (95% CI: 29.2–43.9%).
    • Calcipotriol vs. Placebo: 24.6% higher response rate (95% CI: 15.1–34.1%).

  • sPGA 0/1 Response:

    • Benvitimod: 66.3% (228/344) achieved sPGA 0/1.
    • Calcipotriol: 63.9% (108/169), both significantly superior to placebo (33.5%, 58/173; P<0.05).

Secondary Efficacy Outcomes

  • PASI 50:

    • Benvitimod: 67.3% (231/344).
    • Calcipotriol: 69.8% (118/169), both higher than placebo (40.5%, 70/173; P<0.05).

  • PASI 90:

    • Benvitimod: 32.6% (112/344), exceeding calcipotriol (20.1%, 34/169; P<0.05) and placebo (3.5%, 6/173; P<0.05).

Long-Term Follow-Up (52 Weeks)

  • Of 59 patients entering long-term follow-up, 50.8% (30/59) experienced recurrence (median time: 36 weeks). Retreatment with benvitimod restored sPGA 0/1 in 73.3% (22/30) by week 52.

Safety Profile

  • Adverse Events (AEs):

    • Benvitimod: 57.3% (197/344) reported AEs, primarily mild-to-moderate skin reactions:
    • Pruritus: 21.2% (73/344).
    • Follicular papules: 10.8% (37/344).
    • Contact dermatitis: 6.7% (23/344).
    • Calcipotriol: 36.1% (61/169) with AEs (pruritus: 10.1%).
    • Placebo: 31.2% (54/173) with AEs.

  • Serious AEs:

    • Benvitimod: 1.2% (4/344; 2 cases of contact dermatitis).
    • Calcipotriol: 1.2% (2/169; 1 psoriasis exacerbation).
    • Placebo: 1.2% (2/173).

No systemic AEs or laboratory abnormalities were attributed to benvitimod. Discontinuation rates due to AEs were 8.4% (29/344) for benvitimod vs. 2.9% (5/169) for calcipotriol.

Discussion

Benvitimod demonstrated superior efficacy to placebo and calcipotriol in PASI 75 response, with comparable sPGA 0/1 rates to calcipotriol. Its PASI 90 response (32.6%) highlights potential for high disease clearance, a critical unmet need in psoriasis management. The safety profile aligns with localized therapies, though higher application-site reactions (e.g., pruritus) necessitate patient education.

The 52-week follow-up revealed sustained efficacy in 49.2% of patients, with retreatment success in 73.3% of relapsed cases, suggesting benvitimod’s utility in long-term disease control. As an aryl hydrocarbon receptor (AhR) modulator, benvitimod targets inflammatory pathways implicated in psoriasis, offering a non-steroidal alternative to corticosteroids and vitamin D analogs.

Conclusion

This phase III trial establishes 1% benvitimod cream as an effective and safe topical therapy for mild-to-moderate plaque psoriasis. With 50.4% achieving PASI 75 and 66.3% attaining sPGA 0/1 at 12 weeks—along with manageable local AEs—benvitimod addresses a critical gap in long-term topical treatment options. Its novel mechanism via AhR modulation warrants further exploration in broader populations and combination regimens.

doi.org/10.1097/CM9.0000000000001221

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