Phase II clinical trial of bexarotene gel 1% in psoriasis

Journal of Drugs in Dermatology, May, 2007 by Debra Breneman, Pranav Sheth, Vivian Berger, Vahid Naini, Victor Stevens

Abstract

We report the results of a nonrandomized, open-label pilot trial investigating the safety, tolerability, and efficacy of bexarotene gel 1% in treating chronic mild to moderate plaque psoriasis.

Twenty-four adults with mild to moderate stable plaque psoriasis involving 15% or less of their body surface were enrolled. Patients applied bexarotene gel 1%, using an application frequency escalation regimen, starting at once every other day and increasing to 4 times daily as tolerated and beneficial for up to 24 weeks.

The primary efficacy instrument was a Physician's Global Assessment (PGA) score evaluating the overall response to treatment. This utilized individual signs of psoriasis and the percent of body surface area involvement. Safety assessments included physical examinations, recording of adverse events, and laboratory safety evaluations.

Fifteen out of 24 enrolled patients (63%) achieved at least 50% improvement by PGA score at 2 or more consecutive visits, and 6 (24%) achieved clearing of 90% or more. Six patients maintained a response throughout 8 weeks of follow-up. An increased response appeared to correlate with a higher frequency of gel application. Adverse events occurred primarily at application sites and were mild or moderate in severity.

Bexarotene gel 1% was active in treating mild to moderate plaque psoriasis with achievement of durable responses in some patients and was well-tolerated. A randomized, placebo-controlled study would be useful in confirming these results.

Introduction

The ability of retinoids to modulate epidermal hyperprolif-eration, disturbed differentiation, and cutaneous inflammation has led to their extensive use in the treatment of psoriasis. (1) Retinoids exert their therapeutic effects by activating retinoid receptors, which are ligand-dependent nuclear receptors that control gene expression. Two subfamilies of retinoid receptors, retinoic acid receptors (RAR) and retinoid X receptors (RXRs), each control a series of overlapping as well as unique target gene pathways. There are 4 times more RXR receptors than RAR receptors in the skin. (2,3)

Acitretin and tazarotene--retinoids currently used for psoriasis--primarily activate RAR pathways. Recently, a multicenter dose-ranging study showed that oral bexarotene--a novel RXR-selective retinoid--may have efficacy in the treatment of plaque psoriasis. (4) However, several patients developed hypertriglyceridemia and asymptomatic hypothyroidism, well-known side effects of oral bexarotene therapy.

Because of the potential efficacy of oral bexarotene in psoriasis, and because of bexarotene's unique receptor binding profile, we evaluated the safety and efficacy of bexarotene gel in patients with mild to moderate plaque psoriasis.

Methods

Study Design

The study was a single-center, open-label study to investigate the safety, tolerability, and efficacy of bexarotene gel 1% in treating patients with chronic mild to moderate plaque psoriasis. All patients were enrolled at the Dermatology Clinical Research Center, Department of Dermatology, University of Cincinnati. Institutional review board approval was obtained before trial initiation, and all patients gave informed written consent prior to study enrollment.

Patient Population

To be eligible for inclusion in the study, patients needed to be 18 years of age or older with chronic stable plaque psoriasis involving 15% or less of the body surface. Hemoglobin, leukocytes, triglycerides, cholesterol, SGOT, SGPT, alkaline phosphatase, bilirubin, creatinine, thyroxine (serum-free T4), and thyroid stimulating hormone (TSH), assessed by clinical laboratory tests, had to be within protocol-defined ranges.

Exclusion criteria were guttate, erythrodermic or pustular psoriasis, concurrent serious uncontrolled illnesses, infections or skin disorders, uncontrolled thyroid disease, uncontrolled hyperlipidemia, the use of topical treatments for psoriasis within 2 weeks of study initiation, ultraviolet light therapy (PUVA, UVB), systemic therapy for psoriasis, or investigational drug use within 4 weeks of study initiation, females who were pregnant or breastfeeding, and patients who were unwilling to minimize their exposure to sunlight.

Dosing Regimen

Patients were instructed to apply bexarotene gel 1% (Targretin[R]) using an application escalation regimen based on tolerability starting at once every other day (QOD) and increasing after one week to once-daily (QD) applications. At the start of week 3, patients began alternating QD with twice-daily (BID) applications. During week 4, application frequency was escalated to BID. The frequency of application could further be escalated, at the investigator's discretion, to 3 times a day (TID) and then to 4 times daily (QID). Treatment continued for 16 weeks. Responding patients had the option of continuing treatment for an additional 8 weeks for a total of 24 weeks.

If moderate or severe cutaneous irritation developed, bexarotene gel 1% application could be reduced or suspended for up to 2 weeks. Treatment applications could be held at a patient's maximal tolerated frequency, as judged by the investigator. Patients were also given the option of holding the application frequency at BID or TID, if dictated by convenience.