Oral liarozole vs. acitretin in the treatment of ichthyosis: a phase II/III multicentre, double-blind, randomized, active-controlled study.

BACKGROUND: Liarozole, a retinoic acid metabolism blocking agent, has been granted orphan drug status for congenital ichthyosis by the European Commission and the U.S. Food and Drug Administration. OBJECTIVES: The purpose of this trial was to investigate the efficacy, tolerability and safety of oral liarozole vs. acitretin in patients with ichthyosis. METHODS: In this double-blind comparative trial of liarozole vs. acitretin, 32 patients with ichthyosis were randomized to be treated with either oral liarozole 75 mg in the morning and 75 mg in the evening or with acitretin 10 mg in the morning and 25 mg in the evening for 12 weeks. Clinical efficacy, tolerability and safety were monitored. RESULTS: Between-group comparisons for efficacy and tolerability revealed no statistically significant differences except for scaling on the trunk at baseline which was significantly worse in the liarozole group (P = 0.024) and showed a more pronounced improvement in this group than in the acitretin-treated patients (P = 0.047). Based on the overall evaluation of the response to treatment at endpoint, 10 of 15 patients in the liarozole group and 13 of 16 patients in the acitretin group were considered by the investigator to be at least markedly improved. The expected retinoic acid-related adverse events were mostly mild to moderate and tended to occur less frequently in the liarozole group. No serious adverse events related to the drugs occurred. CONCLUSIONS: The present study indicates that liarozole at a daily dose of 150 mg is equally effective as a treatment for ichthyosis as acitretin but shows a trend towards a more favourable tolerability profile. The results of this trial warrant further clinical trials to confirm efficacy and safety of liarozole as an orphan drug in ichthyosis.

Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Palmoplantar pustular psoriasis (PPP) is a chronic, relapsing condition often recalcitrant to therapy. Synthetic retinoids have been found to be efficacious in the treatment of PPP, but their use is limited by side-effects. Liarozole is an imidazole-like compound that inhibits the retinoic acid (RA) 4-hydroxylase-mediated breakdown of all-trans RA, causing elevation of plasma and cutaneous levels of RA. Thus liarozole acts as a retinoid-mimetic drug. Liarozole has already been found to be effective in the treatment of retinoid-responsive conditions such as chronic plaque psoriasis and ichthyoses. OBJECTIVES: To assess the efficacy and side-effect profile of liarozole in the treatment of PPP. METHODS: We performed a double-blind, randomized, placebo-controlled trial of oral liarozole 75 mg twice daily for 12 weeks in the treatment of PPP. The trial was conducted at two centres and involved 15 patients. RESULTS: Using the PPP Area and Severity Index we found a statistically significant (P = 0.02) improvement in PPP in subjects on liarozole (median 3, range 1.8-14.1) as compared with placebo (median 12.1, range 5-18) by the end of the treatment phase. There was also a statistically significant difference (P = 0.006) in the number of fresh pustules after treatment for the two study groups (liarozole median 2, range 0-18; placebo median 38, range 2-75). The severity of disease (on a scale of 0-8) between the two groups was significantly different at the end of treatment (liarozole median 1, range 1-5; placebo median 3, range 2-6; P = 0.04). No patients withdrew from the trial because of adverse events. The most commonly reported side-effects were pruritus, cheilitis and xerosis but these were rarely severe and resolved rapidly on discontinuation of treatment. Laboratory results, including haematology, liver function tests and serum cholesterol and triglycerides were not significantly different between the liarozole and placebo groups. CONCLUSIONS: The results of this pilot study suggest that liarozole 75 mg twice daily is an effective and well-tolerated therapy for PPP. In addition, the pharmacokinetics of liarozole may help to circumvent side-effects associated with synthetic retinoids and allow its use in premenopausal women.

Treatment of psoriasis with oral liarozole: a dose-ranging study.

BACKGROUND: Liarozole is an inhibitor of the metabolism of all-trans-retinoic acid. Systemic administration increases tissue levels of this endogenous retinoid and has been reported to improve psoriasis in an open, uncontrolled study. OBJECTIVES: A multicentre, double-blind, placebo-controlled, dose-ranging study was therefore undertaken to determine the lowest effective oral dose of liarozole in the treatment of psoriasis vulgaris. PATIENTS/METHODS: Adult male and postmenopausal female patients requiring systemic treatment for psoriasis were randomized to receive placebo or liarozole at total daily doses of 50 mg, 75 mg or 150 mg for 12 weeks. The daily doses were each divided into two equal (morning and evening) doses. Response was assessed using an eight-point global scale to assess improvement and by monitoring the Psoriasis Area and Severity Index (PASI). The primary end-point was the proportion of subjects in each treatment group demonstrating 'marked improvement' or better as assessed on the eight-point scale. The tolerability of the treatment was assessed by recording mucocutaneous effects of retinoids and all adverse events. Biochemical and haematological monitoring were also performed. RESULTS: One hundred and thirty-nine subjects were randomized (118 male and 21 female) and 116 completed the study. A marked improvement or better response was observed in 6% of subjects on placebo, 18% on liarozole 50 mg, 11% on 75 mg and 38% on 150 mg. Only in the 150-mg group was the response rate significantly different to placebo (P < 0.001). Over the treatment period the mean PASI changed from 15.9 to 15.4 on placebo, from 17.4 to 13.8 on liarozole 50 mg, from 17.5 to 14.5 on 75 mg and from 15.8 to 8.8 on 150 mg. Again, only in the group receiving 150 mg was the response significantly better than placebo (P < 0.001). Liarozole was generally well tolerated. Mucocutaneous retinoid effects were generally infrequent and mild. Five subjects were withdrawn from treatment as a result of adverse events that may have been treatment related. These events were abnormalities of liver enzymes in two cases, an episode of erythema multiforme (in a patient receiving placebo), an allergic reaction in one and a rash accompanied by deterioration of the psoriasis in another. There was mild elevation of triglycerides in the groups receiving liarozole 75 mg and 150 mg daily. In males, the serum luteinizing hormone and testosterone levels rose significantly in all the active treatment groups. CONCLUSIONS: The data confirm that liarozole is an effective treatment for psoriasis and indicate that the lowest effective dose is 75 mg twice daily. The drug seems generally to be well tolerated.