Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double-blind, placebo-controlled phase III study

Summary

Background

The use of systemic calcineurin inhibitors for the treatment of patients with psoriasis is limited by toxicity, particularly nephrotoxicity. ISA247, a novel inhibitor, was effective and well tolerated in a phase II study of patients with plaque psoriasis. Therefore its efficacy was assessed in this phase III study.

Methods

451 patients aged 18–65 years with plaque psoriasis involving at least 10% of the body surface area were randomly assigned in equal proportions to receive placebo or ISA247 at 0·2 mg/kg, 0·3 mg/kg, or 0·4 mg/kg orally twice a day in dermatology clinics. The primary endpoint was a 75% reduction in the psoriasis area and severity index (PASI 75) score at week 12. Treatment allocation was concealed from patient and physicians doing the assessments by use of sealed envelopes. The method of analysis was by modified intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00244842.

Findings

107, 113, and 116 patients were assigned to the ISA247 0·2 mg/kg, 0·3 mg/kg, and 0·4 mg/kg groups, respectively, and 115 to the placebo group. At week 12, PASI 75 scores were achieved in the ISA247 0·2 mg/kg, 0·3 mg/kg, and 0·4 mg/kg groups by 14 (16%; 95% CI 9–24) of 105, 26 (25%; 17–24) of 111, and 44 (47%; 27–57) of 113 patients, respectively, and in the placebo group by 4 (4%; 0–8) of 113 patients. Efficacy was maintained during 24 weeks. Mild to moderate glomerular filtration rate reductions were noted in seven patients in the ISA247 0·4 mg/kg group and in one in the ISA247 0·3 mg/kg group. ISA247 blood concentrations showed a strong correlation with mean percentage reduction in PASI.

Interpretation

ISA247 was safe and effective in the treatment of patients with moderate to severe psoriasis during 24 weeks, with the highest dose providing the best efficacy. The strong correlation between ISA247 concentrations and efficacy might allow for accurate dosing of patients compared with existing calcineurin inhibitors.

Funding

Isotechnika.

Introduction

One of the most effective treatments for psoriasis is the calcineurin inhibitor ciclosporin.1, 2, 3 However, the side-effect profile of ciclosporin, in particular nephrotoxicity, restricts its long-term use.4, 5, 6, 7 Studies have shown that new biological treatments, in particular infliximab,8, 9 are safe and effective for treatment of plaque psoriasis. However, with their high cost, inconvenience of administration, and few data on long-term safety and effectiveness, their widespread use might not be possible.¹⁰

ISA247 (Isotechnika, Edmonton, AB, Canada) is a novel calcineurin inhibitor intended for the treatment of autoimmune diseases, such as psoriasis and uveitis, and prevention of organ transplant rejection. It differs from ciclosporin by a chemical modification of the functional group at the aminoacid-1 residue (figure 1). This modification has improved the molecule in two ways. First, ISA247 binds more tightly to calcineurin than does ciclosporin, leading to a more complete inhibition of calcineurin. Second, the metabolism of ISA247 has been shifted away from aminoacid-1, which is the major site of metabolism for ciclosporin. This shift leads to a faster elimination of metabolites and a lower drug and metabolite load after the administration of ISA247 than with ciclosporin. In turn, fewer metabolites lead to improved pharmacokinetic and pharmacodynamic predictability.

In animal models, ISA247 was more potent and had a more favourable side-effect profile than ciclosporin, particularly with regards to renal toxicity.11, 12, 13 Consistent with these preclinical data, results of a phase II study of patients with stable plaque psoriasis showed that ISA247 was effective and well tolerated, without much change in blood pressure or concentrations of lipids or triglycerides.¹⁴ Therefore the efficacy of a commercial preparation of ISA247 was assessed in this phase III clinical trial.