title: Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double-blind, placebo-controlled phase III study.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Probity Medical Research, Waterloo, ON, Canada. kapapp@probitymedical.com
authors.forename: K
authors.initials: K
authors.lastname: Papp
authors.forename: R
authors.initials: R
authors.lastname: Bissonnette
authors.forename: L
authors.initials: L
authors.lastname: Rosoph
authors.forename: N
authors.initials: N
authors.lastname: Wasel
authors.forename: C W
authors.initials: CW
authors.lastname: Lynde
authors.forename: G
authors.initials: G
authors.lastname: Searles
authors.forename: N H
authors.initials: NH
authors.lastname: Shear
authors.forename: R B
authors.initials: RB
authors.lastname: Huizinga
authors.forename: W P
authors.initials: WP
authors.lastname: Maksymowych
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000145:classification / Q000188:drug therapy*; D012720:Severity of Illness Index
chemical_list: D065095:Calcineurin Inhibitors; C484071:voclosporin; D016572:Cyclosporine