Randomized Placebo-Controlled Study of ISA247 in Plaque Psoriasis (SPIRIT)

• To investigate the safety and tolerability of voclosporin. [ Time Frame: Twelve and twenty four weeks ] [ Designated as safety issue: Yes ]
• To investigate the pharmacokinetics and pharmacodynamics of voclosporin after chronic dosing in a subset of subjects. [ Time Frame: Twelve and twenty four weeks ] [ Designated as safety issue: No ]
• To evaluate the effect of voclosporin on subject quality of life [ Time Frame: Twelve and twenty four weeks ] [ Designated as safety issue: No ]

• To investigate the safety and tolerability of ISA247
• To investigate the pharmacokinetics and pharmacodynamics of ISA247 after chronic dosing in a subset of subjects
• To evaluate the effect of ISA247 on subject quality of life

The purpose of this study is to determine which dose of voclosporin is effective in the treatment of plaque psoriasis compared to placebo.

Psoriasis is a chronic skin condition that can have a significant impact on patient's physical and mental well being. The most common form of psoriasis is plaque psoriasis. Targeted treatments in psoriasis have been reported recently, yet cyclosporine, a calcineurin inhibitor (CNi) remains one of the treatments which has the greatest efficacy. Voclosporin represents the possibility of a calcineurin inhibitor which is not only as efficacious as cyclosporine A, but also has an improved toxicity profile.

Comparison(s): Voclosporin at 3 dose levels (0.2, 0.3, and 0.4 mg/kg twice a day)compared to placebo.

• Drug: voclosporin
  voclosporin 0.2, 0.3, or 0.4 mg/kg po BID
• Drug: Placebo
  Placebo

• Placebo Comparator: 1
  Intervention: Drug: Placebo
• Active Comparator: 2
  Intervention: Drug: voclosporin
• Active Comparator: 3
  Intervention: Drug: voclosporin
• Active Comparator: 4
  Intervention: Drug: voclosporin

• Gregory CR, Kyles AE, Bernsteen L, Wagner GS, Tarantal AF, Christe KL, Brignolo L, Spinner A, Griffey SM, Paniagua RT, Hubble RW, Borie DC, Morris RE. Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model. Transplantation. 2004 Sep 15;78(5):681-5.
• Stalder M, Bîrsan T, Hubble RW, Paniagua RT, Morris RE. In vivo evaluation of the novel calcineurin inhibitor ISATX247 in non-human primates. J Heart Lung Transplant. 2003 Dec;22(12):1343-52.
• Abel MD, Aspeslet LJ, Freitag DG, Naicker S, Trepanier DJ, Kneteman NM, Foster RT, Yatscoff RW. ISATX247: a novel calcineurin inhibitor. J Heart Lung Transplant. 2001 Feb;20(2):161.
• Papp K, Bissonnette R, Rosoph L, Wasel N, Lynde CW, Searles G, Shear NH, Huizinga RB, Maksymowych WP. Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double-blind, placebo-controlled phase III study. Lancet. 2008 Apr 19;371(9621):1337-42. doi: 10.1016/S0140-6736(08)60593-0.

Inclusion Criteria:

• Plaque psoriasis ≥ 6 months prior to screening.
• Diagnosis of stable, plaque psoriasis; i.e. psoriasis must not be spontaneously improving or worsening in the 4 weeks prior to the screening visit.
• Plaque psoriasis involving ≥10% of the body surface area (BSA) at screening and prior to randomization at the day 0 visit.
• PASI score ≥10 at screening and prior to randomization at the day 0 visit.
• Not pregnant or nursing or planning to become pregnant during the course of the study.
• Sexually active women of childbearing potential or less than 1 year post-menopausal and sexually active men who are not surgically sterile must use a reliable form of birth control during study treatment and for at least 3 months after the last dose of study drug. Surgically sterile females are not considered to be of childbearing potential. Reliable forms of birth control include oral or depot contraceptives, and double-barrier methods.
• Written informed consent prior to washout and screening procedures.
• Able to keep study appointments and cooperate with all study requirements, in the opinion of the investigator.

Exclusion Criteria:

• Has generalized erythrodermic, guttate, or pustular psoriasis.
• Have other dermatoses that would interfere with the evaluation of psoriasis, at the discretion of the investigator.
• A current malignancy or history of malignancy within 5 years or a history of lymphoma at any time. Subjects can be enrolled with a history of squamous or basal cell carcinoma that has been surgically excised or removed with curettage and electrodesiccation.
• Has current, uncontrolled bacterial, viral, or fungal infections that require intravenous antibiotics or antifungals or had had such infections within 60 days prior to screening.
• A history of streptococcal infection that required oral antibiotics within 30 days prior to screening.
• A known history of tuberculosis.
• Serologic evidence or known latent human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C (HCV) virus.
• Uncontrolled hypertension as defined by systolic blood pressure ≥150 mm Hg or diastolic blood pressure ≥ 90 mm Hg.
• MDRD GFR ≤ 60 ml/min.
• Variation between the screening and Visit 1 GFR ≥30%.
• Alanine transaminase, aspartate transaminase, or gamma-glutamyl transferase ≥ 3x upper limit of normal (ULN).
• White blood cell count ≤ 2.8 x 109/L.
• Triglycerides ≥ 3x ULN.
• Requires the following prohibited medications or treatments during the washout or treatment period: drugs potentiating the nephrotoxicity of voclosporin such as NSAID's or ACE inhibitors, drugs interfering with its pharmacokinetics; drugs considered to contribute to psoriasis flare; or, systemic and topical psoriasis medication (including psoralen/ultraviolet A light treatment) that may interfere with assessment of study drug efficacy.
• Has used any investigational drug or device within 28 days or 5 half lives (whichever is longer) prior to the screening visit.
• Has taken biological agent(s), except flu shots, tetanus shots, or boosters, within 3 months of the start of treatment. Biological agents include any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man.
• Previous exposure to voclosporin.
• A history of clinically defined allergy to cyclosporine or any of the constituents of the voclosporin formulation (vitamin E, medium chain triglyceride oil, Tween 40, ethanol).
• A history of alcoholism or drug addiction within 1 year prior to study entry.
• Weighs <45 kg (99 lbs) or > 140 kg (308 lbs).
• A history of disease, including mental/emotional disorder that would interfere with the subject's participation in the study, or that might cause the administration of ISA247 to pose a significant risk to the subject, in the opinion of the investigator.