INTRODUCTION
Psoriasis is a chronic inflammatory, systemic immune-mediated disease of that affects the skin and joints and is associated with multiple comorbidities1. The effect on quality of life is severe with patients reporting social discomfort, embarrassment, reduced mental functioning, and physical pain.2,3
Despite the beneficial effect of the current agents approved for moderate to severe psoriasis, many patients discontinue treatment with biologics or traditional systemic medications because of loss or lack of efficacy, monitoring and safety issues, and lack of tolerance.4
The Gi protein-associated A3 adenosine receptor (A3AR) has been found to be overexpressed in inflammatory cells, whereas low expression of the receptor is found in normal cells.5,6 The high receptor expression is also reflected in the peripheral blood mononuclear cells of psoriasis patients.7,8
CF101 is an orally bioavailable A3AR agonist inducing anti-inflammatory effect via de-regulation of the Wnt and the nuclear factor kappa-B (NF-κB) signal transduction pathways, leading to the inhibition of tumor necrosis factor-α (TNF-α), interleukin-6 and IL-12, macrophage inflammatory proteins, and receptor activator of NF-κB ligand (RANKL).9,10 CF101’s anti-inflammatory effect has been demonstrated in Phase 2 studies in patients with rheumatoid arthritis and with psoriasis, showing efficacy and an excellent safety profile.11,12 In an earlier Phase 2 placebo controlled study in patients with moderate-to-severe plaque psoriasis, CF101 at a dose of 2 mg BID demonstrated a statistically significant improvement compared to control as evidenced a 35.3% rate of PASI ≥50 response and a 23.5% rate of achieving a PGA score of 0 or 1 at week 12. CF101 was safe and well tolerated at doses as high as 4 mg BID for 12 weeks.11
In the current Phase 2/3 study, CF101 treatment of patients with moderate-to-severe plaque psoriasis has been further investigated, with the demonstration of favorable safety and efficacy through 32 weeks of treatment.
PATIENTS AND METHODS
Patients
Male and female subjects, aged 18-80, diagnosed with moderate-to-severe plaque psoriasis for at least 6 months’ duration with Physician’s Global Assessment (PGA) ≥3, Psoriasis Area Severity Index (PASI) score ≥10, body surface area involvement ≥10%, who were candidates for systemic treatment or phototherapy, were enrolled into the study.
Main exclusion criteria were: other clinical forms of psoriasis, treatment with systemic retinoids, corticosteroids, or immuno-suppressants within 6 weeks of the baseline visit; treatment with moderate-high potency topical corticosteroids (Class I–III), treatment with phototherapy or Dead Sea climato-therapy within 4 weeks of the baseline visit; treatment with a biological agent within a period of time equal to five times its circulating half-life or 30 days, whichever is longer, prior to the baseline visit; pregnancy; and severe infections or other conditions that would confound the study evaluations or endanger patient safety. The conduct of this trial was approved by all local Ethics Committees in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patients before inclusion in the study (NCT00428974).
Study Design
This was a Phase 2/3, multicenter, randomized, double-blind, placebo-controlled study performed in 2 segments. In Segment 1, eligible subjects were randomly assigned to parallel dosing groups of orally administered CF101 1 mg, CF101 2 mg, or matching placebo tablets twice daily (BID) in a 1:1:1 ratio for a 12-week blinded placebo-controlled period (BPCP). At week 12, following the completion of Segment 1, an interim analysis was performed including data from 103 subjects (33 subjects in the CF101 1 mg BID dose group, 33 in the CF101 2 mg BID dose group, and 37 in the BID placebo group). Based on efficacy results of the interim analysis, the CF101 1 mg dose group was eliminated for futility. Therefore, only 2 treatment groups remained in the study.
Under the subsequent protocol amendment, which implemented Segment 2 of the trial, an additional 223 patients were enrolled and assigned in 1:1 ratio to placebo or CF101 2 mg taken orally BID for 16 weeks in a BPCP. At the end of 16 weeks, an open label extension (OLE) period started; subjects assigned to CF101 2 mg were continued on CF101 2 mg, while subjects originally assigned to placebo were reassigned to CF101 2 mg BID.
Disease severity during both segments was assessed using PASI and static PGA scores.
Subjects returned for safety and efficacy assessments and for new supply of study medication at weeks 4, 8, 12, 16, 20, 24, and 28, and for final study assessments at week 32.
Efficacy and Safety
The primary efficacy endpoint during Segment 2 of the trial was the proportion of subjects achieving PASI 75 at week 12, and the secondary efficacy endpoints were the proportion of subjects achieving PASI 75 at week 16 and the proportions of subjects achieving PGA of 0 or 1 at weeks 12 and 16. Efficacy for the OLE period was determined by the change in the proportion of subjects who achieved PASI 75 over time within each group.
Safety assessments for both segments, including BPCP and OLE, included treatment-emergent adverse events (TEAEs) and