Treatment of Plaque-Type Psoriasis With Oral CF101: Data from a Phase II/III Multicenter, Randomized, Controlled Trial

August 2016 | Volume 15 | Issue 8 | Original Article | 931 | Copyright © August 2016

Michael David MD,a Dimitar Konstantinov Gospodinov MD,b Nicola Gheorghe MD,c Grisha Stefanov Mateev MD,d Mariyana Venelinova Rusinova MD,e Evgeniya Hristakieva MD,f Laura Gheuca Solovastru MD,g Rita.V. Patel MD,h Calin Giurcaneanu MD,i Mariela Chepileva Hitova MD,j Anca Ioana Purcaru MD,j Beti Horia MD,k Iliya Iliev Tsingov MD,l Rumyana Kaloferova Yankova MD,m Miroslava Ilieva Kadurina MD,n Michal Ramon MD,o Maria Rotaru MD,p Olga Simionescu MD,q Vasile Benea MD,r Zdravka Velichkova Demerdjieva MD,s Maria Rodica Cosgarea MD,t Horia Silviu Morariu MD,u Ziv Michael MD,v Patricia Cristodor MD,w Carmen Nica MD,x Michael H. Silverman MD,y David R. Bristol PhD,y Zivit Harpaz MSc,y Motti Farbstein BSc,y Shira Cohen MSc,y and Pnina Fishman PhDy

aRabin Medical Center, Beilinson, Petach-Tikva, Israel;
bUMHAT D-r Georgi Stranski EAD, Pleven, Bulgaria;
cSpitalul Clinic Judetean de Urgenta “Sf. Apostol Andrei” Constantal. Constanta, Romania;
dDCC “Fokus-5”-MIOC, EOOD, Sofia, Bulgaria;
eCentrul Medical de Diagnostic si Tratament Ambulator Neomed SRL Brasov, Brasov, Romania;
fSpitalul Clinic Judetean de Urgenta Sibiu, Sibiu, Romania;
gUMHAT Stara Zagora EAD, Zagora,Bulgaria;
hCenter for Skin and Venereal Diseases Ltd, Sofia, Bulgaria;
iMHAT Doverie AD Department of Gastroenterology Sofia, Bulgaria;
jCentrul Medical de Diagnostic, Brasov, Romania;
kMount Sinai School of Medicine, New York, NY;
lDCC “Sveti Georgi” EOOD-Plovdiv, Plovdiv, Bulgaria;
mCentrul Medical SANA SRL, Bucuresti, Romania;
nMHAT Varna at MMA Sofia, Varna, Bulgaria;
oRambam Medical Center, Haifa, Israel;
pSpitalul Clinic Municipal de Urgenta Timisoara, Timisoara, Romania;
qCentrul Medical Unirea SRL, Bucuresti, Romania;
rSpitalul Clinic Dr. Victor Babes, Bucuresti, Romania;
sMHAT Tokuda Hospital Sofia, Sofia, Bulgaria;
tSpitalul Clinic Dr. Victor Babes, Bucuresti, Romania;
uSpitalul Clinic Judetean Mures, Jud. Mures, Romania;
vHa'emek Medical Center, Afula, Israel;
wSpitalul Clinic Judetean Mures, Jud. Mures, Romania;
xCentrul Medical Unirea SRL, Bucuresti, Romania;
yCan-Fite BioPharma Ltd., Kiryat-Matalon, Petach-Tikva, Israel

Abstract
BACKGROUND: CF101, an adenosine A3 receptor agonist, is an orally bioavailable small molecule drug presenting an anti-psoriatic effect demonstrated in a Phase 2 clinical trial in psoriasis patients.
OBJECTIVE: To evaluate the safety and efficacy of CF101 treatment in a Phase 2/3 study in patients with moderate to severe plaque-type psoriasis.
METHODS: This multicenter, double-blind, 2-segment, placebo-controlled study randomized subjects with moderate to severe plaque psoriasis to CF101 1 or 2 mg, or placebo twice daily. At either week 12 (Segment 1) or 16 (Segment 2), the placebo group crossed over to CF101 BID through week 32 in an open-label fashion. At week 12, following an interim analysis, the CF101 1mg group was discontinued due to futility. The primary endpoint was proportion of patients achieving ≥75% improvement in Psoriasis Area Severity Index (PASI 75). Efficacy testing was performed using the Cochran-Mantel Haenszel test, the primary analysis of PASI 75 was performed at the 0.035 significance level.
RESULTS: CF101 had an excellent safety profile at all tested dosages with a profile similar to the placebo group. The most common adverse events were infections and gastrointestinal events, and there was no cumulative intolerance over the 32-week dosing period. The study did not meet the primary endpoint of PASI 75 at week 12 (2 mg: 8.5% vs. placebo: 6.9%, P=0.621). However, at week 32, PASI mean percent improvement with CF101 2 mg was 57% (P<0.001) compared to baseline, with linear improvement in PASI 50 (63.5%), 75 (35.5%), 90 (24.7%), and 100 (10.6%).
CONCLUSIONS: Oral CF101 was found to be safe and very well tolerated, demonstrating evidence of efficacy in patients with moderate to severe plaque psoriasis through 32 weeks of treatment.

J Drugs Dermatol. 2016;15(8):931-938.

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