Cytochroma Inc (MARKHAM, Ontario, Canada), an integrated specialty pharmaceutical company engaged in the development and commercialization of proprietary products related to vitamin D deficiency and novel vitamin D therapies to treat hyperproliferative disorders such as psoriasis and cancer, has initiated the recruitment of patients with chronic plaque psoriasis for a phase II
clinical trial with CTA018 cream. CTA018 is a novel vitamin D analog with a dual mechanism of action designed to be both a strong activator of the vitamin D signaling pathway and a potent inhibitor of CYP24 activity, the key cytochrome P450 enzyme responsible for the catabolism of calcitriol, the biologically active form of vitamin D. Inhibition of CYP24 promotes stability of endogenous, intracellular calcitriol and reduces potential resistance to treatment. CTA018 binds to the vitamin D receptor less potently (10-fold less) than calcitriol. However, in preclinical studies comparing the relative induction of the overall activation of vitamin D signaling, CTA018 is 25-times and 41-times more potent, respectively, than the current vitamin D analogue market leaders calcipotriol (Dovonex®) and calcitriol (Silkis®) at their marketed concentrations for the treatment of psoriasis.

The phase II study is a multicenter, randomized, double-blind, parallel-group comparative study in subjects with mild-to-moderate chronic plaque psoriasis. The anticipated enrollment for the trial is 140 subjects at 14 clinical sites in the US. Subjects will be placed into one of four separate dosing groups comprised of three different concentrations of CTA018 and corresponding cream base (vehicle control). All subjects will receive once daily topical treatment over a maximum of 15% body surface area for 12 consecutive weeks. The primary efficacy endpoint of the trial will be the Physician Static Global Assessment. Local and systemic safety and patient perception of CTA018 cream will be evaluated in addition to several secondary endpoints. The principal investigator of the trial is Dr. Mark Lebwohl, professor and chairman, department of dermatology, Mount Sinai Medical Center, New York.

CTA018 was previously studied in two phase I clinical trials and demonstrated to be both well tolerated and efficacious in the treatment of patients with psoriasis. A phase Ia study, involving 17 healthy subjects with mild-to-moderate plaque psoriasis, was designed to characterize the local efficacy and safety of three concentrations of CTA018. The phase Ia study was a randomized, double-blind, within-subject comparison of three doses of CTA018 (3, 10, and 20μg/g), a vehicle control, and an active control (0.1% betamethasone). Each subject received all five creams applied topically to the skin using a microplaque assay every 24 hours for 13 consecutive days with a 7-day, post-treatment follow-up. No adverse events were considered to have a probable relationship to treatment. All three doses were efficacious in reducing the severity of psoriasis and, moreover, showed significant residual efficacy 1 week after the treatment compared to placebo.

The phase Ib study, involving 28 subjects with plaque psoriasis, was designed to characterize the local and systemic safety of CTA018. The phase Ib study was a multicenter, four-arm, randomized, open-label, parallel-group comparison study of three doses of CTA018 (1, 3, and 10 μg/g) and a vehicle control. Subjects had CTA018 or vehicle cream applied topically to psoriatic plaques on 5% of body surface area every 24 hours for 13 consecutive days with a 7-day. post-treatment follow-up. Pharmacokinetics of CTA018 over 48 hours, postdosing, was studied in the high-dose group, which did not produce detectable systemic levels of CTA018. There were no severe or serious adverse events reported. All three doses were deemed safe and not likely to produce local or systemic adverse effects.

CTA018 was designed by Gary H. Posner, PhD, Scowe Professor of Chemistry at Johns Hopkins University, and is protected under patents and patent applications relating to noncalcemic, antiproliferative and transcriptionally-active vitamin D analogs exclusively licensed to Cytochroma Inc from Johns Hopkins University.

—A. Techman

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