Chelsea Therapeutics International, Ltd. announced confirmation by the US Food and Drug Administration (FDA) that its proposed phase II protocol for CH-4051 in rheumatoid arthritis has been approved by the agency. Chelsea plans to initiate patient screening next month and initiating treatment in October.

This multi-national, double-blind, randomized phase II trial of CH-4051, an orally available metabolically stable antifolate, is intended to evaluate the safety and efficacy of CH-4051 in a 250-patient head-to-head study against methotrexate (MTX). Patients with rheumatoid arthritis who are experiencing an inadequate response to MTX treatment will be randomized to receive daily oral doses of 0.3 mg, 1.0 mg, 3.0 mg or 3.0 mg plus folate of CH-4051 or 20 mg weekly dose of MTX plus folate supplement for 12 weeks following a two-week MTX-washout. The primary efficacy analysis will be conducted using the hybrid American College of Rheumatology, or ACR, score (hACR), which allows for a more comprehensive assessment of treatment benefit across all seven symptomatic and functional components of the standard ACR 20/50/70 evaluations historically used in RA trials.

"Although MTX is considered the standard of care in RA, both as a monotherapy and in combination with other RA treatments, the dosing and maximal therapeutic benefit of MTX is limited by well-documented tolerability issues, long-term safety concerns and variable bioavailability," commented Dr. Simon Pedder, president and CEO of Chelsea Therapeutics. "Given that CH-4051 is metabolically stable and that all of our preclinical and clinical work suggests enhanced absorption, dramatically increased potency and improved tolerability over MTX, we believe CH-4051 will be safe and highly efficacious in a historically treatment-resistant patient population."

The trial is being conducted with a staggered start wherein the first patients will be randomized to receive either 0.3 mg or 1.0 mg of CH-4051 daily or 20 mg MTX weekly in combination with a folate supplement. After 10 patients in both the 0.3 mg and 1.0 mg CH-4051 cohorts complete treatment and assuming no safety concerns are observed, the study will begin randomizing patients into all five study cohorts to receive either 0.3 mg, 1.0 mg or 3.0 mg of CH-4051 daily, 3.0 mg of CH-4051 daily in combination with a folate supplement or 20 mg MTX weekly with a folate supplement.

Chelsea intends to conduct an un-blinded interim efficacy analysis after approximately 50 per cent of patients in the two lower CH-4051 dose groups complete treatment and expect to report results from this analysis in the third quarter of 2011. Full study results, inclusive of all dose groups, are expected in mid-2012.

As previously reported, results from Chelsea's Phase I single and multiple ascending dose studies demonstrated that CH-4051 was well tolerated at doses up to and including 7.5mg, a dose range likely to be effective for multiple autoimmune disorders. The 5mg dose was as well tolerated as placebo. No serious adverse events occurred during the study and pharmacokinetic data indicated dose proportionate increases in plasma levels of CH-4051. Furthermore, it was revealed that plasma concentrations in the study were comparable to those seen in animal pharmacology studies in which CH-4051 demonstrated superior suppression of RA than both the maximally tolerated dose of methotrexate and equivalent doses of CH-1504.

CH-4051 is the L-isomer of CH-1504 and second drug candidate from Chelsea's portfolio of orally bioavailable, non-metabolized antifolates. Both are orally available molecules with anti-inflammatory, autoimmune and anti-tumor properties that potently inhibit dihydrofolate reductase, an enzyme required for cell proliferation. Preclinical and clinical data to date suggests superior safety and tolerability, as well as increased potency versus MTX, currently the leading antifolate treatment and standard of care for a broad range of abnormal cell proliferation diseases. Diseases that may potentially be treated with these compounds include rheumatoid arthritis, psoriasis, Crohn's disease, ankylosing spondylitis, uveitus, psoriatic arthritis and several different kinds of cancer.

Chelsea Therapeutics is a biopharmaceutical development company that acquires and develops innovative products for the treatment of a variety of human diseases.