CHARLOTTE, N.C., April 27, 2009 (GLOBE NEWSWIRE) -- Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) announced positive findings from its Phase I trial of CH-4051, the L-isomer of CH-1504 and second drug candidate from its portfolio of orally bioavailable, non-metabolized antifolates. Data from this single and multiple ascending dose study demonstrated that CH-4051 is safe and well tolerated up to a maximally tolerated dose of 7.5mg.
This randomized, double-blind, placebo-controlled study was conducted at Kendle International's Clinical Pharmacology Unit in the Netherlands. The primary objective of the study was to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses of CH-4051 in healthy male volunteers and to determine the maximally tolerated dose (MTD).
The single ascending dose (SAD) phase of the study evaluated 5mg, 10mg, 20mg and 40mg doses of CH-4051. Each group contained 6 volunteers randomized 5:1 to receive either CH-4051 or placebo. In this escalating dose study, each cohort of subjects received a higher dose of the drug than the preceding cohort.
Based on the findings from the SAD study, Chelsea selected 5mg, 7.5mg, 10mg and 20mg of CH-4051 for evaluation in a multiple ascending dose (MAD) study with the objective of exploring a wide range of doses, including and exceeding those believed to be therapeutically relevant. In the MAD study, 32 subjects in 4 cohorts of 8 volunteers were randomized 6:2 to receive repeat daily oral doses of CH-4051 or placebo for 14 consecutive days.
Results 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. High doses of CH-4051 demonstrated mostly mild toxicities, with the 10mg and 20mg doses groups reporting both gastrointestinal side-effects and reversible liver enzyme elevations. No serious adverse events occurred during the study. The dose range determined to be safe and well tolerated in this study is substantially higher than the 0.25mg to 1.0mg dose range of CH-1504 that demonstrated comparable efficacy and improved safety and tolerability to methotrexate in a recent Phase II rheumatoid arthritis trial.
Pharmacokinetic data obtained in this study indicated dose proportionate increases in plasma levels of CH-4051. Furthermore, it was revealed that plasma concentrations in this study are 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.
Consistent with preclinical findings to date, a comparison of data from this study and the results of prior Phase I evaluations of CH-1504 suggests that CH-4051 has improved absorption with an approximately two-fold improvement in bioavailability compared to CH-1504, yet is better tolerated on the basis of both its dose to side-effect profile and plasma concentration to side-effect profile.
"The findings from this Phase I trial continue to validate the strength of Chelsea's antifolate portfolio," commented Dr. Simon Pedder, Chelsea's President and Chief Executive Officer. "Having recently demonstrated proof-of-concept with our first antifolate, CH-1504, in rheumatoid arthritis, we are particularly pleased to see the results from this trial further support the potential of CH-4051 to be an equally well tolerated drug candidate at doses up to 7.5mg. These findings position CH-4051 to be evaluated for superior efficacy to methotrexate - clearly positioning CH-4051 as a promising first-line therapy in rheumatoid arthritis and other autoimmune diseases."
About Chelsea Therapeutics
Chelsea Therapeutics is a biopharmaceutical development company that acquires and develops innovative products for the treatment of a variety of human diseases. Chelsea's most advanced drug candidate, Droxidopa, is an orally active synthetic precursor of norepinephrine initially being developed for the treatment of neurogenic orthostatic hypotension. Currently approved and marketed in Japan for the treatment of symptomatic orthostatic hypotension, freezing gait in Parkinson's disease and intradialytic hypotension, Droxidopa has accumulated over 15 years of proven safety and efficacy, historically generating annual revenues of approximately $50 million in Japan. In addition to Droxidopa, Chelsea is also developing a portfolio of metabolically inert oral antifolate molecules engineered to have potent anti-inflammatory and anti-tumor activity to treat a range of immunological disorders, including two clinical stage product candidates: CH-1504 and CH-4051. Preclinical and clinical data suggests superior safety and tolerability, as well as increased potency versus methotrexate (MTX), currently the leading antifolate treatment and standard of care for a broad range of abnormal cell proliferation diseases including RA.
This press release contains forward-looking statements regarding future events. These statements are just predictions and are subject to risks and uncertainties that could cause the actual events or results to differ materially. These risks and uncertainties include our need to raise operating capital, our history of losses, risks and costs of drug development, risk of regulatory approvals, our reliance on our lead drug candidates droxidopa and CH-1504, reliance on collaborations and licenses, intellectual property risks, competition, market acceptance for our products if any are approved for marketing, reliance on key personnel including specifically Dr. Pedder.