* Study Successfully Demonstrated Comparable Efficacy of Multiple Doses of CH-1504 to Methotrexate * All Doses of CH-1504 Showed Almost Two-Fold or Greater Reduction in Liver Enzyme Elevations * Improved Tolerability with Fewer GI Related Adverse Events and No GI Related Dropouts Reported for CH-1504
CHARLOTTE, N.C., March 18, 2009 (GLOBE NEWSWIRE) -- Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) announced that a preliminary analysis from its recently completed 12-week Phase II clinical trial in rheumatoid arthritis (RA) demonstrated that patients treated with once daily oral doses of CH-1504 at 0.25mg, 0.50mg and 1.0mg showed comparable ACR20/50/70 response rates to patients treated with a standard 20mg oral dose of methotrexate (MTX) administered once weekly. In addition, the efficacy of CH-1504 was associated with improved tolerability and reduced hepatotoxicty compared to the MTX.
"That CH-1504, even across this low dose range, can achieve comparable ACR response rates to a standard dose of methotrexate, validates the scientific rational that the known metabolites of methotrexate are not required for efficacy," commented Dr. Edward Keystone, M.D., FRCP(C), Professor of Medicine, Rheumatology Division at The University of Toronto, Canada, and principle investigator for the study. "Further, that all doses of CH-1504 show a clinically relevant decrease in ALT elevations compared to methotrexate is in keeping with the principle that methotrexate metabolites likely contribute to the liver toxicities and tolerability issues associated with methotrexate treatment and is suggestive of the potential for a non-metabolized antifolate, such as CH-1504, to provide a better, safer treatment option for RA patients."
Efficacy Results
MTX CH-1504
--------- -------------------------------
20mg 0.25mg 0.50mg 1.00mg
weekly daily daily daily
Number (N) 52 48 48 53
ACR 20 %(N) 38.5%(20) 43.8%(21) 39.6%(19) 34.0%(18)
ACR 50 %(N) 13.5%(7) 8.3%(4) 10.4%(5) 5.7%(3)
ACR 70 %(N) 5.8%(3) 2.1%(1) 4.2%(2) 0.0%(0)
Avg Decrease for
all patients in:
Swollen Joints % 47.0% 38.5% 51.2% 52.7%
Tender Joints % 34.8% 26.5% 33.4% 35.2%
Patients showing>20%
improvement in:
Swollen Joints %(N) 73.1%(38) 70.8%(34) 83.3%(40) 79.2%(42)
Tender Joints %(N) 65.4%(34) 58.3%(28) 62.5%(30) 71.7%(38)
Safety Results
As expected, CH-1504 proved to be safe and well tolerated at all dose levels. Most significantly while adverse events were generally mild in all arms of the study, liver enzyme elevations, as measured by serum ALT, were measurably lower at all doses of CH-1504 compared to the MTX arm.
The most common clinically meaningful adverse events noted in the clinical trial were abnormal liver function tests and gastrointestinal (GI) side effects. Additionally, the only withdrawal for treatment related adverse gastrointestinal effect was from the MTX arm and was the result of severe nausea and vomiting.
MTX CH-1504
--------- -------------------------------
20mg 0.25mg 0.50mg 1.00mg
weekly daily daily daily
n=52 n=48 n=48 n=53
Dropouts (N) 7 5 4 9
Related Adverse
Event (N) 1 0 1 1
Other (N) 6 5 3 8
ALT >1xULN %(N) 13.5%(7) 4.2%(2) 6.3%(3) 7.5%(4)
Gastrointestinal %(N) 5.8%(3) 2.1%(1) 2.1%(1) 3.8%(2)
(diarrhea, gastritis,
nausea, dyspepsia)
"These important clinical trial results represent a significant milestone for Chelsea, as the data demonstrates CH-1504 has clinically meaningful activity on par with methotrexate," commented Dr. Simon Pedder, President and CEO of Chelsea. "I am particularly pleased to see CH-1504 is a differentiated product with a unique profile and improved patient tolerability after only 12-weeks of treatment. These findings, coupled with the broad level of activity across multiple efficacy measures, has significant implication across the breadth of our antifolate pipeline. We are highly encouraged by these findings and look forward to further developing this platform and maximizing the potential for an efficacious and well tolerated treatment alternative to methotrexate."
Study Design
A total of 201 MTX naive patients with moderate to severe RA were enrolled in this multi-national, double blind Phase II trial and randomized on a 3:1 basis to receive either CH-1504 (0.25mg, 0.50mg or 1.00mg once daily oral doses) or MTX (20.00mg once weekly oral dose). The trial included a 12-week treatment period and 4-week follow-up. As is standard clinical practice for MTX patients in the U.S., all patients in both MTX and CH-1504 arms of the study were given a 10mg folate supplement once weekly on the day after the blinded dose of MTX. Folic acid reduces the incidence of liver-function-test abnormalities and gastrointestinal intolerance often associated with methotrexate use.
The primary efficacy endpoint of this study was to determine the percent of patients with ACR 20 response at the end of 12 weeks. An ACR 20 response is a standard efficacy measure that requires at least a 20% improvement in American College of Rheumatology (ACR) criteria. To be considered an ACR 20 responder, patients must demonstrate at least a 20% improvement in tender and swollen joint counts and show a comparable improvement in three of the following five parameters: physician global assessment of disease, patient global assessment of disease, patient assessment of pain (VAS), C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire (HAQ) score.
Conference Call Today at 8:30 AM ET
Chelsea will discuss the CH-1504 Phase II clinical trial results and antifolate program today, March 18, 2009, at 8:30 AM Eastern Time. Interested investors may participate in the conference call by dialing 877-723-9518 (domestic) or 719-325-4744 (international). A replay will be available for one week following the call by dialing 888-203-1112 for domestic participants or 719-457-0820 for international participants and entering passcode 9654175 when prompted. Participants may also access both the live and archived webcast of the conference call on Chelsea's web site at www.chelseatherapeutics.com.
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.