CHARLOTTE, N.C., March 2, 2009 -- Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) announced that results from its Phase II trial of Droxidopa, a synthetic precursor of norepinephrine, demonstrated a dose dependent, statistically significant benefit across multiple, clinically relevant assessment criteria for intradialytic hypotension (IDH).
"While there have been significant advancements in dialysis technology and clinical practice in the last several years, intradialytic hypotension remains a very common adverse event that can cause not only significant patient discomfort but can often lead to the disruption or discontinuation of dialysis sessions thereby decreasing the treatment efficacy and increasing the patient's morbidity and therapeutic costs," commented Dr. Rekha Halligan, M.D., Ph.D., Kidney & Hypertension Institute, Bayview Nephrology, Inc., and principle investigator for the study. "This study provides clear evidence that the prophylactic use of Droxidopa not only safely improved blood pressure but, more significantly, dramatically decreased the number of treatment interventions resulting from intradialytic hypotension."
The double-blind, randomized, placebo controlled Phase II trial was an exploratory study designed to evaluate the safety and efficacy of four weeks of therapy with either 400mg or 600mg oral Droxidopa in patients who experience a symptomatic decrease in systolic blood pressure of greater than or equal to 20 mmHg during hemodialysis. Following a two-week run-in period to establish a baseline for all measurements, patients in this 3-arm study received a single oral dose of Droxidopa or placebo 1 hour prior to each dialysis treatment over a four-week period. The study recruited 85 patients at 15 sites, including 10 DaVita dialysis centers, in the United States.
In order to determine useful clinical endpoints for a Phase III program, the trial evaluated the efficacy of Droxidopa using multiple clinically relevant measures, including: the change from baseline in average mean arterial blood pressure during dialysis; the change from baseline in average mean nadir (lowest) blood pressure (BP) during dialysis; the number of treatment interventions, including early termination, required during dialysis sessions; and the change from baseline in mean postdialytic BP during the final two weeks of the study period.
Significant Decrease in Severity of Blood Pressure Drops During Dialysis:
While the study did not achieve an improvement in mean arterial blood pressure during dialysis, Droxidopa demonstrated a significant benefit in limiting the severity of the drop (nadir) in blood pressure during treatment. Patients receiving 600mg of Droxidopa showed a mean improvement in arterial blood pressure, as recorded every 20 minutes during dialysis, of 1.95 mmHg versus an improvement of 1.60 mmHg for placebo and a mean decline of 0.12 mmHg for patients receiving 400mg of Droxidopa. Droxidopa demonstrated a statistically significant benefit in limiting the severity of the drop (nadir) in blood pressure experienced by patients suffering from IDH, as measured by the comparison of the mean change from baseline in average drop from pre-dialysis systolic blood pressure to lowest systolic blood pressure during dialysis relative to placebo. Patients receiving 600mg of Droxidopa demonstrated an average improvement from baseline relative to placebo of 8.25 mmHg (p=0.031) in mean nadir systolic BP during dialysis compared to an average improvement of 10.80 mmHg (p=0.004) reported by patients receiving 400mg.
Statistically Significant Reduction in Required Termination of Dialysis Sessions:
Likely related to the decrease in the severity of BP drops demonstrated by both doses of Droxidopa, the most significant and clinically important finding from the study related to the reduction of the incidence and severity of treatment interventions demonstrated by patients on Droxidopa. Treatment interventions resulting from IDH include inversion of the patient, flushing of saline, changes in ultrafiltration rate and, in the most severe cases, stopping of the dialysis session. Both doses of Droxidopa showed an improvement in the overall number of patients requiring treatment interventions during dialysis including early termination of dialysis sessions. Of the 23 patients on placebo, 7 (30.4%) required the termination of at least one of their dialysis sessions as a result of symptoms associated with IDH, unchanged from baseline incidence of dialysis termination. This compares to 3 (10%) of the 30 patients receiving 400mg of Droxidopa for whom dialysis sessions were stopped, a 50% decrease in terminations from their baseline run-in period. Only 1 (3.1%) of the 31 patients receiving 600mg of Droxidopa had dialysis sessions interrupted as a result of IDH, an 87.5% decrease from baseline. This finding was highly statistically significant at P=0.008 and, as with most outcome parameters, showed a clear dose-response.
Significant Improvement in Recovery of Systolic Blood Pressure Post-Dialysis:
In addition to dramatic drops during treatment, the clinical manifestation of IDH includes a patient's decreased postdialytic BP. Continued hypotension following dialysis results in significant immobility, prolonged recovery times, and increased on-site patient monitoring periods. To evaluate the efficacy of Droxidopa in improving blood pressure immediately following dialysis, the study compared the mean change from pre-dialysis BP to BP five minutes post-dialysis. Both Droxidopa treatment groups, 400mg (7.80 mmHg; P=0.025) and 600mg (9.16 mmHg; P=0.022) demonstrated a significant mean improvement in postdialytic BP relative to placebo. In terms of percentages, patients receiving 400mg of Droxidopa demonstrated a mean improvement in BP drop of 43.1% relative to placebo, where 600mg demonstrated a mean improvement of 45.2%.
Safe and Well Tolerated:
The data also showed that Droxidopa was extremely well tolerated by patients with the most common treatment related side effect reported being headache (3%). No treatment related serious adverse events or treatment related withdrawals were reported, however, one patient receiving placebo died as a result of coronary artery disease.
"I am pleased to report that Droxidopa demonstrated unequivocal benefit and indication of dose response in multiple measures of intradialytic hypotension, particularly in alleviating the serious adverse events and complications, such as dialysis disruption," commented Dr. Simon Pedder, Chelsea's President and Chief Executive Officer. "There is a significant unmet market need for a safe and effective treatment for hypotension associated with dialysis and we believe Droxidopa will prove to be a meaningful treatment option for these patients. Given the robust effect demonstrated in this trial, we are confident that, following consultation with the FDA, we can demonstrate a statistically significant benefit in a Phase III program enabling us to file for the first marketing approval of a therapeutic agent for intradialytic hypotension in the US."
Droxidopa is Chelsea's most advanced investigational product and is currently in development for the treatment of neurogenic orthostatic hypotension (NOH) as its lead indication. Chelsea plans to file for its first marketing approval for Droxidopa in NOH following the completion of its ongoing pivotal Phase III program.
About Droxidopa and Intradialytic Hypotension (IDH)
Intradialytic hypotension, or IDH, is the most common adverse event during routine hemodialysis. IDH is often defined as a decrease in systolic blood pressure by 20 mm Hg or a decrease in mean arterial pressure by 10 mmHg. IDH has been reported in approximately 20% of all hemodialysis patients, with elderly patients reporting higher incidences. Many adverse hemodialysis events, including headaches, lightheadedness, nausea, cramps, and seizures, are associated with IDH. These complications can routinely interrupt dialysis sessions, resulting in insufficient uremia toxin removal and necessitating repetition of the procedure. Interruptions due to IDH increase the costs of both the dialysis treatment sessions and the long-term care of less healthy hemodialysis patients.
Pivotal clinical studies conducted by Dainippon Sumitomo Pharmaceuticals (DSP) have demonstrated the efficacy of Droxidopa in the treatment of vertigo, dizziness and weakness associated with hypotension in hemodialysis patients. Subsequently, in 2000, after showing benefit in clinical trials, DSP received expanded marketing approval in Japan for this indication.
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 reliance on collaborations and licenses, risks and costs of drug development, regulatory approvals, intellectual property risks, our reliance on our lead drug candidate CH-1504, our history of losses and need to raise more money, competition, market acceptance for our products if any are approved for marketing, reliance on key personnel including specifically Dr. Pedder, management of rapid growth, and the need to acquire or develop additional products.
CONTACT: Chelsea Therapeutics Nick Riehle, Chief Financial Officer 704-973-4201 Kathryn McNeil, Investor/Media Relations 718-788-2856