Chelsea Therapeutics International Ltd. has initiated patient dosing in the first of two pivotal Phase III studies of Droxidopa, for use in treating sudden drops in blood pressure, a nervous system disorder known as neurogenic orthostatic hypotension (NOH).

Both Phase III studies are expected to be completed by year-end 2008, allowing for a new drug application to be filed with the FDA early in 2009, the Charlotte, N.C.-based company said.

If approved, oral daily Droxidopa would compete with midodrine, the only U.S.-approved drug for symptomatic orthostatic hypotension. U.S. sales of midodrine were about $60 million in 2005, said Nick Riehle, chief financial officer of Chelsea.

The company expects Droxidopa to be better tolerated than midodrine, sold by Shire Inc., of Basingstoke, UK, under the brand name ProAmatine. The approved product carries a tough "black box" warning for supine hypertension (high blood pressure lying down, low blood pressure standing up).

According to Chelsea, nearly 300,000 patients suffer from chronic symptomatic NOH in the U.S. and EU combined.

Droxidopa works by increasing the supply of norepinephrine, a neurotransmitter that sends signals to the blood vessels and the heart to improve orthostatic blood pressure and alleviate symptoms such as dizziness.

Chelsea has not yet determined if it will need additional financing to see Droxidopa through Phase III testing and the regulatory process, Riehle said, noting that the company has the ability to call warrants totaling $12 million. In addition, he said, the company could out-license its antifolate compounds. However, he said the firm is not precluding financing for its future investments.

The first Phase III trial to begin dosing Droxidopa, called Study 302, is a placebo-controlled trial designed to measure improved symptoms in NOH patients over a two-week period.

The primary endpoint in the randomized study will be the relative symptomatic change, as measured on a scale designed to rate symptoms (dizziness or lightheadedness) stemming from low blood pressure.

The study length is about five weeks, including up to two weeks for dose titration. Patients not responding to treatment during the titration period will be excluded from the trial.

Both Phase III studies will seek to evaluate 118 patients each, according to Chelsea. The company said it expects to activate about 35 study sites in North American and 15 in Europe, with enrollment expected to increase as more sites are brought online in the coming weeks.

Droxidopa, developed by and licensed from Japan's Dainippon Sumitomo Pharma Co., received initial approval in Japan in 1989 for use in patients with orthostatic hypotension, syncope, Parkinson's disease and other conditions. In 2000, Droxidopa's use was expanded in that country to prevent vertigo, dizziness and weakness associated with orthostatic hypotension in hemodialysis patients.

In addition to the Droxidopa Phase III trials, Chelsea recently initiated a Phase II trial comparing the efficacy and tolerability of its CH-1504 to methotrexate in rheumatoid arthritis. CH-1504 is a nonmetabolized antifolate designed to avoid the kidney and liver toxicities associated with methotrexate.

The double-blind, 200-patient trial will compare CH-1504 dosed daily at 0.25 mg, 0.5 mg and 1 mg to weekly 20-mg doses of methotrexate, with a primary endpoint of an American College of Rheumatology 20 response after 12 weeks.

CH-1504 also is in Phase II trials for psoriasis and inflammatory bowel disease.