Completing a special protocol assessment process with the FDA, Alexion Pharmaceuticals Inc. plans to begin a Phase III program of eculizumab for the chronic orphan blood disorder known as paroxysmal nocturnal hemoglobinuria (PNH).

The Cheshire, Conn.-based company expects to enroll 75 patients in each of two trials: a pivotal study called TRIUMPH and a companion safety trial called SHEPHERD.

Last month, Alexion announced a similar agreement with the FDA to move into Phase III trials its heart drug, pexelizumab.

"For one biotechnology company to have three SPAs for three indications in just the past few months, we think it is without precedent," said Leonard Bell, the company's CEO. "It's a very important accomplishment."

Alexion's stock (NASDAQ:ALXN) rose 74 cents on Tuesday to close at $16.80.

The company announced the start of a Phase III program in June for pexelizumab in patients undergoing coronary artery bypass graft (CABG) surgery and for patients experiencing acute myocardial infarction (AMI) treated with primary percutaneous intervention. Both trials received FDA clearance under the SPA program. Pexelizumab is partnered with Procter & Gamble Pharmaceuticals Inc., an affiliate of Cincinnati-based Procter & Gamble Co. Alexion expects to seek approval of pexelizumab in CABG in the second half of 2005 and in AMI patients within the next two to three years. (See BioWorld Today, June 15, 2004.)

Alexion, on Tuesday, said it initiated enrollment in pexilizumab's trial for CABG. The trial will enroll 4,000 patients in North America and Europe over the next year to 15 months.

Having designed its pivotal trials using the FDA's SPA process, Alexion has "a written agreement with the FDA on a primary endpoint, as well as key aspects of the protocol design," Bell told BioWorld Today.

Eculizumab's TRIUMPH pivotal trial will include sites in the U.S., Canada, Europe, Australia and New Zealand. It will examine the effects of the drug on the co-primary endpoints of hemoglobin stabilization and blood transfusion in hemolytic transfusion-dependent PNH patients during six months of therapy. The double-blind, randomized, placebo-controlled study will begin within a few months.

It soon will be followed by the SHEPHERD safety trial in hemolytic PNH patients with a history of transfusion. That trial, an open-label, non-randomized, non-placebo-controlled study, also will enroll patients in the same five countries.

With both trials starting sometime in the second half of the year, Alexion expects to report results in 2005. A biologics license application could come in late 2005 or early 2006, Bell said.

"We expect to commercialize eculizumab in PNH in North America and Europe on our own," he said.

In a previous study of eculizumab in PNH patients, those treated with eculizumab showed a substantial decrease in the destruction of red blood cells, as lactate dehydrogenase levels fell from a mean of 3,111 IU per liter to a mean of 594 IU per liter (p=0.002), and the mean percentage of PNH red blood cells increased from 36.7 percent to 59.2 percent (p=0.005). The study was conducted in the UK at two sites and included 11 patients treated for three months. Results helped reduce patient transfusion rates and episodes of hemoglobinuria. The drug also was shown to be safe and well tolerated. The results were published in a February issue of the New England Journal of Medicine.

Eculizumab is part of a new class of anti-inflammatory therapeutics called terminal complement inhibitors. Alexion has orphan drug status for eculizumab in the U.S. and Europe. The product also is in Phase II development in rheumatoid arthritis and membranous nephritis.

PNH is a blood disorder characterized by the onset of severe anemia, chronic fatigue and intermittent episodes of dark-colored urine. Half of the patients diagnosed die within 10 years. Patients are at an increased risk of forming life-threatening blood clots. They have an acquired deficiency of proteins that normally protect red blood cells from a component of the body's natural defense system.

Physicians currently prescribe either steroids or other immunosuppressive drug therapies to help patients deal with the symptoms of anemia.

"There's no drug in development or on the market for PNH," said Bell, who estimates the market size is between 2,000 and 10,000 patients in the U.S.

Since there are no other approved products for the disease, the market potential is unknown.

"We would expect that it would be similar to other orphan indications, where there's a small number of patients," Bell said.

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