Eculizumab Could Be Paroxysmal Nocturnal Hemoglobinuria Breakthrough

December 13, 2002

Jane Salodof MacNeil

Dec. 13, 2002 (Philadelphia) - Preliminary results from an ongoing open-label phase Ib clinical trial suggest an experimental drug called eculizumab could be the first to alleviate symptoms of paroxysmal nocturnal hemoglobinuria (PNH).

Data on the first 11 patients show that three months of eculizumab therapy reduced the need for blood transfusions by 68%. An 81% reduction in biochemical parameters of hemolysis was also reported, and duration of clinical paroxysms went down by 90% from 2.1 days per patient per month to 0.2.

"With leukemia trials you have to wait months and years to see if there's a benefit. You knew immediately with this drug," principal investigator Peter Hillmen, MB, ChB, PhD, told Medscape. "[The patients] came in the next week, and they were fine."

Dr. Hillmen, a clinical hematologist at The General Infirmary at Leeds in the U.K., presented the results here at the American Society of Hematology annual meeting.

The paper was chosen because eculizumab would be the first targeted therapy with relevance to PNH, according to Russell Ware, MD, PhD, of Duke University Medical Center, co-chair of the session on acquired disorders.

Dr. Ware called the work "very exciting" in an interview with Medscape, but cautioned, "There's still a lot of work to be done. They need to study dosing, side effects — both short and long term — and risks as well as benefits to patients."

An acquired genetic disorder, PNH occurs in roughly one in 200,000 people, according to Dr. Hillmen.

Patients with PNH are deficient in the PIG-A enzyme and consequently their cells cannot protect themselves from complements in the blood. As a result, red blood cells are prone to lysis, producing blood in the person's plasma and urine, which often becomes dark red.

Patients typically become anemic, suffer significant fatigue, and have a high risk of dying from thrombosis. They are usually treated with steroids such as prednisone, immunosupressive drugs, and blood transfusions.

Eculizumab is a long-acting C5 inhibitor that Alexion Pharmaceuticals Inc. of Cheshire, Connecticut, is also testing in rheumatoid arthritis. Inhibition of complements 5-9 is associated with slightly higher risk of meningococcal infection, according to Dr. Hillmen. Only one case has been observed among 500 patients who have taken the drug so far, he said, including the rheumatoid arthritis trials.

"That's pretty good, and yet a case of meningitis might not be trivial," Dr. Ware noted.

The PNH trial was conducted with Alexion support at two sites in the U.K. Patients received 600 mg of eculizumab each week for four weeks, after which the dose was switched to 900 mg every two weeks.

Ten patients have completed the 12-week treatment, and all chose to enter a 12-month extension trial. Another trial was at 10 weeks when the data was reported. All patients had at least four transfusions in the 12 months prior to the trial (average, 9 transfusions). The seven patients whose platelets levels were above 100 had the best response. Those with platelets levels below 100 did not improve as dramatically, Dr. Hillmen said, suggesting the drug is less effective in patients with bone marrow failure.

Quality-of-life measures showed improvement in physical functioning, global health status, fatigue, and dyspnea parameters. Dr. Hillmen said some patients in the study had been so debilitated by fatigue that they had not worked for as long as 30 years.

"He overtook me on the stairs last week," Dr. Hillmen said of one of the most debilitated patients prior to treatment. "It had that dramatic an effect,"

The investigators reported that the drug was well tolerated. Muscle and joint aches and pains, upper respiratory infection, and headache were the most frequent adverse events.

A spokesman for Alexion Pharmaceuticals told Medscape that the company plans to work with the U.S. Food and Drug Administration's orphan drug program to design what will probably be a phase II/III trial.

ASH 44th Annual Meeting: Abstract 154. Presented Dec. 9, 2002.

Reviewed by Gary D. Vogin, MD

Jane Salodof MacNeil is a freelance writer for Medscape.