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Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterised by hemolytic anemia, thrombosis and red urine due to breakdown of red blood cells. PNH is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane. more...

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Signs and symptoms

Quite paradoxically, the destruction of red blood cells (hemolysis) is neither paroxysmal or nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). On-going hemolysis is a more common characteristic.

A common finding in PNH is the presence of breakdown products of RBCs (hemoglobin and hemosiderin) in the urine.

An inconsistent, but potentially life-threatening, complication of PNH is the development of clot in the veins (venous thrombosis). These clots (thrombi) are often found in the hepatic (causing Budd-Chiari syndrome), portal (causing portal vein thrombosis), and cerebral veins (causing cerebral venous thrombosis).

Many patients with bone marrow failure (aplastic anemia) develop PNH (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH.


A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called Ham's acid hemolysis test, is performed if the sugar test is positive for hemolysis.

Modern methods include flow cytometry for CD55, CD16 and CD59 on white and red blood cells. Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells.


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Alexion Pharmaceuticals Reports Three-Year Cumulative Clinical Data of Eculizumab Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria
From PR Newswire, 12/12/05

- Sustained Improvements in Hemolysis, Red Blood Cell Survival and Transfusions Observed in Pilot Extension Study -

- Results Presented at American Society of Hematology Meeting -

CHESHIRE, Conn., Dec. 12 /PRNewswire-FirstCall/ -- Patients with paroxysmal nocturnal hemoglobinuria (PNH) given eculizumab, a novel terminal complement inhibitor, have shown sustained and significant reductions in red blood cell destruction and in the need for blood transfusions, according to preliminary three-year cumulative results of an open-label extension study presented by investigators from Leeds Teaching Hospital, St. George's Hospital and Alexion Pharmaceuticals, Inc. at the 47th Annual American Society of Hematology Meeting and Exposition in Atlanta, Saturday December 10th. The 10 patient open-label extension program of an initial pilot trial is being conducted in the United Kingdom at two sites. All patients have now completed at least three years of chronic eculizumab therapy. In addition to reductions in hemolysis and the need for transfusions, the results also showed a sustained and stable increase in PNH red blood cell counts. PNH is a rare form of anemia for which there is no currently specific treatment.

Eculizumab is a monoclonal antibody drug that blocks the terminal complement pathway of the immune system. Terminal complement has been linked to the destruction of red blood cells, or hemolysis, characteristic of PNH, as PNH blood cells are deficient in natural inhibitors of the complement cascade.

"As patients have now commenced their fourth year of treatment with eculizumab, we continue to be encouraged by the durable improvements in hemolysis and transfusion requirements obtained in this ongoing clinical trial," said Peter Hillmen, M.B. Ch.B., Ph.D., Consultant Haematologist of The General Infirmary at Leeds, Leeds, UK, and lead investigator of the continuing study.

Following the initial 12-week pilot trial (reported in the February 5, 2004 issue of the New England Journal of Medicine), all 11 patients chose to participate in two consecutive one-year extension studies, the first of which has been recently published (October 1, 2005 issue of the journal Blood). Ten of the original 11 patients enrolled into a third one-year extension study and continue on eculizumab. The preliminary analysis showed that the substantial reduction in intravascular hemolysis demonstrated in the pilot study was maintained throughout all extension phases as levels of lactate dehydrogenase decreased from a mean of 3233 +/- 648 during the 12 months before treatment to 656 +/- 37 following treatment for at least 36 months (p=0.004). This reduction in hemolysis coincided with a sustained and stable increase in the absolute number of PNH red blood cells from 1.37 x 10(12)/liter to 2.37 x 10(12)/liter at maximum response. The increase in PNH red blood cells was associated with a decrease in the mean and median transfusion rates from 2.1 and 1.8 units/patient/month during the 12 month period prior to eculizumab therapy to 0.3 and 0.3 units/patient/month (p=0.002), respectively, through the at least 36 month treatment period. Seven of the 10 patients treated with eculizumab alone, or in combination with erythropoeitin in aplastic patients, became transfusion independent for at least the last 17 months of the study. Preliminary analysis shows that eculizumab continues to be well tolerated in these patients. The most common adverse events are headaches, upper respiratory tract infection and nausea. The adverse event profile for eculizumab-treated patients in this study is similar to that of placebo- treated patients in other patient population trials of eculizumab.

Eculizumab, an investigational drug therapy, has been granted Orphan Drug Status in the PNH indication from both the U.S. and European regulatory agencies to treat PNH. If approved for PNH, eculizumab would represent the first drug from a new class of anti-inflammatory therapeutics -- terminal complement inhibitors -- as well as the first drug available specifically for patients suffering from PNH. Estimates suggest that approximately 2,000 - 10,000 people in the U.S., and a similar number in Europe, suffer from this disease.

"We are encouraged that the ongoing extension of the pilot trial with eculizumab has continued to show sustained improvements in hemolysis and transfusions and that eculizumab continues to be well tolerated after more than three years of treatment," noted Leonard Bell, M.D., Chief Executive Officer of Alexion. "In anticipation of pivotal PNH trial data early next year, we are keenly focused on progressing our internal efforts to compile our regulatory applications for eculizumab in PNH and to advance our commercialization preparations both in the U.S. and Europe."

Alexion previously reached an agreement with the FDA on the design of TRIUMPH, a pivotal Phase III efficacy trial with eculizumab in PNH patients, and the companion Phase III trial called SHEPHERD, under the FDA's Special Protocol Assessment (SPA) process. It is expected that, if successful, the combined trials will comprise the application that will serve as the primary basis of review for the approval of a Biologics License Application (BLA) for eculizumab in the PNH indication.

TRIUMPH is a double-blind, randomized, placebo-controlled multi-center Phase III pivotal trial examining the effects of eculizumab on the co-primary endpoints of hemoglobin stabilization and blood transfusion in hemolytic, transfusion-dependent PNH patients during six months of therapy. The final treatment under TRIUMPH is anticipated to occur near the end of 2005, with top line results expected during the first quarter of 2006.

SHEPHERD is an open-label, non-placebo-controlled, multi-center clinical trial primarily aimed at generating additional safety data with eculizumab in a broader population of hemolytic PNH patients with a history of transfusions. The primary objective of SHEPHERD is safety, and efficacy measures will also be obtained. The SHEPHERD protocol includes 12 months of treatment with a six month interim analysis.

PNH is a blood disorder characterized by the onset of severe anemia, chronic fatigue and intermittent episodes of dark colored urine, known as hemoglobinuria. PNH patients are also at increased risk of forming life-threatening blood clots, or thromboses, which are a leading cause of death in this disease. People with PNH have an acquired deficiency of proteins that normally protect red blood cells from a component of the body's natural defense system, known as the complement cascade. Lack of these complement inhibitor proteins leaves PNH red blood cells susceptible to destruction (hemolysis), which is manifest as a reduction in blood hemoglobin, causing patients to become anemic. In some cases, these patients are dependent on blood transfusions. Currently, physicians prescribe either steroids or other immunosuppressive drug therapies to help patients cope with the symptoms of anemia, as no drugs are currently approved to specifically treat PNH.

Alexion is engaged in the discovery and development of therapeutic products aimed at treating patients with a wide array of severe disease states, including hematologic and cardiovascular disorders, autoimmune diseases and cancer. Alexion's two lead product candidates, pexelizumab and eculizumab, are currently undergoing evaluation in several clinical development programs, including two Phase III trials of eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Under the Special Protocol Assessment (SPA) process, the FDA has agreed to the design of protocols for the two trials of eculizumab in PNH patients that could, if successful, serve as the primary basis of review for approval of a licensing application for eculizumab in the PNH indication. Eculizumab has also been studied in rheumatoid arthritis and membranous nephritis. The Company's Phase III trial of pexelizumab in coronary artery bypass graft (CABG) surgery patients undergoing cardiopulmonary bypass (CPB) failed to achieve its primary endpoint, and the Company is assessing the impact of the of this study, known as PRIMO-CABG2, on its ongoing Phase III trial of pexelizumab in acute myocardial infarction (AMI) patients. The pexelizumab trials are conducted in collaboration with Procter and Gamble Pharmaceuticals. Under the SPA process, the FDA has agreed to the design of protocols for the Phase III pexelizumab trials that could, if successful, serve as the primary basis of review for approval of licensing applications for the two indications. Preliminary results from the PRIMO-CABG2 trial of pexelizumab indicate that the trial is unlikely to support filing for licensing approval of pexelizumab in the CABG indication. Alexion is engaged in discovering and developing a pipeline of additional antibody therapeutics targeting severe unmet medical needs, through its wholly owned subsidiary, Alexion Antibody Technologies, Inc. This press release and further information about Alexion Pharmaceuticals, Inc. can be found at: http:/

This news release contains forward-looking statements, including statements related to timing of announcement of clinical trial results and the progression of Alexion's drug candidates towards commercial sales. Forward- looking statements are subject to factors that may cause Alexion's results and plans to differ from those expected, including the results of pre-clinical or clinical studies (including termination or delay in clinical programs), the need for additional research and testing, decision of the FDA not to approve (or to materially limit) marketing of one or both of Alexion's two drug candidates, delays in arranging satisfactory manufacturing capability, inability to acquire funding on timely and satisfactory terms, delays in developing or adverse changes in commercial relationships, the possibility that results of earlier clinical trials are not predictive of safety and efficacy results in later clinical trials, dependence on Procter & Gamble Pharmaceuticals for development and commercialization of pexelizumab, the risk that third parties won't agree to license any necessary intellectual property to us on reasonable terms, and a variety of other risks set forth from time to time in Alexion's filings with the Securities and Exchange Commission, including but not limited to the risks discussed in Alexion's Annual Report on Form 10-K for the year ended July 31, 2005 and in our other filings with the Securities and Exchange Commission. P&GP retains the development rights and the termination rights discussed in Alexion's Form 10-K referred to above. Alexion does not intend to update any of these forward- looking statements to reflect events or circumstances after the date hereof, except when a duty arises under law.

CONTACT: Leonard Bell, M.D., Chief Executive Officer, Alexion Pharmaceuticals, Inc., +1-203-272-2596; Patricia Garrison (Scientific Media), +1-917-322-2567, or Rhonda Chiger (Investors), +1-917-322-2569, both of Rx Communications; Robert Stanislaro (Business and Financial Media), Noonan/Russo, +1-212-845-4268

Web site: http:/

COPYRIGHT 2005 PR Newswire Association LLC
COPYRIGHT 2005 Gale Group

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