Soliris Reduced Measures Of Thrombosis, Inflammation In PNH Patients

Ruzanna Harutyunyan's picture
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Soliris (eculizumab), a terminal complement inhibitor developed by Alexion Pharmaceuticals, Inc. (Nasdaq: ALXN), was observed by investigators to reduce blood measures associated with undiagnosed blood clots and inflammation in patients with PNH.

A separate study found that Soliris was observed to reduce indicators of pulmonary artery hypertension (PAH) in patients with paroxysmal nocturnal hemoglobinuria (PNH), according to a new analysis of clinical trial data. Both sets of data were presented in oral sessions yesterday at the 50th Annual Meeting of the American Society of Hematology.

"The common, severe and progressive clinical consequences of PNH are becoming more apparent as researchers gain more experience and basic knowledge with regard to this disease," said Leonard Bell, M.D., Chief Executive Officer of Alexion.

Blood Markers of Thrombin Generation and Inflammation

Research titled "Eculizumab Therapy Results in Rapid and Sustained Decreases in Markers of Thrombin Generation and Inflammation in Patients with PNH" was presented yesterday in an oral session at the ASH annual meeting by Ilene Ceil Weitz, M.D., Assistant Clinical Professor of Medicine, Jane Anne Nohl Division of Hematology, Keck School of Medicine of the University of Southern California.

Recently published research showed that patients with PNH were observed to have 92 percent fewer blood clots (thromboses) during treatment with Soliris compared to the period of time prior to Soliris treatment. To better understand the mechanism for this observed reduction, researchers used highly sensitive laboratory tests to track levels of blood markers in order to determine the effect of Soliris on markers of thrombin generation and inflammation among eight patients with PNH, only one of which had been previously diagnosed with a blood clot.

Results showed that prior to treatment with Soliris, patients with PNH exhibited a hypercoagulable state as indicated by elevated levels of key inflammatory and pro-thrombotic measures. Soliris treatment was associated with statistically significant decreases in key blood measures, including LDH levels (p=0.0001), D-dimers (p=0.0057), thrombin-antithrombin complex or TAT (0.01), interleukin 6 or Il-6 (p=0.04), and tissue factor microparticles or TFMP (0.02) during the four-week induction phase of treatment. All decreases in D-dimers, TAT, Il-6, TFMP, and LDH were sustained in the maintenance phase of treatment.

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The authors concluded that the study patients, most of whom did not have clinical evidence of thrombosis and were also not previously transfused, exhibited a hypercoagulable state. In these patients, Soliris treatment was observed to result in a decrease in measures of thrombin generation and inflammation. These changes appeared to be independent of the observed reduction in hemolysis.

"This data deepens our understanding of the complex interactions in the blood that result in dangerous inflammation and blood clots in patients with PNH," said Dr. Weitz. "It also suggests that many patients with PNH, even without a clinical thrombosis, exhibit a high risk for blood clotting, and provides hope for patients and physicians, since thrombosis is the leading cause of premature death in PNH and the most feared complication of the disease."

Pulmonary Hypertension

Research titled "Eculizumab Reduces Pulmonary Hypertension through Inhibition of Hemolysis-Associated Nitric Oxide Consumption in Patients with Paroxysmal Nocturnal Hemoglobinuria" was presented in an oral session yesterday at the ASH annual meeting by Anita Hill, M.D., of the Department of Haematology, Bradford Royal Infirmary, Bradford, United Kingdom.

Using data from the Phase III TRIUMPH study of Soliris, Dr. Hill and her colleagues evaluated the efficacy of Soliris in the regulation of cell-free plasma hemoglobin levels, nitric oxide depletion and subsequent cardiovascular morbidities in patients with PNH. This analysis found that 47 percent of patients with PNH (34 of 73) suffered from pulmonary hypertension before starting the trial. In this study, PAH was measured by an elevated blood level of NT-proBNP, which has been shown to be highly predictive of PAH and an independent predictor of mortality in other hemolytic diseases. At the start of the study, levels of hemolysis and nitric oxide consumption were shown to be much greater in PNH (more than 6- and 10-fold, respectively) than in patients with other hemolytic diseases.

Patients treated with Soliris experienced a 50 percent reduction in the incidence of PAH over the course of the 26-week treatment period, from 52.5 percent to 26.3 percent, while PAH did not change with placebo (39.4% to 43.8%) (P<0.001). Additionally, Soliris-treated PNH patients experienced significantly improved shortness of breath compared to placebo, as measured by the EORTC QLQ-C30 quality of life survey (P<0.001).

"A careful analysis of blood levels in PNH patients shows that hemolysis, the red blood cell destruction that defines the disease, consumes nitric oxide in the blood which is likely to result in an increase in cardiovascular complications as shown in other hemolytic diseases," said Dr. Hill. "This study confirms that PAH is common in hemolytic PNH patients and also suggests that the anti-hemolytic effect of Soliris treatment significantly increases nitric oxide and consequently reduces pulmonary hypertension in patients with PNH."

Pulmonary artery hypertension is a rare, progressive disorder characterized by high blood pressure (hypertension) of the pulmonary arteries, the blood vessels that carry blood from the heart to the lungs. Symptoms of pulmonary hypertension can be severe and include shortness of breath (dyspnea), chest pain, fatigue, and fainting episodes.

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