This article is more than 5 years old. Information may no longer be current.

Eculizumab reduced hemolysis and transfusions in SHEPHERD

Issue: April 1, 2007

Add topic to email alerts

Receive an email when new articles are posted on

Please provide your email address to receive an email when new articles are posted on .

Subscribe

Added to email alerts

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

Back to Healio

We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com.

Back to Healio

Patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab in the open-label phase-3 SHEPHERD trial experienced markedly reduced intravascular hemolysis and improved anemia with placebo-like tolerability, according to data presented at the American Society of Hematology 48th Annual Meeting and Exposition in Orlando, Fla.

Eculizumab (Soliris, Alexion) is a humanized monoclonal antibody that inhibits terminal complement activation, said Neal S. Young, MD, a principal investigator in the hematology branch of the NIH.

That complement activation leads to chronic intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) and symptoms including anemia, fatigue, thrombosis (mostly venous, but also arterial), poor quality of life, difficulty in functioning, pain, hemoglobinuria and need for transfusions.

Data from an earlier phase-3 placebo-controlled trial (TRIUMPH [Transfusion Reduction Efficacy and Safety Clinical Investigation, a Randomized, Multicenter, Double-Blind, Placebo-Controlled, Using Eculizumab in Paroxysmal Nocturnal Hemoglobinuria]) in transfusion-dependent PNH demonstrated reductions in both intravascular hemolysis and transfusions. SHEPHERD (Safety in Hemolytic PNH Patients Treated with Eculizumab: A Multi-center Open-label Research Design Study) encompassed a broader PNH population, including those with significant cytopenia and lower transfusion requirements.

SHEPHERD consisted of 97 patients. They were assigned IV eculizumab (once a week for four weeks) at 600 mg, then 900 mg the fifth week followed by 900 mg biweekly for a total of 52 weeks of treatment.

Inclusion criteria

Inclusion criteria were a history of PNH of more than six months, one or more transfusions during the last two years, evidence of intravascular hemolysis (lactate dehydrogenase [LDH] >1.5 upper limits of normal), platelet counts 30,000 mm³ or more, and PNH red blood cell proportions 10% or more.

Median age was 41 and median duration of PNH was 4.9. The median requirement for packed red blood cells in the prior year was 8 units.

LDH AUC was significantly reduced, compared with pretreatment levels (median, –632,264 U/L per day; P<.001). Furthermore, LDH (normal range, 103 U/L to 223 U/L) was reduced from a median of 2,051 U/L at week 0 to 269 U/L at week 52.

Transfusion independence was observed by 51% of the patients for the entire one-year period (P<.001), and endogenous PNH red blood cell mass was significantly increased (44%; P<.001). Hemoglobin levels increased significantly as well.

Median units of packed red blood cells dropped from 8 per patient at baseline to 0 (P<.001) during the year of treatment with eculizumab. Among patients requiring more than 25 units of packed red blood cells at baseline, the median requirement was 7.5 units (P<.001).

In addition, fatigue score improvements were reported within a week, and were sustained for the entire study period. Overall global health assessment, patient functioning and disease-related symptoms were also significantly improved.

The most frequent adverse events were headache (52.6%), nasopharyngitis (32.0%), nausea (20.6%).

Russell Rother, PhD, senior vice president of research at Alexion Pharmaceuticals, said in an interview that following the first two doses of eculizumab, the incidence of headache was similar to that of placebo-treated patients in the TRIUMPH study.

“We know that headache is a real adverse event, but it is generally not severe and is easily treated,” Rother said. Only 2% of patients experienced adverse events considered to be definitely related to the study drug, and none were significantly higher than those reported in the TRIUMPH study placebo group. Also, no infections were considered to be definitely related to eculizumab treatment.

“Eculizumab was well tolerated and markedly reduced intravascular hemolysis leading to improvement in anemia,” Young said.

“Treatment options are extremely limited for PNH patients,” Rother said. “No drugs are approved and none have been shown to be effective in reducing hemolysis, the central manifestation of the disease. In our trials, every patient treated with eculizumab has had reduced hemolysis.”

According to Rother, the results from SHEPHERD show eculizumab to be effective and safe in a more typical PNH population, compared with that studied in the previous TRIUMPH study. – by Walter Alexander

For more information:

• Young NS, Antonioli E, Rotoli B, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in patients with paroxysmal nocturnal hemoglobinuria: interim SHEPHERD phase III clinical study. Poster #971. Presented at: American Society of Hematology 48th Annual Meeting and Exhibition; Dec. 9-12, 2006; Orlando, Fla.