Acute hemolysis in PNH managed with intensive Empaveli dosing

Treatment regimen found to be safe and well tolerated; no new side effects ID'd

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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An intensive dosing regimen of Empaveli (pegcetacoplan) effectively managed events of acute red blood cell destruction, called hemolysis, in people with paroxysmal nocturnal hemoglobinuria (PNH), according to an ongoing clinical study’s interim data.

Also, the intensive regimen was found to be safe and well tolerated in these patients, with no new side effects identified compared with previous studies.

“The management of acute [breakthrough hemolysis] events in patients with PNH on complement inhibitors is an evolving field. With continued and expanded use of proximal [C3] inhibitors, management will become more optimal and patients at higher risk of acute [breakthrough hemolysis] events easier to identify,” the researchers wrote in “Management of acute breakthrough hemolysis with intensive pegcetacoplan dosing in patients with PNH,” which was published in Blood Advances.

In PNH, blood cells, particularly oxygen-carrying red blood cells, are destroyed due to the over-activation of the complement cascade, a part of the immune system that helps fight off infections.

Empaveli is a complement inhibitor that targets C3, a complement protein. By preventing complement activation, Empaveli can prevent hemolysis and ease PNH symptoms. It’s approved in the U.S. for adults with PNH, including those who’d never been treated for the disease and those switching from other approved therapies. The therapy is also approved in Europe, where it’s sold as Aspaveli, for adults with PNH who remain anemic after having received treatment with the C5 inhibitors Soliris (eculizumab) or Ultomiris (ravulizumab).

“While clinicians had more than 20 years of experience in managing [breakthrough hemolysis] on C5 inhibitors, there is currently very limited guidance on the management of hemolysis on proximal [C3] complement inhibitors,” the researchers wrote. Breakthrough hemolysis events refer to episodes wherein patients have symptoms associated with red blood cell destruction while they’re receiving treatment for PNH.

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Intensive Empaveli dosing regimen

Here, researchers analyzed interim data from a subset of adults with PNH participating in an ongoing open-label extension study (NCT03531255) and received an intensive dosing regimen of Empaveli after an acute hemolysis event. Hemolysis events were defined as episodes wherein lactate dehydrogenase (LDH; a marker of hemolysis) levels were two times above the upper normal limit, accompanied by at least one new or worsening hemolysis symptom, such as low hemoglobin, the oxygen-carrying protein in red blood levels.

Thirteen patients, who accounted for 9% of the total number who entered the open-label extension, received intensive Empaveli dosing as of March 2022 and were included in the analysis. The patients were between the ages of 20 to 72, and most were men. At the time they entered the study, all were receiving 1,080 mg of Empaveli twice weekly.

Immediately before the event that triggered intensive dosing, eight patients were still on the twice-weekly regimen, while four were receiving treatment every three days, and one three times a week. For these patients, a median time of 77 weeks (about 1.5 years) had passed since they’d entered the study and had the acute hemolysis event that qualified them for intensive dosing, which consisted of a single, 1,080 mg dose into the vein (four patients) or a 1,080 mg dose injected under the skin on three consecutive days (nine patients).

LDH levels decreased in all 13 patients between days seven to 12 after intensive dosing. For eight of them, that decrease occurred within the first two days.

After the initial drop in hemoglobin caused by the hemolytic event, its levels improved in all the patients, regardless of whether they received red blood cell transfusions, which were required in about a third of them.

The new data support the effective management of acute hemolytic events in patients on Empaveli with intensive dosing, with all acute events considered resolved, according to the researchers. Also, intensive treatment was found to be generally safe and well tolerated, with no new side effects identified compared with those reported in previous Empaveli studies. A total of 22 side effects, mostly mild and not related to treatment, occurred in about half the patients.

“Further investigation is required to complement the clinical data presented … to better understand the optimization of [Empaveli] treatment in individual patients and to allow identification of biomarkers indicative of [breakthrough hemolysis] risk to prevent their occurrence,” the researchers wrote.