Zilucoplan reduces blood cell destruction in untreated PNH

The experimental therapy no longer under development for this indication

Marisa Wexler MS avatar

by Marisa Wexler MS |

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Treatment with the experimental medication zilucoplan reduced blood cell destruction in previously untreated people with paroxysmal nocturnal hemoglobinuria (PNH) in Phase 2 clinical trials.

However, PNH patients who switched to zilucoplan from an approved PNH therapy experienced more blood cell destruction, results showed.

That’s according to findings detailed in the study, “Phase II trials of zilucoplan in paroxysmal nocturnal hemoglobinuria,” published in HaematologicaThe work was funded by UCB Pharma.

UCB was developing zilucoplan to treat PNH, but the company has stopped development of the therapy in this indication.

PNH is characterized by red blood cell destruction, known as hemolysis, due to overactivation of a part of the immune system called the complement cascade. Zilucoplan is an experimental treatment that works to block complement activation by inhibiting a protein called C5.

The approved PNH treatments Soliris (eculizumab) and Ultomiris (ravulizumab), both sold by Alexion, also work by targeting the C5 protein, but whereas these approved treatments are administered via an intravenous (into-the-vein) infusion, zilucoplan is designed to be given via a subcutaneous (under the skin) injection that can be performed at home.

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Two Phase 2 clinical trials tested zilucoplan

Zilucoplan was tested in people with PNH in two Phase 2 clinical trials (NCT03078582 and NCT03030183). In both studies, patients were given daily treatment with zilucoplan for 12 weeks, with the main goal of evaluating whether the therapy could reduce levels of the hemolysis marker lactate dehydrogenase (LDH).

Patients who completed either study had the option to continue receiving zilucoplan treatment in a long-term extension study (NCT03225287).

In this study, researchers reported data from 29 patients who participated in these studies. Ten patients started on zilucoplan as a first complement-targeting treatment for PNH, while the other 19 were switched to zilucoplan after failing to adequately respond to treatment with Soliris.

Findings showed that, for the 10 patients starting zilucoplan as a first treatment, the therapy led to a dramatic reduction in LDH levels. After about two weeks of treatment, average levels of this hemolysis marker were at about 1.6 times the upper limit of normal, and remained steady for the rest of the study.

Five of these patients had received at least one blood transfusion in the six months before entering the study; while on zilucoplan, two of these individuals had no need for additional transfusions.

These findings in previously untreated patients were overall “similar to those previously reported with [Solirlis]” as an initial treatment, the scientists said.

Among the 19 patients who switched from Soliris to zilucoplan, average LDH levels increased somewhat during the trials. This increase was particularly pronounced among patients who required blood transfusions.

Laboratory experiments suggested that this finding may be explained by PNH-specific changes in the molecular biology of blood cells that occur when both zilucoplan and Soliris are in the bloodstream simultaneously (which happens during the switch from one to the other), leading to atypical complement activation that cannot be stopped by blocking C5.

“We expand upon the findings of other research groups to provide a rationale for increased hemolysis in patients who switched from” Soliris to zilucoplan, the researchers wrote.

Zilucoplan was generally well tolerated in these studies; no serious side effects related to the treatment were reported. Common side effects included headache, hemolysis, dizziness, fatigue, and bruising at the injection site.