Trial of PNH therapy vemircopan halted after frequent hemolysis
Medication raised hemoglobin but caused recurring red blood cell loss
Vemircopan, a therapy that Alexion, AstraZeneca Rare Disease was developing for paroxysmal nocturnal hemoglobinuria (PNH), increased hemoglobin levels in a Phase 2 study, but frequent episodes of hemolysis — the destruction of red blood cells — were noted.
In a Phase 2 clinical trial (NCT04170023), most participants experienced intravascular hemolysis — red blood cell destruction inside blood vessels — “which led to the early termination of the trial,” researchers wrote in “Efficacy and Safety of Vemircopan as Monotherapy in Patients With Paroxysmal Nocturnal Hemoglobinuria,” which was published in Blood Advances.
In PNH, red blood cells become susceptible to hemolysis due to attack driven by the overactivation of the complement system, a group of proteins that normally function as part of the immune system to protect the body against infection. Hemolysis can occur in (intravascular) and outside (extravascular) blood vessels.
Complement inhibitors like Ultomiris (ravulizumab) and Soliris (eculizumab) help control hemolysis by blocking the action of C5, a protein in the complement system. However, not all patients respond well to these medications, and many continue to experience symptoms and require blood transfusions within the first months of treatment.
Therapy designed to target earlier step in complement pathway
Similar to Voydeya (danicopan) — which is approved as an add-on treatment for PNH — vemircopan is designed to block a complement protein called factor D, which acts at an earlier step in the complement system. This was expected to stop the cascade of reactions that lead to hemolysis while lasting longer in the blood compared with Voydeya, thereby easing symptoms of PNH.
The company-sponsored, open-label Phase 2 clinical trial included 29 adults diagnosed with PNH. Of these, 12 had never received treatment for PNH, 11 switched from Soliris, and six continued from earlier testing with then-experimental Voydeya. All took vemircopan tablets by mouth twice per day for 12 weeks, then entered a long-term extension.
The main goal was to track changes in hemoglobin — the protein in red blood cells that carries oxygen — over 12 weeks. Those who were new to treatment or who switched from Soliris — but not those who switched from Voydeya — showed clinically meaningful improvements. Their hemoglobin increased by a mean of more than 3.6 and 3.3 g/dL, respectively. These improvements were noted as early as week three and were maintained throughout the extension study.
However, 22 participants (75.9%) experienced a total of 58 episodes of breakthrough intravascular hemolysis during treatment with vemircopan (excluding a period of dose adjustment). This meant that even though their hemoglobin had reached higher circulating levels, they still experienced episodes of hemolysis inside blood vessels.
Intravascular hemolysis was the main reason participants required blood transfusions during the clinical trial. Eleven episodes were considered serious, and more than half were tied to very high levels of lactate dehydrogenase — a marker of hemolysis. Seven cases required hospitalization.
Overall, despite improvements, “vemircopan resulted in suboptimal and inconsistent terminal complement blockade and prevention of [intravascular hemolysis],” the researchers wrote. Two of the researchers had already reported that switching from vemircopan to Ultomiris could lead to sudden hemolysis.
Combining two complement inhibitors that act at different steps in the cascade could offer a safer and more reliable way to treat PNH. “Strategies to mitigate the critical risk of [breakthrough intravascular hemolysis] with dual inhibition with a terminal complement inhibitor may be warranted,” the researchers concluded.
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