Switching PNH treatment carries risk of severe hemolysis: Report
Complications ensue when treatment targets change, researchers say
The cases of three people with paroxysmal nocturnal hemoglobinuria (PNH) who experienced serious complications after switching from an experimental medicine to the approved PNH treatment Ultomiris (ravulizumab) highlight the potential for serious risks when switching from a PNH treatment targeting earlier steps of complement activation to one targeting later steps, researchers said.
Their study, “Massive hemolysis in paroxysmal nocturnal hemoglobinuria after switching from proximal complement inhibitor to anti-C5 therapy: A lesson not to be forgotten,” was published in the American Journal of Hematology.
PNH is characterized by hemolysis, the destruction of red blood cells, due to the activation of a group of immune proteins that make up the body’s complement system. Hemolysis in PNH can be divided into two types: intravascular hemolysis (IVH), which occurs inside blood vessels; and extravascular hemolysis (EVH), which occurs outside blood vessels in tissues.
Several treatments for PNH are available; all of them generally work to prevent complement activation. The first PNH treatments to win widespread approvals were Ultomiris and Soliris (eculizumab), both of which specifically target a complement protein called C5. These C5 inhibitors, which target later steps of complement activation, are generally effective at stopping IVH, but aren’t as good at blocking EVH.
More recently, a new generation of PNH treatments targeting earlier steps in the cascade of complement activation have been developed. These medications, known as proximal complement inhibitors, are typically better than C5 inhibitors at stopping EVH.
Patients switched when treatment discontinued
Here, researchers described the experiences of three people with PNH who had participated in a clinical trial (NCT04170023) of an experimental proximal complement inhibitor, vemircopan, which is no longer being developed following lackluster trial results. After vemircopan’s development stopped, the three patients switched to Ultomiris, which was one of the only approved PNH medicines available at the time. Patients received their first doses of Ultomiris a few weeks before taking their last dose of vemircopan.
While on vemircopan, all of the patients had fairly well-controlled hemolysis. But after switching to Ultomiris, all three patients experienced a sudden increase in hemolysis. In two of the individuals, this led to “very severe and symptomatic” anemia due to a sudden increase in EVH.
The researchers said the cases illustrate the potential for serious complications when switching from a proximal complement inhibitor to a terminal C5 inhibitor.
“We show for the first time, that rebound hemolysis following the discontinuation of effective treatment with proximal complement inhibitors is a major clinical risk that cannot be fully prevented by switching to anti-C5 therapy,” they wrote.
There aren’t any guidelines for how to manage these risks, so developing such guidelines will be critical for treating PNH, they said.
All three patients were eventually started on another proximal complement inhibitor, Fabhalta (iptacopan), which was given through a compassionate use program because it wasn’t approved at the time.
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