Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare, acquired, life-threatening disease of the blood. The name comes from one of the clinical consequences of the disease -- the breakdown of red blood cells and consequent release of hemoglobin into the urine. It often results in dark-colored urine most prominently seen in the morning.
PNH is caused by deficiency in glycophosphatidylinositol-anchored biosynthesis, leaving red blood cells susceptible to destruction -- i.e., hemolysis -- by the body's complement system.
Though the condition is rare, its diagnosis is straightforward, mainly with flow cytometry, once it is suspected -- often in patients with symptoms of intravascular hemolysis with no known cause. The rarity can lengthen the time between symptom onset and final diagnosis, according to Charles Parker, MD, of the Division of Hematology and Hematologic Malignancies at the University of Utah School of Medicine in Salt Lake City. But, he added, that has become less of a concern because of increasing recognition of the disease, "particularly the awareness of PNH in association with bone marrow failure."
The course the disease takes can vary widely.
Besides complement-mediated intravascular hemolysis, PNH is marked by bone marrow failure and risk of blood clotting (thrombophilia). According to Parker, while chronic hemolysis is central to the symptoms and physical findings of PNH , mild hemolysis can include symptoms of fatigue, rapid heartbeat, headaches, chest pain and difficulty breathing when exercising. If severe, hemolysis can result in additional symptoms including disabling fatigue, dysphagia, painful abdominal contractions that affect the abdomen and esophagus, and erectile dysfunction and impotence in men.
Blood clots -- most commonly venous thrombosis -- occur in approximately 15%-30% of persons with PNH. In addition, all patients with PNH will have some degree of bone marrow dysfunction, Parker said.
"The only way to cure the disease is by bone marrow transplant," Parker told MedPage Today. "But the symptoms of the disease, particularly the hemolysis, can be treated with complement inhibitors, and because the inhibitors are quite effective, transplant is typically used for patients who don't respond adequately to complement inhibitor therapy. And these are mostly patients who have severe bone marrow failure, in addition to the hemolytic component of the disease."
Two complement inhibitors, eculizumab (Soliris) and ravulizumab (Ultomiris), are FDA-approved as treatments for PNH. They work by blocking the C5 component of complement.
These complement inhibitors are "quite effective at blocking intravascular hemolysis, which is the main symptomatic element of PNH," said Parker. "But the thrombotic component of the disease also seems to be ameliorated by the complement inhibitors, and the thrombosis has been the complication that causes the most morbidity and mortality in PNH."
Eculizumab was the first of the drugs to be approved for PNH. In a small study published in Blood, researchers found significantly worse survival in patients with PNH in the 7 years immediately before eculizumab relative to the period after, when mortality between patients on eculizumab and the normal population was equivalent. In addition, eculizumab appears to be protective against thrombosis, with a rate of 5.6 events per 100 patient-years before eculizumab, compared to 0.8 events per 100 patient-years while on eculizumab.
The second complement inhibitor, ravulizumab, was approved in 2018. Its approval was based on two trials. The phase III ALXN1210-PNH-301 study included patients with PNH who had never received treatment with complement inhibitors, while the ALXN1210-PNH-302 study study included patients who were clinically stable after having been treated with eculizumab for at least the past 6 months. Both showed that ravulizumab was noninferior to eculizumab.
The two medications have different characteristics though both are delivered intravenously. Ravulizumab is given at higher doses than eculizumab, which means infusions take longer. However, patients receiving ravulizumab can have their treatments further apart -- 4 to 8 weeks -- rather than typically 2 weeks for patients on maintenance therapy with eculizumab.
"These complement inhibitors don't treat the underlying disease itself," Parker pointed out. "But they do block the intravascular hemolysis, which is the main symptomatic element of PNH. So, they've been a real benefit to patients with PNH."
Other drugs are being investigated, with pegcetacoplan -- a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b -- the closest to approval.
While C5 inhibitors prevent intravascular hemolysis, many PNH patients on these drugs continue to experience a degree of anemia and need regular transfusions. According to an article in Frontiers in Immunology, different factors contribute to residual anemia during eculizumab treatment, including underlying bone marrow dysfunction, residual intravascular hemolysis, and the emergence of C3-mediated extravascular hemolysis. Thus, patients may remain anemic and in need of transfusion despite treatment with a C5 inhibitor.
The PEGASUS phase III trial is evaluating pegcetacoplan in adults with PNH, and, according to its investigators, the agent "has the potential to control both intravascular and extravascular hemolysis in PNH."
Results of the study, presented at the American Society of Hematology 2020 meeting now underway, showed that pegcetacoplan demonstrates "superiority to eculizumab in hemoglobin level, and improved clinical outcomes at week 16 with transfusion avoidance in most patients." The investigators, led by Peter Hillmen, MBChB, PhD, of the University of Leeds in England, further characterized pegcetacoplan's safety profile as comparable to that of eculizumab.
"The efficacy of pegcetacoplan validates the prevention of extravascular as well as intravascular hemolysis in PNH, leading to a potential new therapeutic option," Hillmen and his colleagues concluded.