Persistent hemolytic anemia presents a significant challenge for patients with paroxysmal nocturnal hemoglobinuria (PNH), particularly those who have undergone anti-C5 therapy or lack access to oral treatments targeting complement dysregulation. However, a recent study published in the New England Journal of Medicine has illuminated the promising effectiveness of iptacopan, an oral factor B inhibitor, in enhancing hematologic and clinical outcomes for individuals grappling with persistent anemia in the context of PNH.
Led by Latour and colleagues, the study conducted two phase 3 trials spanning 24 weeks, focusing on patients with hemoglobin levels below 10 g/dL. The first trial involved patients already receiving anti-C5 therapy, who were randomly assigned to either continue with their current treatment or switch to iptacopan. Meanwhile, the second trial focused on patients who had not previously received complement inhibitors but exhibited elevated lactate dehydrogenase (LDH) levels (>1.5 times the upper limit of normal). These patients received iptacopan monotherapy.
In the initial trial, 51 out of 60 patients who received iptacopan, demonstrated a rise in hemoglobin levels of at least 2 g per deciliter from their baseline, with 42 achieving a hemoglobin level of at least 12 g per deciliter, all without requiring transfusion. Conversely, none of the 35 patients treated with anti-C5 therapy reached these targeted levels. Similarly, in the subsequent trial, 31 out of 33 patients observed a minimum increase of 2 g per deciliter in hemoglobin levels from their baseline without the need for red-cell transfusion. In the first trial, 59 out of 62 iptacopan recipients and 14 out of 35 individuals undergoing anti-C5 therapy did not necessitate or undergo transfusion; likewise, in the second trial, no patients required or underwent transfusion. Iptacopan treatment not only elevated hemoglobin levels but also mitigated fatigue, reduced levels of reticulocytes and bilirubin, and maintained mean LDH levels below 1.5 times the upper normal limit. Despite this, headache emerged as the most commonly reported adverse event associated with iptacopan.
In addition to the quantitative enhancements in hemoglobin levels, iptacopan treatment brought about qualitative advantages. Patients reported decreased fatigue, indicating an enhancement in their overall well-being. Furthermore, markers such as reticulocyte and bilirubin levels, which serve as indicators of hematologic function, exhibited favorable alterations following iptacopan treatment.
The significance of these findings extends beyond the efficacy of iptacopan to its safety profile. The study highlighted that iptacopan monotherapy proved to be both effective and safe, eliminating the necessity for additional combined terminal blockade therapies. By targeting the complement system proximally at the alternative pathway, iptacopan presents a novel approach to addressing persistent anemia associated with complement dysregulation.
The researchers concluded that the study not only advances the knowledge regardiing the pathophysiology underlying anemia, but also opens the door to a potentially transformative therapeutic option for patients grappling with this challenging condition. As further research progresses, iptacopan holds the potential to become a cornerstone in the management of anemia, offering prospects for improved outcomes and enhanced quality of life for patients globally.
Reference
Peffault de Latour R, Röth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, et al. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. New England Journal of Medicine. 2024 Mar 14;390(11):994–1008.