Hemolysis Be Gone: Iptacopan’s Role in Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell (HSC) disorder characterized by complement-mediated hemolytic anemia, smooth muscle dystonia, thrombosis, bone marrow failure, and, in some cases, transformation to aplastic anemia or myelodysplastic syndromes.¹  PNH is caused by acquired mutations in the PIGA gene, which is responsible for biosynthesis of glycosylphosphatidylinositol-anchored proteins. PIGA mutations render PNH blood cells deficient of key complement inhibitory proteins on the cell surface, including complement decay-accelerating factor (CD55) and membrane inhibitor of reactive lysis (CD59). When a mutation-carrying HSC clone expands, mature blood cells deficient of these complement inhibitors are susceptible to complement-mediated intravascular hemolysis and are simultaneously exacerbated during alternative complement-triggering events (e.g., infection, surgery), leading to morbidity and mortality.¹ 

Prior to recent advances in therapy, five-year mortality rates for PNH could be as high as 30%. The development of anti-C5 therapies has been a game-changer for this disease. First to be approved by the U.S. Food and Drug Administration was a humanized anti-C5 monoclonal antibody (the terminal complement inhibitor eculizumab), which set a very high therapeutic bar by improving quality of life and nearly normalizing survival. However, eculizumab requires frequent intravenous administration. This issue was addressed with the development of a longer-acting derivative, ravulizumab, which only requires infusion every eight weeks.^2,3  Regardless, 20% of patients treated with C5 inhibitors continue to require red cell transfusion support for ongoing symptomatic anemia,⁴  which is attributable to residual hemolysis from continued activation of the proximal complement pathways, leading to opsonization of PNH erythrocytes with C3 fragments.^5,6  This has paved the way for the development of more upstream complement inhibitors targeting the alternative pathway, such as the anti-C3 agent pegcetacoplan.⁷ 

Recently, the first-in-class, oral, small-molecule factor B proximal complement inhibitor iptacopan has made headway in several phase II trials. In a study conducted by Antonio M. Risitano, MD, PhD, and colleagues, the addition of iptacopan at 200 mg twice daily to standard eculizumab markedly diminished chronic residual intravascular hemolysis, as measured by change in baseline lactate dehydrogenase (LDH) and rise in hemoglobin concentrations.⁸  Notably, these benefits were maintained during extension of the original study and in 70% of patients who discontinued standard-of-care treatment and continued on monotherapy with iptacopan. In another phase II study, Jun Ho Jang, MD, PhD, and colleagues demonstrated iptacopan monotherapy-controlled levels of intravascular hemolysis without breakthrough extravascular hemolysis in treatment-naive patients with PNH.⁹ 

Such observations led to the multicenter study by Régis Peffault de Latour, MD, PhD, and colleagues assessing the primary efficacy and safety of two phase III open-label trials — APPLY-PNH, which randomized 97 patients with PNH who had persistent anemia despite anti-C5 therapy to either iptacopan monotherapy (62 patients) or the continuation of anti-C5 therapy (35 patients), and APPOINT-PNH, a single-arm trial that investigated iptacopan monotherapy in 40 treatment-naive patients with hemolytic PNH.

In both trials, investigators incorporated an eight-week screening period to identify patients with confirmed PNH by flow cytometry, with mean hemoglobin concentrations of 10g/dL and no evidence of bone marrow failure. APPLY-PNH included patients who had been on stable doses of eculizumab or ravulizumab for six months or longer, while those in APPOINT-PNH were required to not have previously received complement inhibitor therapy, as well as to show evidence of LDH levels equal to or greater than 1.5 times the upper limit of normal. The screening periods for both studies were followed by 24 weeks of treatment and subsequent 24-week extension periods. Patients in APPLY-PNH were randomly assigned in an 8:5 ratio to either receive iptacopan monotherapy at 200 mg twice daily or to continue anti-C5 therapy. All patients in APPOINT-PNH received iptacopan monotherapy at 200 mg twice daily. In APPLY-PNH, the primary endpoints were increase in hemoglobin of 2 g/dL or more from baseline and increase in hemoglobin concentration of 12 g/dL or more without red cell transfusion. The primary endpoint for APPOINT-PNH was increase in hemoglobin of 2 g/dL or more from baseline without red cell transfusion. The primary endpoints were met in both trials.

In APPLY-PNH, iptacopan monotherapy showed superiority, with an estimated 82% of patients (95% CI 73.4, 90.2) demonstrating an increase in hemoglobin of 2 g/dL or more from baseline without red cell transfusion, compared to just 2.0% of patients (95% CI 1.1, 4.1) receiving anti-C5 therapy (95% CI 71.3-87.6; p<0.0001). Additionally, an estimated 69% of patients on iptacopan (95% CI 58.3, 78.9) achieved hemoglobin levels of 12 g/dL or more, compared with only 2.0% (95% CI 0.9-4.0) of those receiving anti-C5 therapy (95% CI 56.3, 76.9; p<0.0001). In APPOINT-PNH, an estimated 92.2% of patients (95% CI 82.5, 100) demonstrated an improvement of 2 g/dL or more in hemoglobin without red cell transfusion, while 62.8% (95% CI 47.5, 77.5) achieved hemoglobin levels of 12 g/dL or more without red cell transfusion. Treatment with iptacopan appeared to be safe in both studies, with overall improvement in levels of fatigue and no discontinuation due to adverse events, the most common of which was headache.

There were several limitations to both studies, including the open-label design of APPLY-PNH and the single-group design of APPOINT-PNH. Investigators tried to mitigate these issues by incorporating objective laboratory-based endpoints, as well as protocol-defined transfusion criteria to reduce bias in APPLY-PNH and prespecifying success criteria in APPOINT-PNH. The short follow-up in both studies adds additional limitations, specifically in the form of thromboembolic and infectious complications.