The use of danicopan as an add-on therapy in a ravulizumab-treated adult patient with paroxysmal nocturnal hemoglobinuria (PNH) and concomitant stage IV renal failure has induced a marked improvement of anemia and of clinically significant extravascular hemolysis in absence of deterioration of renal function

Abstract

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired blood disorder characterized by chronic hemolytic anemia, thrombosis and a variable degree of bone marrow failure. Complement C5 inhibitor therapy with eculizumab or, more recently, with ravulizumab may improve hemolysis and clinical outcomes in naive PNH patients. However, some patients remain anemic and/or develop anemia during the course of their disease due to clinically significant extravascular hemolysis (EVH). Danicopan is a first-in-class, oral, small-molecule factor D inhibitor, that showed highly selective, clinically relevant inhibitory effects on the alternative pathway in preclinical studies and prevent breakthrough intravascular and extravascular hemolysis. In patients with an inadequate hematological response to eculizumab (hemoglobin <9•5 g/dL), switching to danicopan has been shown to normalise markers of extravascular hemolysis in most patients, leading to improved hemoglobin concentrations. We here present a 80-years old adult PNH patient who was treated with danicopan due to deterioration of anemia secondary to extravascular hemolysis. PNH diagnosis was performed in 2012. At that time stage IV renal failure, hypertension, hypothyroidism, and hyperuricemia were observed. PNH clone size was higher than 80% in both neutrophils and monocytes and 40% in RBC. Laboratory tests were as follows: Hb 7.5-8.5 g/dL, LDH 1650 UL (135-214 -normal values) (8 x ULN), hyperchromic urine, elevated reticulocyte count, and very low level of aptoglobin. A few months later, the patient started eculizumab therapy at a standard dose of 900 mg every 2 weeks. In 2019, this patient was treated with biosimilar eculizumab (phase 3 trial- ABP959-Amgen) till spring 2022. She was then treated with another biosimilar eculizumab (Samsung Bioepis) for one year. From early 2022, we observed a progressive decrease in Hb level, associated with an increase in reticulocyte count, and indirect biluribin level and the appearance of positivity for the direct antiglobulin test (Coombs test). In May 2023 the patient started ravulizumab therapy. In September 2024, despite good control of IVH by ravulizumab, clinical signs of extravascular hemolysis became more prominent and the decision to add proxymal inhibitor danicopan was taken. At baseline (before starting danicopan treatment), median Hb was 8.6 g/dL (8.0–9.1), LDH 1.2× ULN (1.1–2.0), unconjugated bilirubin 1.9 mg/dL (0.8–3.49), and reticulocytes 160×10⁹/L (155–310), direct antiglobulin test (DAT) was positive for Ig, aptoglobin concentration was reduced. Flow cytometry data showed 48.81% GPI-deficient RBC, 97.6% PNH neutrophils, and 86% monocytes. Patient was in good clinical condition, ECOG 0. Creatinine concentration 1.5-2.0 (creatinine clearance : 25-35 mil/min). Due to the presence of renal insufficiency, danicopan was started at a dosage of 100 mg x 3/day. Three weeks later, danicopan was escalated at a dosage of 150 mg x 3/day for two months. At weeks 12 , despite good reported compliance to oral treatment, Hb level and lab tests related to EVH were stable. The dose of danicopan was then escalated at 200 mgx3/day. At week 20, a progressive improvement of Hb level was observed (11.6 g/dL- range 10.5- 11.7). In conclusion, danicopan has demonstrated high efficacy in increasing hemoglobin level (range 2.3-3 g/dL), and reducing markers of hemolysis in a PNH patient with concomitant stage IV renal failure, having an inadequate hematological response to either eculizumab or ravulizumab (hemoglobin <9•5 g/dL). Interestingly, renal function was not affected by the combined use of ravulizumab and danicopan, during a 11 months- follow-up observation period.