P774: Substantial Increases in Paroxysmal Nocturnal Hemoglobinuria (Pnh) Red Blood Cell Clone Size With Oral Iptacopan Monotherapy Confirms Control of Hemolysis in Complement Inhibitor-Naïve PNH Patients

Latour, Régis Peffault de; Han, Bing; Maciejewski, Jaroslaw P.; Ueda, Yutaka; Fu, Rong; Zhang, Li; Kulasekararaj, Austin; Röth, Alexander; Chew, Lee Ping; Jang, Jun Ho; Wong, Lily; Panse, Jens; Yap, Eng Soo; Marano, Luana; Fontbrune, Flore Sicre de; Yang, Chen; Banerjee, P. S.; Wang, Zhixin; Thorburn, Christine; LI, Shujie; Dahlke, Marion; Risitano, Antonio M.

doi:10.1097/01.hs9.0000970000.03386.8c

Cited by 3 publications

(2 citation statements)

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“…The APPOINT-PNH (NCT04820530) is a single-arm, phase III clinical trial with iptacopan in treatment-naïve patients. The first results of this study support the efficacy and safety of iptacopan [ 84 , 85 ]. These promising findings suggest that iptacopan monotherapy can become a potentially practice-changing outpatient and preferred therapeutic option for patients with hemolytic PNH.…”

Section: Treatmentsupporting

confidence: 61%

Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment

Bravo-Perez,

Guarnera,

Williams

et al. 2023

Medicina

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Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis. This review summarizes the biology and current treatment strategies for PNH with the aim of reaching a general audience with an interest in hematologic disorders.

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Section: Treatmentsupporting

confidence: 61%

Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment

Bravo-Perez,

Guarnera,

Williams

et al. 2023

Medicina

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“…The second report evaluated BTH occurrence in the APPLY and APPOINT‐PNH trial demonstrating a reduced rate of BTH events. The latter were mostly easy to manage and mostly occurred under complement activating conditions (pharmacodynamic BTH) and did not require drug discontinuation 53 …”

Section: Alternative Pathways Inhibitorsmentioning

confidence: 99%

Complement inhibition in paroxysmal nocturnal hemoglobinuria: From biology to therapy

Versino,

Fattizzo

2024

Int J Lab Hematology

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Complement inhibitors are the mainstay of paroxysmal nocturnal hemoglobinuria (PNH) treatment. The anti‐C5 monoclonal antibody eculizumab was the first treatment to improve hemolysis, thrombotic risk, and survival in PNH although at the price of a life‐long intravenous fortnightly drug. Additionally, suboptimal response may occur in up to 2/3 of patients with persistent anemia due to incomplete control of intravascular hemolysis, development of upstream C3‐mediated extravascular hemolysis (EVH), or concomitant bone marrow failure. Ravulizumab, a longer half‐life anti‐C5 developed from eculizumab, administered every 8 weeks, improved patient convenience, and reduced pharmacokinetic breakthrough hemolysis (BTH) by establishing more stable anti‐C5 concentrations. More recently, several other anti‐C5 compounds (crovalimab, pozelimab, tesidolumab, cemdisiran, zilucoplan, and coversin) are on study in clinical trials. Upstream inhibition of complement cascade was also explored with the anti‐C3 pegcetacoplan, and with the alternative pathway inhibitors iptacopan (anti‐factor B) and danicopan (anti‐factor D). These drugs efficiently target EVH and are able to improve anemia and transfusion need in suboptimal responders to anti‐C5. The route and schedule of administration (twice weekly subcutaneously for pegcetacoplan and twice or thrice oral daily dosing for iptacopan and danicopan, respectively) are very convenient but pose novel issues regarding adherence. Additionally, both anti‐C5 and upstream inhibitors do not resolve the unmet need of pharmacodynamic BTH events due to complement amplifying conditions such as infections, traumas, and surgery. In this review, we will recapitulate PNH physiopathology, clinical presentation, and diagnosis and describe available and developing drugs that will lead to a precision medicine approach for this rare though heterogenous disease.

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Iptacopan Efficacy and Safety to Treat Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Meta-Analysis

Dighriri,

Al-Qahtani,

Almutairi

et al. 2024

Cureus

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Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon blood condition caused by complement-mediated hemolysis. In early clinical studies, iptacopan, an oral factor B inhibitor, showed promise in treating PNH. This systematic review aimed to compile information on the effectiveness and safety of iptacopan for PNH. A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. The Medline, Embase, PubMed, and Cochrane Central databases were searched for randomized controlled trials (RCTs) and observational studies that evaluated iptacopan for PNH. The primary efficacy outcomes were hemoglobin and lactate dehydrogenase (LDH) changes. A fixed-effects model was used for the meta-analysis. Six studies (three prospective cohorts, two RCTs, and one non-randomized trial) were included, comprising 197 patients. Iptacopan therapy significantly increased hemoglobin levels (mean differences (MD) = 12.98 g/L; 95% CI: 11.82-14.13; p < 0.0001) and decreased LDH (MD = -83.55 IU/L; 95% CI: -83.77 to -83.34; p < 0.0001). Subgroup analyses revealed more significant hemoglobin increases in European vs. Asian populations, studies with baseline Hb > 10 g/dL vs. < 10 g/dL, and studies lasting > 24 weeks vs. ≤ 24 weeks. LDH decreases were more pronounced in studies with baseline LDH > 500 IU/L vs. < 500 IU/L. The incidence of adverse events ranged from 66% to 90%, with the most common being headache, nasopharyngitis, and diarrhea. Serious adverse events occurred in 0-20% of patients across studies. Only one patient withdrew because adverse effects were reported across all studies. Preliminary data support iptacopan's effectiveness in improving hemoglobin levels and lowering hemolysis in PNH, both as a monotherapy and in combination with usual treatment. The safety profile appears to be excellent, with a minimal incidence of major adverse events and treatment discontinuation. Further studies are needed to validate the effectiveness and safety of larger, longer-term trials. Iptacopan is a viable oral therapy option for PNH.

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P774: Substantial Increases in Paroxysmal Nocturnal Hemoglobinuria (Pnh) Red Blood Cell Clone Size With Oral Iptacopan Monotherapy Confirms Control of Hemolysis in Complement Inhibitor-Naïve PNH Patients

Cited by 3 publications

References 0 publications

Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment

Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment

Complement inhibition in paroxysmal nocturnal hemoglobinuria: From biology to therapy

Iptacopan Efficacy and Safety to Treat Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Meta-Analysis

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