Novartis' First-in-Class Complement Factor B Inhibitor Iptacopan Demonstrates Significant Efficacy in Paroxysmal Nocturnal Hemoglobinuria by Targeting the Root Cause of Complement-Mediated Hemolysis
Jun 15, 2021 00:23
CST Updated
00:23
Novartis
Drug Development and Manufacturing
PNH red blood cell hemolysis (Image source: standardofcare.com)
June 14, 2021 /BioonBIOON/ --Novartis(Novartis) recently announced data from a Phase 2 clinical study (NCT03896152) evaluating iptacopan (LNP023) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). The results showed that, in PNH patients who had not previously received C5 inhibitors,Treatment with iptacopan monotherapy for 12 weeks significantly reduced intravascular and extravascular hemolysis, with most patients achieving rapid and sustained transfusion independence.In this study, iptacopan was well tolerated, with no unexpected safety findings.
New research results demonstrate the potential of iptacopan as monotherapy for the treatment of PNH. Results from another open-label Phase II study (NCT03439839), previously published in *The Lancet Haematology*, showed that in PNH patients receiving standard-of-care therapy (the C5 inhibitor Soliris [eculizumab]) but who continued to experience active hemolysis,Iptacopan as add-on therapy significantly improved hematologic response and disease activity.Biomarker. This benefit was maintained in patients who discontinued Soliris treatment.
PNH is a rare, life-threatening blood disorder characterized by complement-mediated hemolysis, thrombosis, and impaired bone marrow function, leading toAnemia, fatigue and other debilitating symptoms that significantly impair patients' quality of life. Despite treatment with current standard-of-care anti-C5 therapies, a substantial proportion of PNH patients remain anemic and transfusion-dependent.
Chemical structure of iptacopan (Image source: medchemexpress.com)
Iptacopan is a first-in-class, oral, potent, selective, small-molecule, reversible Factor B inhibitor. Factor B is a key serine protease in the alternative pathway of the complement system. Currently, iptacopan is being developed for the treatment of several complement-mediated kidney diseases with significant unmet medical needs, including paroxysmal nocturnal hemoglobinuria (PNH), IgA nephropathy (IgAN), C3 glomerulopathy (C3G), and atypical hemolyticUremiaSyndrome (aHUS), Membranous Nephropathy (MN).
Recently published Phase II data show that,Iptacopan treatment for IgAN reduced proteinuria and stabilized renal function, while treatment for C3G reduced the rate of decline in estimated glomerular filtration rate (eGFR) and stabilized renal function.
Iptacopan isNovartisThe most advanced asset in the nephrology pipeline targets the alternative complement pathway, a key driver of complement-driven renal diseases (CDRD). Previously, iptacopan has been granted Orphan Drug Designation (ODD) by the US FDA and EU EMA for the treatment of PNH and C3G, ODD by the EMA for the treatment of IgAN, and grantedFDAGranted Breakthrough Therapy Designation (BTD) for the treatment of PNH, and awarded Priority Medicines (PRIME) designation by the EMA for the treatment of C3G.
Complement Activation Cascade - Therapeutic Modulation Target for PNH (Image source: PMC6060635, click image to view full size)
NCT03896152 is a multinational, multicenter, open-label, randomized, 2-cohort, dose-ranging phase 2 study conducted in 13 adult patients with PNH who had active hemolysis within the previous 3 months and had not received complement inhibitor therapy, evaluating the efficacy, safety, and pharmacokinetics/pharmacodynamics of iptacopan as monotherapy.
The results showed that,All patients who completed 12 weeks of treatment (n=11) met the primary endpoint: lactate dehydrogenase (LDH) levels decreased by at least 60%. LDH is a biomarker for intravascular hemolysis.Importantly, except for one patient who received a single red blood cell (RBC) transfusion, no other patients required blood transfusions during the 12-week treatment period. Patients’# Other HemolysisBiomarkeralso showed improvement, with a significant increase in the proportion of PNH-type RBCs, indicating that both intravascular and extravascular hemolysis were comprehensively controlled.
During the 12-week treatment period, no serious adverse events or thromboembolic events were reported, and no unexpected safety findings were observed. Two patients discontinued iptacopan treatment before completing the 12-week treatment: one due to a non-serious headache, and the other due to a physician decision following worsening of pre-existing neutropenia. The most commonAdverse Reactionswere headache (31%), abdominal discomfort (15%), increased blood alkaline phosphatase (15%), cough (15%), oropharyngeal pain (15%), fever (elevated body temperature; 15%), and upper respiratory tract infection (15%).
NovartisJohn Tsai, Head of Global Drug Development and Chief Medical Officer, stated: "PNH is a rare, life-threatening blood disease that requires new treatment options. These positive results further reinforce the potential of iptacopan as a promising oral monotherapy. We are excited to continue exploring the potential of iptacopan as a new standard of care for PNH in our ongoing Phase 3 studies." (Bioon.com)