Novartis' investigational oral monotherapy iptacopan has shown positive results in the Phase III APPOINT-PNH study, demonstrating clinically meaningful increases in hemoglobin levels in complement-inhibitor-naïve adults with paroxysmal nocturnal hemoglobinuria (PNH). The study met its primary endpoint, with a significant proportion of patients achieving a hemoglobin-level increase of 2 g/dL or more from baseline without the need for blood transfusions at 24 weeks.
The APPOINT-PNH trial (NCT04820530) is a Phase III, multinational, multicenter, open-label, single-arm study evaluating the efficacy and safety of twice-daily, oral iptacopan monotherapy (200 mg) in adult PNH patients who had not previously been treated with complement inhibitors, including anti-C5 therapies. The primary endpoint was the proportion of participants achieving an increase in hemoglobin levels from baseline of 2 g/dL or more in the absence of red blood cell (RBC) transfusions at 24 weeks.
Key Findings from APPOINT-PNH
Topline results indicated that a significant proportion of patients treated with iptacopan achieved clinically meaningful hemoglobin-level increases compared to baseline, without requiring blood transfusions. The safety profile of iptacopan monotherapy was consistent with previously reported data. Detailed data will be presented at an upcoming medical meeting and included as part of global regulatory submissions in 2023.
"We are very encouraged by the results of the complement-inhibitor-naïve data from the Phase III APPOINT-PNH trial," said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. "This second iptacopan readout for PNH underscores the robust potential for this therapy, enabling us to submit a broad regulatory package with the goal of iptacopan potentially becoming the first oral monotherapy for PNH."
Iptacopan's Mechanism of Action
Iptacopan is an investigational first-in-class, orally administered targeted factor B inhibitor of the alternative complement pathway. It acts upstream of the C5 terminal pathway, preventing both intravascular and extravascular hemolysis in PNH. By targeting a key part of the biology responsible for PNH, iptacopan offers an oral monotherapy option.
PNH and Unmet Needs
PNH is a rare, chronic, and serious complement-mediated blood disorder affecting an estimated 10-20 people per million worldwide. Patients with PNH have an acquired mutation in their hematopoietic stem cells, leading to the production of RBCs susceptible to premature destruction by the complement system. This results in intravascular and extravascular hemolysis, causing anemia, thrombosis, fatigue, and other debilitating symptoms.
Despite treatment with anti-C5 therapies like eculizumab or ravulizumab, a significant proportion of PNH patients remain anemic, fatigued, and dependent on blood transfusions, highlighting a significant unmet need.
Ongoing Research and Regulatory Designations
Iptacopan is also being investigated in Phase III studies for complement-mediated kidney diseases (CMKDs) such as C3 glomerulopathy, IgA nephropathy, and atypical hemolytic uremic syndrome, as well as in several additional indications in Phase II. The FDA has granted iptacopan Breakthrough Therapy Designation in PNH and orphan drug designations for PNH and C3G. The EMA has granted PRIME designation for C3G and orphan drug designation in IgAN.
