Novartis Submits NDA for First-in-Class Oral PNH Drug Iptacopan in China

On June 14, the CDE website showed that Novartis' iptacopan hydrochloride capsule (iptacopan) marketing application was accepted for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

On April 26 this year, Novartis announced that the Phase III APPOINT-PNH study of Iptacopan monotherapy for untreated PNH adult patients (including those not treated with anti-C5 antibodies) met its primary endpoint. Secondary endpoints also showed clinically meaningful improvements.

APPOINT-PNH (NCT04820530) is a single-arm, open-label, multicenter, Phase III clinical trial designed to evaluate the efficacy and safety of iptacopan monotherapy in adult patients with PNH who have not received prior treatment with complement inhibitors (including anti-C5 antibodies). The study enrolled 40 adult PNH patients with an average hemoglobin (Hb) level <10 g/dL, lactate dehydrogenase (LDH) >1.5x the upper limit of normal, and who had not received prior complement inhibitor therapy. Participants were treated with iptacopan monotherapy at a dose of 200 mg twice daily.

The primary endpoint was the proportion of patients achieving a ≥2 g/dL increase in hemoglobin levels from baseline within 24 weeks without red blood cell transfusion (RBCT). Secondary endpoints included the proportion of patients with hemoglobin levels ≥12 g/dL (without RBCT), the proportion of patients avoiding transfusion, change in hemoglobin levels from baseline, change in FACIT-Fatigue scores from baseline, change in absolute reticulocyte count (ARC) from baseline, percentage change in LDH levels from baseline, incidence of clinical breakthrough hemolysis, and incidence of major adverse vascular events.

The results showed that the trial met the primary endpoint, with 92.2% of patients achieving a ≥2 g/dL increase in hemoglobin levels from baseline without red blood cell transfusion (RBCT). Secondary endpoints demonstrated clinically meaningful improvements, with 97.6% of patients avoiding transfusions and 62.8% of patients reaching a sustained hemoglobin level of ≥12 g/dL without RBCT. The safety profile was consistent with previously reported data.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a complement-mediated chronic rare blood disorder. According to statistics, the incidence of PNH is about one to two per million, with a higher incidence in Asian populations compared to Europe and America. It can occur at any age but is commonly seen in people aged 30-40. PNH patients have a mutation in the PIG-A gene, leading to the absence of important complement regulatory proteins CD55 and CD59 on the surface of blood cells. As a result, cells are more susceptible to complement activation. The main clinical manifestations include hemolysis, bone marrow hematopoietic failure, and thrombosis. Anti-complement C5 therapy (Eculizumab or Ravulizumab) has been the internationally recognized standard treatment for PNH. However, after anti-C5 treatment, a significant number of patients still experience residual anemia, fatigue, and transfusion dependence, severely affecting their quality of life.

Iptacopan is a first-in-class, oral inhibitor targeting the complement alternative pathway B factor, developed by Novartis. The product acts upstream of the terminal C5 pathway, simultaneously controlling both intravascular and extravascular hemolysis, addressing the limitations of anti-C5 antibodies while providing patients with an oral monotherapy option. In February this year, Iptacopan received Breakthrough Therapy Designation from the CDE.

In addition to PNH, Iptacopan is currently in critical research stages for many other complement-mediated diseases (CMD), including renal diseases such as C3 glomerulopathy (C3G), IgA nephropathy (IgAN), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN), lupus nephritis (LN), as well as immune thrombocytopenic purpura (ITP) and cold agglutinin disease (CAD).

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