RARE Daily

Novartis Experimental Therapy Bests C5 Inhibitors in Phase 3 PNH Study

December 8, 2022

Rare Daily Staff

Novartis reported that its phase 3 APPOINT-PNH study of its experimental therapy iptacopan in complement-inhibitor-naïve adults with paroxysmal nocturnal hemoglobinuria demonstrated superiority over anti-C5 therapies (eculizumab or ravulizumab) and showed a significant proportion of patients treated with the drug achieved clinically meaningful hemoglobin-level increases without the need for blood transfusions at 24 weeks.

The safety profile of iptacopan monotherapy was consistent with previously reported data, the company said. Detailed data will be presented at an upcoming medical meeting and included as part of global regulatory submissions in 2023.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, and serious complement-mediated blood disorder. People with PNH have an acquired mutation in some of their hematopoietic stem cells (which are located in the bone marrow and can grow and develop into red blood cells, white blood cells and platelets) that causes them to produce RBCs that are susceptible to premature destruction by the complement system. This leads to intravascular destruction of red blood cells within blood vessels and destruction of red blood cells mostly in the spleen and liver, which cause anemia, the formation of blood clots, fatigue, and other debilitating symptoms that can impact people’s quality of life.

PNH has a significant unmet need not addressed by anti-C5 therapies (eculizumab or ravulizumab). Despite treatment with anti-C5s, a large proportion of people with PNH remain anemic, fatigued, and dependent on blood transfusions.

Iptacopan is an experimental, first-in-class, orally administered targeted factor B inhibitor of the alternative complement pathway. It acts upstream of the C5 terminal pathway, preventing not only intravascular but also extravascular hemolysis in PNH. In doing so, iptacopan targets a key part of the biology responsible for PNH while offering an oral monotherapy option.

It is currently in development for a number of other complement-mediated diseases where significant unmet needs exist, including kidney diseases C3G, IgAN, atypical hemolytic uremic syndrome, membranous nephropathy, lupus nephritis, and blood disorders immune thrombocytopenic purpura (ITP) and cold agglutinin disease.

Based on disease prevalence, unmet need and data from phase 2 studies, iptacopan has received U.S. Food and Drug Administration Breakthrough Therapy Designation in PNH, orphan drug designations from the FDA and European Medicines Agency in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN.

The phase 3 APPOINT-PNH is a multinational, multicenter, open-label, single-arm study to evaluate the efficacy and safety of twice-daily, oral iptacopan monotherapy (200 mg) in adult PNH patients who are naïve to complement inhibitor therapy, including anti-C5 therapies.

Topline results showed it met its two primary endpoints, with iptacopan demonstrating superiority over anti-C5 therapies (eculizumab or ravulizumab) in adults with PNH experiencing residual anemia despite prior anti-C5 treatment. The study showed a statistically significant and clinically meaningful increase in the proportion of iptacopan-treated patients achieving 2 g/dL or more hemoglobin-level increases from baseline, and 12 g/dL or more hemoglobin levels, both without the need for blood transfusions at 24 weeks, compared to anti-C5 therapies.

“We are very encouraged by the results of the complement-inhibitor-naïve data from the phase 3 APPOINT-PNH trial,” said David Soergel, global head of the cardiovascular, renal and metabolism development unit of 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.”


Photo: David Soergel, global head of the cardiovascular, renal and metabolism development unit of Novartis

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