Novartis, in Challenge to Alexion, Reports Phase 3 PNH Study That Shows Superiority over Existing C5 Inhibitor

Novartis reported that its pivotal phase 3 APPLY-PNH trial met its two primary endpoints, showing its experimental therapy iptacopan was superior to Soliris and Ultomiris in adults with the rare blood disorder paroxysmal nocturnal hemoglobinuria.

PNH is a rare, chronic, and serious complement-mediated 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 red blood cells that are susceptible to premature destruction by the complement system. This leads to destruction of red blood cells within blood vessels and destruction of red blood cells 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.

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 PNH1-3. In doing so, iptacopan may have a therapeutic advantage over anti-C5 therapies by targeting a key part of the biology responsible for PNH while offering an oral monotherapy option.

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

The U.S. Food and Drug Administration granted iptacopan Breakthrough Therapy designation in PNH, and orphan drug designations in PNH and C3G. The European Medicines Agency granted iptacopan orphan drug designation in PNH and IgAN, and PRIME designation for C3G.

Topline results showed a statistically significant and clinically meaningful increase in the proportion of patients treated with iptacopan (200 mg twice daily) achieving hemoglobin-level increases of 2 g/dL or more from baseline without the need for blood transfusions at 24 weeks, compared to anti-C5 therapies, a primary endpoint of the study.

Additionally, there was a statistically significant and clinically meaningful increase in the proportion of patients in the iptacopan arm achieving hemoglobin levels of 12 g/dL or more without the need for blood transfusions at 24 weeks, compared to anti-C5 therapies, also a primary endpoint of the study. Iptacopan was well tolerated with a favorable safety profile consistent with previously reported data.

Detailed results will be presented at an upcoming medical meeting and included as part of global regulatory submissions in 2023.

“These positive topline phase 3 results highlight the practice-changing potential of iptacopan for patients suffering from debilitating anemia and the burden of lifelong blood transfusions as a result of PNH,” said Shreeram Aradhye, president of global drug development and chief medical officer, Novartis.

Author: Rare Daily Staff