An experimental Novartis drug has bested two blockbuster AstraZeneca medicines in a head-to-head clinical trial with results that investigators say could change how physicians treat a debilitating rare blood disorder that destroys red blood cells. With those data in hand, the drugmaker is now planning to submit applications seeking regulatory approvals starting in 2023.

The Novartis drug, iptacopan, is a potential treatment for paroxysmal nocturnal hemoglobinuria (PNH), a disorder of the complement system that leads this part of the immune system to attack red blood cells. The chronic condition can be managed with blood transfusions. The standard of care drugs for PNH are two AstraZeneca products, Soliris and Ultomiris.

In a 10-patient Phase 2 study that added iptacopan to Soliris, patients became transfusion independent. The results, published last year in The Lancet, paved the way for the larger trial whose data were unveiled on Tuesday. In this Phase 3 study, iptacopan, a twice daily pill, was compared to Soliris, dosed as an infusion given every two weeks, and Ultomiris, an infusion administered every eight weeks. The two main goals of this 97-patient study were to measure the increases in hemoglobin levels and to assess how well those levels were sustained after 24 weeks of treatment—both in the absence of transfusions.

Results showed 51 of the 60 patients in the iptacopan arm had hemoglobin rise to more normal levels compared to zero patients treated with the standard of care AstraZeneca drugs. On the measure of how well those levels were sustained, 42 of the 60 patients in the iptacopan group met that threshold compared to zero patients in the control arm. Régis Peffault de Latour, a professor of hematology at Saint-Louis Hospital in Paris and the study’s principal co-investigator, presented those results in New Orleans during the annual meeting of the American Society of Hematology (ASH).

“Single-agent iptacopan may represent a practice-changing, oral, outpatient treatment for PNH patients who are suboptimal responders to eculizumab (Soliris),” he said in the oral presentation. “It will become possibly a preferred treatment option for all patients with hemolytic PNH in the near future.”

PNH stems from an acquired mutation in some hematopoietic stem cells—cells located in the bone marrow that can grow and develop into various types of blood cells—causing them to produce red blood cells that are susceptible to destruction by the complement system, a part of the immune system. Consequently, patients develop anemia, blood clots, fatigue, among other complications. While the AstraZeneca drugs can help PNH patients, Peffault de Latour said up to two thirds of patients who receive these standard treatments are still anemic and still receive regular transfusions.

Novartis estimates that between 10 million and 20 million people worldwide have PNH. Soliris and Ultomiris, which were developed by AstraZeneca’s rare disease unit Alexion, are antibodies designed to block a complement system protein called C5. But not all patients respond sufficiently to these therapies, leaving them anemic, fatigued and dependent on blood transfusions.

Iptacopan is an oral small molecule designed to block an alternative complement pathway called factor B. In the cascade of complement proteins, factor B is upstream of C5. Novartis says this approach prevents the destruction of red blood cells in circulation as well as in the liver and spleen. The drug was discovered at the Novartis Institutes for BioMedical Research.

In addition to PNH, Novartis is developing iptacopan for several other complement-mediated diseases. While the company has projected that the drug’s peak sales could top $3 billion, it has declined to break down that revenue figure by indication. PNH could become the first indication. Reshema Kemps-Polanco, Novartis’s executive vice president, oncology U.S., said during a conference call Tuesday that iptacopan’s oral formulation is a key differentiator for the drug.

“We have a strong track record of success with orals in an infused market, and our intent is for this to become a new standard of care,” she said.

David Soergel, Novartis’s global head of cardiovascular, renal & metabolism development, said the next steps include discussing the clinical trial results with regulators worldwide with the goal of submitting applications in 2023. Submissions in the U.S. and Europe could be filed in the first half of next year, followed by Japan and China in the second half of the year.

Novartis isn’t the first company angling to wrest PNH market share from Soliris and Ultomiris. Apellis Pharmaceuticals won FDA approval last year for Empaveli, a peptide drug that treats PNH by blocking the complement protein C3.

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