AstraZeneca Reports Positive Results from Danicopan as Add-On in PNH

Rare Daily Staff

AstraZeneca’s Alexion reported positive results from its 24-week and long-term extension period of the pivotal ALPHA Phase 3 trial of its experimental therapy danicopan as an add-on to standard of care C5 inhibitor therapies Ultomiris or Soliris in patients with the rare, autoimmune condition paroxysmal nocturnal hemoglobinuria.

The company said danicopan continued to demonstrate clinical benefit for patients with paroxysmal nocturnal hemoglobinuria (PNH) who experience clinically significant extravascular hemolysis. Results from the trial were presented today at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

PNH is a rare and severe blood disorder characterized by the destruction of red blood cells within blood vessels, known as intravascular hemolysis (IVH), and white blood cell and platelet activation that can cause thrombosis (blood clots) and result in organ damage and potentially premature death. Immediate, complete and sustained terminal complement inhibition by blocking the C5 protein with Ultomiris or Soliris helps reduce symptoms and complications, resulting in improved survival for patients with PNH.

Approximately 10 to 20 percent of people living with PNH who are treated with a C5 inhibitor experience clinically significant EVH, which can result in continued symptoms of anemia and require blood transfusions. EVH, is the removal of red blood cells outside of the blood vessels. It can sometimes occur in PNH patients who are treated with C5 inhibitors and can result in continued symptoms of anemia and require blood transfusions.

Danicopan is an experimental oral medicine in development as an add-on to C5 inhibitor therapy Ultomiris or Soliris for patients with PNH who experience clinically significant EVH. It is designed to selectively inhibit Factor D, a complement system protein that plays a key role in the amplification of the complement system response. Danicopan has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration and PRIority MEdicines (PRIME) status by the European Medicines Agency. Danicopan has also been granted Orphan Drug designation in the United States, European Union, and Japan for the treatment of PNH.

Alexion is also evaluating danicopan as a potential monotherapy for geographic atrophy, an irreversible cause of vision loss, in a phase 2 clinical trial.

The pivotal ALPHA phase 3 trial is designed as a superiority study to evaluate the efficacy and safety of danicopan as an add-on to C5 inhibitor therapy Ultomiris and Soliris in patients with PNH who experience clinically significant EVH.

A total of 86 patients were randomized. The prespecified interim analysis (primary analysis) occurred after 63 participants either completed or discontinued from the primary treatment period of 12 weeks. Following the 12-week randomized control period, patients were eligible to enroll in an open-label treatment period for an additional 12 weeks. During the open-label period, participants receiving placebo plus Ultomiris or Soliris switched to danicopan plus Ultomiris or Soliris (placebo-danicopan), and participants receiving add-on therapy with danicopan continued treatment with danicopan add-on therapy (danicopan-danicopan). The open-label treatment period was followed by the option to join a two-year LTE period during which all participants received danicopan add-on therapy. At the time of data cut-off on September 20, 2022, 60 of the 63 patients who were included in the primary analysis had reached 24 weeks and entered the LTE.

Data showed that improvements in mean hemoglobin levels and absolute reticulocyte count (ARC) levels, which were demonstrated at 12 weeks, were maintained through 48 weeks.

“These new data further demonstrate the potential of danicopan as add-on to Ultomiris or Soliris to address the needs of the small subset of patients with PNH who experience clinically significant EVH,” said Austin Kulasekararaj, consultant hematologist at King’s College Hospital, London and investigator in the ALPHA trial. “Expanding on positive 12-week results, the findings demonstrate sustained improvements in hemoglobin levels for up to 48 weeks, while also maintaining disease control, as measured by lactate dehydrogenase levels.”

Photo: Austin Kulasekararaj, consultant hematologist at King’s College Hospital, London and investigator in the ALPHA trial