Factor D Inhibitor Danicopan Approved as Add-On Therapy for PNH

Today, AstraZeneca announced the approval of danicopan (Voydeya) as an add-on therapy to eculizumab (Soliris) or ravulizumab (Ultomiris) in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in the US. Danicopan is an oral first-in-class factor D inhibitor designed to treat adults experiencing extravascular hemolysis (EVH), and its approval was informed by findings from the ALPHA phase 3 trial.¹

EVH affects an estimated 10% to 20% of patients with PNH who are undergoing treatment with a C5 inhibitor, such as eculizumab or ravulizumab. EVH is characterized by the destruction of red blood cells outside of the blood vessels, which can contribute to anemia in patients and lead to necessitated blood transfusions.²

Red Blood Cell | image credit: Bipul Kumar - stock.adobe.com

“The approval of Voydeya offers this small subset of PNH patients an add-on therapy designed to address EVH, while maintaining disease control with Ultomiris or Soliris. Terminal complement inhibition with Ultomiris can address the life-threatening complications of PNH, building on the efficacy and safety of Soliris established over nearly 20 years,” Bart Scott, MD, professor in the Division of Hematology and Oncology at the University of Washington Medical Center and Research Division at the Fred Hutchinson Cancer Center, said in the statement.¹

On June 9, 2023, data from the ALPHA trial were presented at the European Hematology Association Annual Meeting that showcased the efficacy of danicopan to meaningfully increase patients’ hemoglobin levels. Compared with patients treated with placebo, those who received danicopan demonstrated significant improvement in their hemoglobin after 2 weeks, and these benefits continued through week 12 (change from baseline, 0.50 g/dL vs 2.94 g/dL, respectively; P = .0001).² Additionally, patients receiving danicopan were able to avoid transfusions at a higher rate than those administered placebo.

These improvements at 12 weeks constituted the study’s primary end point. Secondary end points were also achieved, with patients in the danicopan group demonstrating hemoglobin improvements of 2 or more g/dL by week 12 without the need of transfusion (difference in danicopan-placebo: 46.9; 95% CI, 29.2-64.7, P < .0001).²

“While EVH is not life-threatening, its manifestations can be burdensome for patients. The ALPHA trial demonstrated that adding danicopan to standard of care with eculizumab or ravulizumab significantly improved fatigue and anaemia and reduced transfusion dependence, while still allowing for sustained control of [intravascular hemolysis] with terminal complement inhibition addressing the thrombotic risks associated with PNH. These results suggest danicopan has the potential to be an important option for the small subset of patients with PNH who experience clinically significant EVH while being treated with eculizumab or ravulizumab,” Jong Wook Lee, MD, PhD, professor in the Department of Haemotology at Seoul St. Mary’s Hospital of The Catholic University of Korea and a participating investigator in the ALPHA trial, commented at the time.²

The most prevalent adverse events recorded throughout the ALPHA trial included nausea, arthralgia, diarrhea, and headache; however, danicopan was regarded as well tolerated and without new safety concerns. No incidences of meningococcal infections, hemolysis-related discontinuations, nor deaths were reported.

“As the ALPHA trial suggests, dual complement pathway inhibition at factor D and C5 may be an optimal treatment approach for this subset of patients with EVH, enabling them to continue with proven standard-of-care therapy,” Marc Dunoyer, CEO of Alexion, said in the statement announcing the approval.¹

At present, danicopan is undergoing review in multiple countries and is currently approved in Japan in the treatment of PNH. Additionally, danicopan has been recommended for approval in the European Union.¹

References

1. VOYDEYA approved in the US as add-on therapy to ravulizumab or eculizumab for treatment of extravascular hemolysis in adults with the rare disease PNH. News release. AstraZeneca. April 1, 2024. Accessed April 1, 2024. https://www.astrazeneca-us.com/media/press-releases/2024/voydeya-approved-in-the-us-as-add-on-therapy-to-ravulizumab-or-eculizumab-for-treatment-of-extravascular-hemolysis-in-adults-with-the-rare-disease-phn.html

2. Danicopan as add-on to Ultomiris or Soliris improved haemoglobin levels and maintained disease control in patients with PNH experiencing signs or symptoms of clinically significant extravascular haemolysis. News release. AstraZeneca. June 9, 2023. Accessed April 1, 2024. https://www.astrazeneca.com/media-centre/press-releases/2023/danicopan-as-add-on-to-ultomiris-or-soliris-improved-haemoglobin-levels-and-maintained-disease-control-in-patients.html