FDA Approves Danicopan as Add-On Therapy for Extravascular Hemolysis in PNH


The FDA has approved danicopan as add-on therapy to ravulizumab or eculizumab for extravascular hemolysis in paroxysmal nocturnal hemoglobinuria.



The FDA has approved danicopan (Voydeya) as an add-on therapy to ravulizumab-cwvz (Ultomiris) or eculizumab (Soliris) for the treatment of extravascular hemolysis in adult patients with paroxysmal nocturnal hemoglobinuria (PNH).1

This regulatory decision was supported by findings from the phase 3 ALPHA trial (NCT04469465), for which results from the 12-week primary evaluation period were published in The Lancet Haematology.2 Treatment with danicopan met the trial’s primary end point of increased hemoglobin levels from baseline to week 12. The least squares mean (LSM) change from baseline was 2.94 g/dL (95% CI, 2.52-3.36; n = 42) with danicopan plus ravulizumab or eculizumab vs 0.50 g/dL (95% CI, –0.13 to 1.12; n = 21) with placebo plus ravulizumab or eculizumab (LSM difference, 2.44 g/dL; 95% CI, 1.69-3.20; P < .0001).1,2 The trial also met all key secondary end points, including transfusion avoidance rates and change in Functional Assessment of Chronic Illness Therapy – Fatigue score.1

“The approval of [danicopan] offers this small subset of [patients with] PNH an add-on therapy designed to address extravascular hemolysis while maintaining disease control with [ravulizumab] or [eculizumab],” Bart Scott, MD, a professor in the Division of Hematology and Oncology at the University of Washington Medical Center, and a professor in the Clinical Research Division at Fred Hutchinson Cancer Center, both in Seattle, stated in a press release.1 “Terminal complement inhibition with [ravulizumab] can address the life-threatening complications of PNH, building on the efficacy and safety of [eculizumab] established over nearly 20 years.”

The double-blind, placebo-controlled, multiple-dose ALPHA trial investigated the efficacy and safety of danicopan as an add-on to C5 inhibition with ravulizumab or eculizumab in patients at least 18 years of age with PNH who experienced clinically significant extravascular hemolysis.1,3 Eligible patients included those who had been receiving an approved C5 inhibitor for at least 6 months before day 1 of the trial and had platelet counts of at least 30,000 µL and absolute neutrophil counts of at least 500 µL.3

Patients were randomly assigned in a 2:1 fashion to receive danicopan (n = 49) or placebo (n = 24) in addition to ongoing ravulizumab or eculizumab therapy for 12 weeks.1,2 At 12 weeks, patients in the placebo arm were switched to receive danicopan plus ravulizumab or eculizumab, and patients in the danicopan arm remained on this treatment for an additional 12 weeks. Patients who completed the 24-week treatment period were eligible to participate in a 2-year long-term extension period where they could continue to receive danicopan plus ravulizumab or eculizumab. The open-label portion of the study is ongoing.

Patients received danicopan at an initial dose of 150 mg 3 times per day, which could be escalated to 200 mg 3 times per day based on clinical response.2 Eculizumab infusion was administered every 2 weeks at doses ranging from 900 mg to 1500 mg, and ravulizumab was administered monthly or every 8 weeks at doses ranging from 3000 mg to 3600 mg.

ALPHA demonstrated danicopan to be well tolerated, and investigators identified no new safety concerns. The most common treatment-emergent adverse effects (AEs) were headache, arthralgia, diarrhea, and nausea.1 Grade 3 AEs observed in the danicopan arm were increased alanine aminotransferase (4%), leukopenia (2%), neutropenia (4%), cholecystitis (2%), COVID-19 (2%), increased aspartate aminotransferase (2%), and increased blood pressure (2%).2 Serious AEs reported in the danicopan arm were cholecystitis and COVID-19, which occurred in 1 patient each. No serious AEs were related to danicopan, and no deaths related to the study drugs were reported in the trial.

“The approval of [the] first-in-class, Factor D inhibitor [danicopan] marks an important advancement in the treatment of [patients with] PNH and builds on our leadership and commitment to bring forward innovation in complement science,” Marc Dunoyer, chief executive officer of Alexio, the group within AstraZeneca focused on rare diseases, said in a news release.1 “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 extravascular hemolysis, enabling them to continue with proven standard-of-care therapy.”

Previously, danicopan was granted breakthrough therapy designation by the FDA and PRIME status by the European Medicines Agency. Furthermore, the agent was granted orphan drug designation in the United States, European Union (EU), and Japan for the treatment of patients with PNH. Danicopan was approved in Japan for this indication, and approval is recommended in the EU.1


  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. Lee JW, Griffin M, Kim JS, et al. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023;10(12):e955-e965. doi:10.1016/S2352-3026(23)00315-0
  3. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(23)00315-0/abstract
  4. Danicopan as add-on therapy to a C5 inhibitor in paroxysmal nocturnal hemoglobinuria (PNH_ participants who have clinically evident extravascailar hemolysis (EVH) (ALPHA). ClinicalTrials.gov. Updated February 6, 2024. Accessed April 1, 2024. https://clinicaltrials.gov/study/NCT04469465
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