FDA Approves Danicopan With C5 Inhibitor Therapy to Treat EVH in Adults With Paroxysmal Nocturnal Hemoglobinuria


Positive phase 3 trial results showed that danicopan was more effective than placebo when treating extravascular hemolysis in paroxysmal nocturnal hemoglobinuria.

FDA approval stamp -- Image credit: waldemarus | stock.adobe.com

Image credit: waldemarus | stock.adobe.com

About the Trial

Trial Name: Danicopan as Add-on Therapy to a C5 Inhibitor in Paroxysmal Nocturnal Hemoglobinuria (PNH) Participants Who Have Clinically Evident Extravascular Hemolysis (EVH) (ALPHA)

ClinicalTrials.gov ID: NCT04469465

Sponsor: Alexion Pharmaceuticals, Inc.

Completion Date: January 16, 2024

The FDA announced its approval of danicopan (Voydeya; AstraZeneca) as an add-on therapy to ravulizumab (Ultomiris; AstraZeneca) or eculizumab (Soliris; AstraZeneca) for the treatment of extravascular hemolysis (EVH) in adult patients with paroxysmal nocturnal hemoglobinuria (PNH). The approval comes after positive results from the ALPHA phase 3 clinical trial (NCT04469465).1

Danicopan is a first-in-class, oral Factor D inhibitor that addresses the needs of approximately 10% to 20% of patients with PNH who experience clinically significant EVH during treatment with a C5 inhibitor. It selectively inhibits Factor D—a complement system protein that is significant in the amplification of the complement system response—and when activated in an uncontrolled manner, the complement over responds, resulting in the body attacking healthy cells. In addition to being approved in the United States, danicopan is also approved in Japan when used in combination with a C5 inhibitor therapy for certain adults with PNH. Further, danicopan is currently being evaluated as a potential monotherapy to treat geographic atrophy in a phase 2 clinical trial.1,2

“The approval of [danicopan] offers this small subset of PNH patients an add-on therapy designed to address EVH, while maintaining disease control with [ravulizumab] or [eculizumab],” said professor Bart Scott, MD, Division of Hematology and Oncology at the University of Washington Medical Center, and Clinical Research Division at Fred Hutchinson Cancer Center, in a press release. “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.”1

ALPHA is a double-blind, placebo-controlled, multiple-dose, global phase 3 trial that evaluates the efficacy and safety of danicopan as an add-on therapy to treatment with a C5 inhibitor—revulizumab or eculizumab—in patients with PNH who experience clinically significant EVH. The enrolled patients were randomly assigned to receive either danicopan (n = 49) or placebo (n = 24) in addition to their ongoing ravulizumab or eculizumab therapy.1

After the 63 study participants either completed or discontinued from the 12-week primary treatment period, danicopan had met the primary efficacy endpoint. According to the findings, patients who received danicopan in addition to their C5 inhibitor therapy showed better changes in hemoglobin from baseline to week 12 (2.94 [.211] g/dL vs 0.50 [.313] g/dL, respectively; p < .0001). The investigators noted that the first sign of improvements was observed by week 2 and was maintained through week 12.2

Further, danicopan had met all key secondary end points, unlike placebo. The findings demonstrated that approximately 59.5% of patients who received danicopan with their C5 inhibitor therapy had experienced an improvement in hemoglobin of 2 g/dL or more at week 12 in the absence of transfusion (difference in danicopan-placebo: 46.9, 95% CI: 29.2–64.7, p < .0001). Additionally, patients treated with danicopan had avoided transfusion and remained transfusion-free through week 12, unlike those who received placebo.2

The study results had also indicted improvements in fatigue and absolute reticulocyte count, which is another indicator of clinically significant EVH. Additionally, the investigators noted observing more significant changes in lactate dehyrodenase from baseline to week 12 in those who were treated with danicopan plus ravulizumab or eculizumab (-23.49 [8.29] U/L) compared with placebo (-2.92 [11.91] U/L).2

The most commonly reported treatment-emergent adverse events (TEAEs) reported by enrolled study participants were headache (10.2%), nausea (8.2%), arthralgia (8.2%), and diarrhea (8.2%) in the danicopan arm. No TEAEs were grade 4 or 5 in severity, and results demonstrated that danicopan is well-tolerated, with no new safety concerns identified during the trial.1,2

“The approval of first-in-class, Factor D inhibitor [danicopan] marks an important advancement in the treatment of PNH and builds on our leadership and commitment to bring forward innovation in complement science,” said Marc Dunoyer, CEO of Alexion, in the press release. “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.”1

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