Danicopan Improves Hemoglobin, Reduces Transfusion Requirements in Eculizumab-Treated Patients With PNH

First-in-class oral factor D inhibitor danicopan improved hemoglobin (Hb) and reduced transfusion requirements in transfusion-dependent patients with paroxysmal nocturnal hemoglobinuria (PNH) who had previously experienced a suboptimal response to eculizumab, according to findings from a phase II study published in Blood.

The approval of eculizumab, a C5 inhibitor monoclonal antibody that blocks terminal complement activation and intravascular hemolysis (IVH), “revolutionized the treatment of PNH,” according to study authors. Many patients with PNH who are treated with eculizumab experience improved symptoms related to IVH, reduced thromboembolic events, as well as improved quality of life and survival. A small proportion of patients, however, still experience residual anemia after treatment, and some of these patients also remain transfusion dependent.

Most patients treated with C5 inhibitors, such as eculizumab or ravulizumab, will achieve transfusion independence, explained corresponding study author Robert A. Brodsky, MD, of the Johns Hopkins University School of Medicine. “However, roughly 15-20% continue to require occasional transfusions, mostly due to C3 fragment deposition and extravascular hemolysis in the spleen and liver,” he explained. “Danicopan blocks complement upstream of the C3 convertase, thereby preventing extravascular hemolysis.”

Dr. Brodsky and colleagues evaluated the safety and efficacy of a 24-week course of danicopan with eculizumab in 12 patients with PNH. These patients had previously experienced an inadequate response to eculizumab alone, as evidenced by their need for transfusion.

Patients in this study received oral danicopan at an initial starting dose of 100 mg or 150 mg three times per day. Patients also received concomitant eculizumab at their normal dose and schedule. Dose escalations to a maximum of 200 mg three times per day were permitted at four-week intervals, based on safety outcomes and Hb levels through week 12.

Participants who completed the 24-week treatment course and achieved a clinical benefit were eligible to move into a long-term extension phase of the study, which examined outcomes associated with continuous danicopan and eculizumab dual therapy.

The median age of patients in the phase II study was 48 years (range = 19-72). Despite stable eculizumab treatment, patients had increased levels of lactate dehydrogenase at study entry (mean = 244.5 IU/L; 1.06 × upper limit of normal). All patients were considered anemic, with a mean Hb level of 7.9 mg/dL, and all but one patient had a history of red blood cell (RBC) transfusions, with an average of 2.8 transfusions in the 24-week period before the first danicopan dose.

A significant increase in mean Hb was observed from baseline to week 24, from 7.9 g/dL to 10.3 g/dL. In most patients, the Hb improvement was apparent by week 2 of treatment and was maintained throughout the study.

From baseline to week 24, the researchers also observed mean reductions in absolute reticulocyte counts from 219 to 135×103/μL (p<0.0001), total bilirubin from 2.17 to 1.35 mg/dL (p=0.0094), and direct bilirubin from 0.51 to 0.37 mg/dL (p=0.0093).

In addition, the investigators reported a clinically meaningful reduction in RBC transfusion requirements during the study. Ten of 11 patients in the efficacy analyses received 31 transfusions, totaling 50 units, within a 24-week period before the first danicopan dose.

The FACIT-Fatigue score was used to assess the severity of fatigue, as measured on a scale of 0 to 52. A score lower than 30 indicates severe disease, while higher scores suggest improvements in fatigue. During the study, the mean FACIT-Fatigue score increased significantly by 11 points, from 34 to 45 (p=0.0191).

Limitations of the study included its small sample size, the relatively short duration of follow-up, and the lack of a control arm.

Dr. Brodsky added that it also remains to be determined whether danicopan can be used long-term as a standalone drug “or whether its use will be relegated as an adjunct to C5 inhibition.” He added that more data are needed on the long-term safety of combining C5 and factor D inhibitors.

The study authors reported relationships with Achillion, a subsidiary of Alexion Pharmaceuticals, which funded the study.


Kulesekararaj A, Risitano AM, Maciejewski JP, et al. Phase 2 study of danicopan in paroxysmal nocturnal hemoglobinuria patients with an inadequate response to eculizumab [published online ahead of print, 2021 Jul 27]. Blood. doi: 10.1182/blood.2021011388.