Long-term efficacy and safety of danicopan as add-on therapy to ravulizumab or eculizumab in PNH with significant EVH

Abstract

Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH; hemoglobin [Hb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period 1 (TP1); those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2, and 80 entered LTE. The primary end point was met, with Hb improvements from baseline at week 12 (least squares mean change, 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at week 12, improvements in mean Hb were observed at week 24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. This trial was registered at www.clinicaltrials.gov as #NCT04469465.

Graphical abstract

Figure 1.

Change in Hb across 72 weeks of treatment. Summary of actual Hb values, irrespective of transfusions, over 72 weeks of treatment with danicopan as an add-on therapy. Mean (SD) values of Hb (g/dL) for treatment groups are plotted across each time point, and corresponding n values are shown in the table below. BL, baseline.

Figure 2.

Change in LDH across 72 weeks of treatment. Summary of actual values of LDH over 72 weeks of treatment with danicopan as an add-on therapy. Mean (SD) values of LDH (U/L) for treatment groups are plotted across each time point, and corresponding n value are shown in the table below. BL, baseline.

Figure 3.

Proportion of participants avoiding transfusions while receiving danicopan as an add-on therapy. The number of participants achieving transfusion avoidance are expressed as a percent relative to the total participants in the corresponding treatment group. Corresponding n values are shown at the base of each data point. ∗∗∗P ≤ .001. ∗Defined as participants who remain transfusion free and did not require a transfusion per protocol-specified guidelines. ^†Participants who were RBC transfusion free during the 24 weeks before receiving study drug. ^‡P values are only available for week 12 or TP1.

Figure 4.

Summary of actual ARCs over 72 weeks of treatment. Mean (SD) values of ARCs (×10⁹/L) for treatment groups are plotted across each time point, and corresponding n values are shown in the table below. BL, baseline.

Figure 5.

Summary of FACIT-Fatigue scores over 72 weeks of treatment. Mean (SD) FACIT-Fatigue scores are plotted across each time point, and corresponding n values are shown in the table below. ∗Mean FACIT-Fatigue scores among the general population have been reported to be ∼43.5 to 43.6.^, BL, baseline.