Danicopan add-on therapy demonstrates positive efficacy and safety outcomes in advanced age adults with paroxysmal nocturnal hemoglobinuria and clinically significant extravascular hemolysis: A sub-analysis of the phase 3 ALPHA trial Free

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by intravascular hemolysis, thrombosis, and organ damage. Add-on therapy with danicopan, a first-in-class oral factor D inhibitor, has shown significant improvements to clinical outcomes in adult patients with ravulizumab- or eculizumab-treated PNH and clinically significant extravascular hemolysis (csEVH; defined as hemoglobin [Hb] <9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 10⁹/L), shown by the pivotal phase 3 ALPHA trial (NCT04469465). However, there is limited evidence examining whether this translates to patients with advanced age (≥65 years).

Objective To characterize the efficacy and safety of danicopan add-on therapy in patients with advanced age with PNH and csEVH receiving ravulizumab or eculizumab from the ALPHA trial.

Methods This sub-analysis focused on the primary treatment period of the ALPHA trial, during which adult patients (aged ≥18 years) with PNH and csEVH with ≥6 months of ravulizumab or eculizumab treatment were randomized 2:1 to receive add-on danicopan or placebo (PBO) for 12 weeks. Outcomes were evaluated by age at study enrollment (≥65 and <65 years) and included change from baseline in Hb concentration, ARC, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score up to 12 weeks; the proportion of patients who were transfusion independent at 12 weeks; and the proportion of patients who experienced adverse events (AEs) during the 12-week period.

Results In total, 86 patients were enrolled into ALPHA; 57 were randomized to add-on danicopan (59.6% female, 16 aged ≥65 years, 41 aged <65 years), and 29 were randomized to add-on PBO (69.0% female, 6 aged ≥65 years, 23 aged <65 years). Mean (standard deviation; SD) baseline clinical characteristics were similar between age groups in the danicopan arm (aged ≥65 vs <65 years: Hb concentration, 7.6 [0.9] g/dL vs 7.7 [1.0] g/dL; ARC, 216.0 [40.4] × 10⁹/L vs 260.0 [109.8] × 10⁹/L; FACIT-F, 36.0 [8.5] vs 33.2 [12.2]) and the PBO arm (aged ≥65 vs. <65 years: Hb concentration, 8.3 [0.8] g/dL vs 7.8 [0.1] g/dL; ARC, 201.1 [69.1] × 10⁹/L vs 228.6 [125.7] × 10⁹/L; FACIT-F, 38.3 [9.2] vs 29.9 [10.9]). In the danicopan arm, both age groups showed an increase in mean (SD) Hb concentration from baseline to week 1 (aged ≥65 years, 2.7 [1.0] g/dL; aged <65 years: 1.9 [1.0] g/dL), which was maintained in patients aged ≥65 years and improved in those aged <65 years through to week 12 (aged ≥65 years, 2.8 [1.7] g/dL, 50.0% with an increase ≥2.0 g/dL; aged <65 years: 3.1 [1.4] g/dL, 56.1% with an increase ≥2.0 g/dL). During this period, both age groups also demonstrated a meaningful reduction in mean (SD) ARC (aged ≥65 years, –51.2 [74.4] × 10⁹/L; aged <65 years, –105.3 [97.7] × 10⁹/L) and increases in FACIT-F score (aged ≥65 years, +4.9 [6.4]; aged <65 years, +9.4 [7.9]), which was more pronounced in patients aged <65 years. In comparison, there were no notable improvements in mean (SD) Hb concentration, ARC or FACIT-F from baseline to week 12 in the PBO arm (aged ≥65 vs <65 years: Hb concentration, 0.5 [0.6] g/dL vs 0.8 [0.9] g/dL; ARC, 9.0 [39.0] × 10⁹/L vs 0.1 [54.2] × 10⁹/L; FACIT-F, –4.0 [6.1] vs 4.6 [9.4]). In the danicopan arm, the proportion of patients who were transfusion independent at week 12 was similar between patients aged ≥65 and <65 years (75.0% vs 80.5%, respectively) and was higher compared with those in the PBO arm (30.4% vs 16.7%, respectively). The proportion of patients in the danicopan arm who experienced an AE during 12 weeks of add-on therapy was similar between patients aged ≥65 and <65 years (68.8% vs 78.0%, respectively). In both age groups, the proportion of patients experiencing an AE was lower in the PBO arm, particularly in those aged ≥65 years (50.0% vs 65.2%, respectively).

ConclusionThis sub-analysis demonstrates that danicopan add-on to ravulizumab or eculizumab has a positive efficacy and safety profile in patients with advanced age with PNH and csEVH. During 12 weeks of danicopan add-on therapy, these patients reported meaningful improvements in Hb concentration and ARC, while maintaining transfusion avoidance and a low rate of AEs. Overall, this analysis supports the use of danicopan add-on therapy in patients with advanced age with PNH and csEVH treated with ravulizumab or eculizumab, with no new safety signals.