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

Abstract 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.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.