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 [Hgb] ≤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 (TP) 1; 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 endpoint was met, with Hgb improvements from baseline at week 12 (Wk12) (LS mean change: 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at Wk12, improvements in mean Hgb were observed at Wk24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hgb 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. Registration: Clinicaltrials.gov, NCT04469465.

中文翻译：

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Danicopan 作为 Ravulizumab 或 Eculizumab 的附加疗法在具有显着 EVH 的 PNH 中的长期疗效和安全性。


使用 ravulizumab 或依库珠单抗补体 C5 抑制剂治疗阵发性睡眠性血红蛋白尿症 （PNH） 可改善结局和生存率。一些患者由于有临床意义的血管外溶血（cs-EVH：血红蛋白 [Hgb] ≤9.5 g/dL 和网织红细胞绝对计数 [ARC] ≥120×109/L）而保持贫血。在 3 期 ALPHA 试验中，参与者在 12 周的双盲治疗期 （TP） 1 期间接受口服因子 D 抑制剂达尼可泮（150 毫克，每天 3 次）或安慰剂加拉武利珠单抗或依库珠单抗 1;接受安慰剂的患者在随后的 12 周开放标签 TP2 中改用 Danicopan，并在 2 年长期延长 （LTE） 期间继续治疗。该研究随机分配了 86 名参与者，其中 82 名进入 TP2,80 名进入 LTE。达到主要终点，丹尼克潘在第 12 周 （Wk12） 时 Hgb 较基线改善 （LS 平均变化： 2.8 g/dL）。对于在第 12 周从安慰剂转换为达尼可坦的参与者，在第 24 周观察到平均 Hgb 的改善。Hgb 增加 ≥2 g/dL 的参与者比例、ARC、实现避免输血的参与者比例以及慢性病治疗功能评估 - 疲劳量表评分也观察到类似的趋势。改善一直维持到第 72 周。未观察到新的安全信号。突破性溶血率为 6 例/100 患者年。这些长期数据表明，丹尼可潘联合 ravulizumab/依库珠单抗在持续控制 PNH 中的终末补体活性、血管内溶血和 cs-EVH 方面的持续疗效和安全性。注册：Clinicaltrials.gov、NCT04469465。