在阵发性夜间血红蛋白尿和临床显著的血管外溶血(ALPHA)患者的ravulizumab或eculizumab中加入达尼可泮:一项双盲、随机、3期试验

Jong Wook Lee, Morag Griffin, Jin Seok Kim, Lily Wong Lee Lee, Caroline Piatek, Jun-ichi Nishimura, Cynthia Carrillo Infante, Deepak Jain, Peng Liu, Gleb Filippov, Flore Sicre de Fontbrune, Antonio Risitano, Austin G Kulasekararaj
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引用次数: 0

摘要

背景:临床显著的血管外溶血引起的贫血症状可影响C5抑制剂(ravulizumab或eculizumab)治疗的突发性夜间血红蛋白尿(PNH)患者。该研究的目的是评估danicopan (ALXN2040)的有效性和安全性,danicopan是一种研究性的、一流的口服补体因子D抑制剂,作为ravulizumab或eculizumab的附加治疗,用于PNH和临床显著的血管外溶血患者。salpha是一项正在进行的国际3期随机、双盲、安慰剂对照试验,评估达尼可泮作为ravulizumab或eculizumab的附加治疗。符合条件的患者为患有PNH且有临床意义的血管外溶血的成年人(年龄≥18岁)(血红蛋白≤9.5 g/dL;绝对网织红细胞计数≥120 × 109/L)使用拉乌利珠单抗或埃曲利珠单抗治疗至少6个月。采用互动反应技术系统,患者被随机分配(2:1)到在ravulizumab或eculizumab的基础上添加达尼可潘或安慰剂组,持续12周。根据输血史、血红蛋白和来自日本的患者进行随机分层。初始口服达尼可泮剂量为150mg,每日3次;根据临床反应,可将剂量增加至200mg,每日三次。eculizumab输注剂量水平(每2周)为900 mg至1500 mg,而ravulizumab输注剂量水平(每月或每8周)为3000 mg至3600 mg。主要终点是血红蛋白浓度从基线到第12周的变化。在这里,我们提出了方案预先指定的中期分析,计划在大约75%的参与者随机分配到治疗组,并在12周完成或停止治疗。该试验已在ClinicalTrials.gov注册(NCT04469465)。在2020年12月16日至2022年8月29日期间,参与者被随机分配。在数据截止日期(2022年6月28日),随机分配73人接受治疗,并进行安全性分析(达尼可潘,n=49;安慰剂,n = 24)。方案预先指定的中期疗效分析集包括前63名参与者(达尼可潘,n=42;安慰剂,n = 21)。在第12周,达尼可泮联合ravulizumab或eculizumab与安慰剂联合ravulizumab或eculizumab相比增加了血红蛋白(最小二乘平均值[LSM]从基线变化:达尼可泮,2.94 g/dL [95% CI 2.52至3.36];安慰剂,0.50 g/dL [- 0.13 ~ 1.12];LSM差异为2.44 g/dL [1.69 ~ 3.20];术;0·0001)。达尼可潘组3级不良事件为谷丙转氨酶升高(49例患者中2例[4%])、白细胞减少(1例[2%])、中性粒细胞减少(2例[4%])、胆囊炎(1例[2%])、COVID-19(1例[2%])、天冬氨酸转氨酶升高(1例[2%])、血压升高(1例[2%]),安慰剂组为贫血(24例患者中1例[4%])、血小板减少(1例[4%])、虚弱(1例[4%])。达尼可潘组报告的严重不良事件为胆囊炎(1例[2%])和COVID-19(1例[2%]),安慰剂组报告的严重不良事件为贫血和腹痛,均发生在1例(4%)患者中。研究中没有与研究药物相关的严重不良事件或死亡报告。这些主要的疗效和安全性结果表明,达尼可泮作为ravulizumab或eculizumab的附加治疗可显着改善第12周的血红蛋白浓度,没有新的安全性问题,表明PNH和临床显著的血管外溶血患者的获益-风险概况得到改善。阿斯利康罕见病基金。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial

Background

Symptoms of anaemia due to clinically significant extravascular haemolysis can affect patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with C5 inhibitors (ravulizumab or eculizumab). The aim of this study was to assess the efficacy and safety of danicopan (ALXN2040), an investigational, first-in-class, oral complement factor D inhibitor, as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant extravascular haemolysis.

Methods

ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evaluating danicopan as add-on therapy to ravulizumab or eculizumab. Eligible patients were adults (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9·5 g/dL; absolute reticulocyte count ≥120 × 109/L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; escalation to 200 mg three times a day was permitted based on clinical response. The infusion dose level of eculizumab (every 2 weeks) ranged from 900 mg to 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465).

Findings

Individuals were randomly assigned between Dec 16, 2020, and Aug 29, 2022. At data cutoff (June 28, 2022), 73 individuals were randomly assigned, received treatment, and were analysed for safety (danicopan, n=49; placebo, n=24). The protocol-prespecified interim efficacy analysis set included the first 63 participants (danicopan, n=42; placebo, n=21). At week 12, danicopan plus ravulizumab or eculizumab increased haemoglobin versus placebo plus ravulizumab or eculizumab (least squares mean [LSM] change from baseline: danicopan, 2·94 g/dL [95% CI 2·52 to 3·36]; placebo, 0·50 g/dL [–0·13 to 1·12]; LSM difference, 2·44 g/dL [1·69 to 3·20]; p<0·0001). Grade 3 adverse events in the danicopan group were increased alanine aminotransferase (two [4%] of 49 patients), leukopenia (one [2%]), neutropenia (two [4%]), cholecystitis (one [2%]), COVID-19 (one [2%]), increased aspartate aminotransferase (one [2%]), and increased blood pressure (one [2%]), and in the placebo group were anaemia (one [4%] of 24 patients), thrombocytopenia (one [4%]), and asthenia (one [4%]). The serious adverse events reported in the danicopan group were cholecystitis (one [2%] patient) and COVID-19 (one [2%]) and in the placebo group were anaemia and abdominal pain, both in one (4%) patient. There were no serious adverse events related to study drug or deaths reported in the study.

Interpretation

These primary efficacy and safety results show that danicopan as add-on treatment to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit–risk profile in patients with PNH and clinically significant extravascular haemolysis.

Funding

Alexion, AstraZeneca Rare Disease.

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