背景:临床上显著的血管外溶血引起的贫血症状可影响使用C5抑制剂(ravulizumab或eculizumab)治疗的阵发性夜间血红蛋白尿(PNH)患者。这项研究的目的是评估danicopan(ALXN2040)的疗效和安全性,一个调查,一流的,口服补体因子D抑制剂,作为Ravulizumab或eculizumab在PNH和临床显著血管外溶血患者中的附加治疗。
方法:ALPHA正在进行中,国际,第三阶段,随机,双盲,安慰剂对照试验评估danicopan作为ravulizumab或eculizumab的附加治疗.符合条件的患者为成人(年龄≥18岁),在ravulizumab或eculizumab治疗至少6个月后出现PNH和临床显著血管外溶血(血红蛋白≤9·5g/dL;网织红细胞绝对计数≥120×109/L)。患者被随机分配(2:1)到danicopan或安慰剂添加到ravulizumab或eculizumab12周使用交互式反应技术系统。根据输血史对随机化进行分层,血红蛋白,和来自日本的患者。最初的口服danicopan剂量为每天3次150mg;根据临床反应,允许每天3次增加至200mg。eculizumab的输注剂量水平(每2周)范围为900mg至1500mg,对于ravulizumab(每月或每8周),范围为3000mg至3600mg。主要终点是血红蛋白浓度从基线到第12周的变化。在这里,我们提出了协议预设的中期分析,计划时,约75%的参与者被随机分配到治疗组,并在12周时完成或停止治疗.本试验在ClinicalTrials.gov(NCT04469465)注册。
结果:个人在2020年12月16日至2022年8月29日之间随机分配。在数据截止时(2022年6月28日),73个人被随机分配,接受治疗,并进行了安全性分析(danicopan,n=49;安慰剂,n=24)。协议预设的中期疗效分析集包括前63名参与者(danicopan,n=42;安慰剂,n=21)。在第12周,danicopan+ravulizumab或eculizumab与安慰剂+ravulizumab或eculizumab相比增加了血红蛋白(最小二乘均值[LSM]相对于基线的变化:danicopan,2·94g/dL[95%CI2·52至3·36];安慰剂,0·50g/dL[-0·13至1·12];LSM差异,2·44g/dL[1·69至3·20];p<0·0001)。danicopan组的3级不良事件是丙氨酸转氨酶升高(49例患者中有2例[4%]),白细胞减少症(一[2%]),中性粒细胞减少症(2[4%]),胆囊炎(一[2%]),COVID-19(一种[2%]),天冬氨酸转氨酶增加(1[2%]),血压升高(1[2%]),安慰剂组贫血(24例患者中有1例[4%]),血小板减少症(1[4%]),和虚弱(1[4%])。danicopan组报告的严重不良事件是胆囊炎(1例[2%]患者)和COVID-19(1例[2%]患者),安慰剂组为贫血和腹痛,均在一名(4%)患者中。研究中没有报告与研究药物相关的严重不良事件或死亡。
结论:这些主要疗效和安全性结果表明,danicopan作为ravulizumab或eculizumab的附加治疗在第12周时显著改善了血红蛋白浓度,没有新的安全性问题,提示PNH和有临床意义的血管外溶血患者的获益-风险状况得到改善.
背景:Alexion,阿斯利康罕见疾病。
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).
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Alexion, AstraZeneca Rare Disease.