Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors.

Here, we report the final 48-week data from APPLY-PNH and APPOINT-PNH.

在这里，我们报告了来自APPLY-PNH和APPOINT-PNH的最终48周数据。

Methods

In both APPLY-PNH and APPOINT-PNH trials, patients were aged 18 years or older, with paroxysmal nocturnal haemoglobinuria (red and white blood cell population sizes ≥10%) and without laboratory evidence of bone marrow failure.

在APPLY-PNH和APPOINT-PNH试验中，患者年龄在18岁或以上，患有阵发性夜间血红蛋白尿症（红细胞和白细胞群体大小≥10%），且没有骨髓衰竭的实验室证据。

In APPLY-PNH (an open-label, randomised, phase 3 trial conducted in 39 centres [38 hospitals, one outpatient research clinic] from 12 countries or regions), patients with haemoglobin concentration lower than 10 g/dL on anti-C5 treatment (stable eculizumab or ravulizumab regimen for ≥6 months) were randomly assigned (8:5) via interactive response technology to either receive oral iptacopan 200 mg twice daily (iptacopan group) or to continue their individual intravenous eculizumab or ravulizumab regimen for 24 weeks (anti-C5 group).

在APPLY-PNH（一项开放标签、随机、III期试验，在来自12个国家或地区的39个中心[38家医院，一个门诊研究诊所]进行）中，对接受抗C5治疗（稳定使用eculizumab或ravulizumab方案≥6个月）的血红蛋白浓度低于10 g/dL的患者，通过交互式响应技术随机分配（8:5），接受口服iptacopan 200 mg每日两次（iptacopan组）或继续使用其各自的静脉注射eculizumab或ravulizumab方案24周（抗C5组）。

Randomisation was stratified by type of anti-C5 and receipt of red blood cell (RBC) transfusions in the preceding 6 months.

随机分组是根据抗C5类型和过去6个月内是否接受过红细胞(RBC)输血进行分层。

In APPOINT-PNH (an open-label, single-arm, phase 3 trial conducted in 12 hospitals from eight countries), complement inhibitor-naive patients with paroxysmal nocturnal haemoglobinuria and with haemoglobin concentration lower than 10 g/dL and lactate dehydrogenase (LDH) concentration higher than 1·5 times the upper limit of normal received iptacopan 200 mg twice daily for 24 weeks.

在APPOINT-PNH（一项在8个国家的12家医院进行的开放标签、单臂、3期试验）中，未经补体抑制剂治疗的阵发性夜间血红蛋白尿症患者，如果血红蛋白浓度低于10克/分升且乳酸脱氢酶(LDH)浓度高于正常上限的1.5倍，将接受iptacopan 200毫克，每日两次，为期24周。

Both trials had 24-week extension periods in which all patients received iptacopan monotherapy.

两项试验都有24周的延长期，在此期间所有患者接受了iptacopan单药治疗。

Primary endpoints were the proportion of patients with an increase from baseline in haemoglobin concentration of 2 g/dL or higher (APPLY-PNH and APPOINT-PNH) and haemoglobin concentration 12 g/dL or higher (APPLY-PNH) between weeks 18 and 24, all in the absence of RBC transfusions between weeks 2 and 24; results for these primary endpoints have been reported previously.

主要终点是第18至24周间，基线血红蛋白浓度增加2 g/dL或更高的患者比例(APPLY-PNH和APPOINT-PNH)以及血红蛋白浓度达到12 g/dL或更高的患者比例(APPLY-PNH)，且在第2至24周间没有接受红细胞输血；这些主要终点的结果已经先前报告过。

We report final activity and safety data at the completion of both trials (week 48).

我们在两项试验结束时（第48周）报告了最终的活性和安全性数据。

Prespecified endpoints at week 48 included percentage of patients with a haemoglobin increase from baseline of 2 g/dL or higher or haemoglobin 12 g/dL or higher (including post-transfusion data).

第48周的预定终点包括从基线起血红蛋白增加2 g/dL或更高，或血红蛋白达到12 g/dL或更高的患者百分比（包括输血后的数据）。

Efficacy data were analysed per the intention-to-treatprinciple, and safety was analysed according to the treatment that patients received.

疗效数据按照意向治疗原则进行分析，安全性分析则根据患者实际接受的治疗进行。

APPLY-PNH and APPOINT-PNH are registered with ClinicalTrials.gov, NCT04558918 and NCT04820530, respectively.

APPLY-PNH和APPOINT-PNH已在ClinicalTrials.gov上注册，注册编号分别为NCT04558918和NCT04820530。

Results

In APPLY-PNH, between Jan 25, 2021, and April 8, 2022, 62 patients (43 [69%] female, 19 [31%] male; 48 [77%] White, 12 [19%] Asian, two [3%] Black) were randomly assigned to the iptacopan group and 35 patients (24 [69%] female, 11 [31%] male; 26 [74%] White, seven [20%] Asian, two [6%] Black) to the anti-C5 group; 61 (98%) and 34 (97%), respectively, entered the extension period.

在APPLY-PNH研究中，从2021年1月25日至2022年4月8日，62名患者（女性43名[69%]，男性19名[31%]；白人48名[77%]，亚洲人12名[19%]，黑人2名[3%]）被随机分配到iptacopan组，另外35名患者（女性24名[69%]，男性11名[31%]；白人26名[74%]，亚洲人7名[20%]，黑人2名[6%]）被分配到抗C5组；分别有61名（98%）和34名（97%）进入扩展期。

At trial completion (March 6, 2023), the median duration of iptacopan treatment was 337 days (IQR 168-338).

在2023年3月6日试验结束时，iptacopan治疗的中位持续时间为337天（四分位数间距168-338天）。

In APPOINT-PNH, 40 patients were enrolled between July 19, 2021, and May 17, 2022, and received iptacopan (17 [43%] female, 23 [58%] male; 12 [30%] White, 27 [68%] Asian, one [3%] Black); all entered the extension period.

在APPOINT-PNH研究中，共有40名患者在2021年7月19日至2022年5月17日期间入组，并接受了iptacopan治疗（女性17名[43%]，男性23名[58%]；白人12名[30%]，亚洲人27名[68%]，黑人1名[3%]）；所有患者均进入了扩展期。

At trial completion (April 18, 2023), the median duration of iptacopan treatment was 337 days (IQR 337-344).

在试验结束时（2023年4月18日），iptacopan治疗的中位持续时间为337天（四分位数间距337-344天）。

At week 48, irrespective of RBC transfusions, the number of patients who had an increase in haemoglobin concentration of 2 g/dL or higher was 51 (86%) of 59 in the APPLY-PNH iptacopan group, 21 (72%) of 29 in the APPLY-PNH anti-C5-to-iptacopan group, and 38 (97%) of 39 in APPOINT-PNH.

在第48周时，无论是否接受红细胞输注，血红蛋白浓度增加2 g/dL或以上的患者人数在APPLY-PNH iptacopan组为59人中的51人（86%），在APPLY-PNH anti-C5-to-iptacopan组为29人中的21人（72%），而在APPOINT-PNH组为39人中的38人（97%）。

The number of patients who had haemoglobin concentration of 12 g/dL or higher at week 48 was 40 (68%) of 59 in the APPLY-PNH iptacopan group, 17 (59%) of 29 in the APPLY-PNH anti-C5-to-iptacopan group, and 31 (79%) of 39 in APPOINT-PNH.

在第48周时，血红蛋白浓度达到12 g/dL或以上的患者人数在APPLY-PNH iptacopan组为59人中的40人（68%），在APPLY-PNH anti-C5-to-iptacopan组为29人中的17人（59%），而在APPOINT-PNH组为39人中的31人（79%）。

There were no treatment discontinuations because of treatment-emergent adverse events or deaths.

在治疗期间没有因治疗相关的不良事件或死亡而中断治疗的情况。

Across the 48-week trials, clinical breakthrough haemolysis occurred in seven (7%) of 96 iptacopan-treated patients in APPLY-PNH (including both groups) and two (5%) of 40 in APPOINT-PNH, but it was generally mild or moderate with no iptacopan discontinuation.

在为期48周的试验中，APPLY-PNH（包括两个组别）中有7名（7%）接受iptacopan治疗的患者和APPOINT-PNH中的2名（5%）患者发生了临床突破性溶血，但这些溶血事件通常为轻度或中度，且没有导致iptacopan治疗的中断。

Three major adverse vascular events occurred in APPLY-PNH by trial completion; all were considered unrelated to iptacopan.

APPLY-PNH试验结束时发生了三起主要不良血管事件；所有这些都被认为与iptacopan无关。

The most common treatment-emergent adverse eventwas COVID-19 in APPLY-PNH (iptacopan: 18/62 patients [29%]; anti-C5-to-iptacopan: 8/34 [24%]) and headache in APPOINT-PNH (12/40 [30%]).

APPLY-PNH中最常见的治疗后不良事件是COVID-19（iptacopan组：62名患者中有18例[29%]；抗C5-iptacopan组：34名患者中有8例[24%]），而APPOINT-PNH中最常见的是头痛（40名患者中有12例[30%]）。

Severe and serious treatment-emergent adverse events were experienced by six (10%) and nine (15%) of 62 patients in the APPLY-PNH iptacopan group, respectively; in APPOINT-PNH, these were experienced by four (10%) and eight (20%) of 40 patients, respectively.

在APPLY-PNH iptacopan组的62名患者中，有6名（10%）和9名（15%）分别经历了严重和严重的治疗后不良事件；在APPOINT-PNH中，这些不良事件分别发生在4名（10%）和8名（20%）的40名患者中。

The most common serious treatment-emergent adverse eventwas COVID-19, occurring in one (2%) of 62 patients in the APPLY-PNH iptacopan group and two (5%) of 40 patients in APPOINT-PNH.

最常见的严重治疗后不良事件是COVID-19，发生在APPLY-PNH iptacopan组的62名患者中的1名（2%）和APPOINT-PNH的40名患者中的2名（5%）。

No severe treatment-emergent adverse events occurred in more than one patient.

没有超过一名患者出现严重的治疗后不良事件。

interpretation

Long-term data indicate durable haemolysis control with iptacopan in paroxysmal nocturnal haemoglobinuria, maintained normal or near-normal haemoglobin, and no new safety concerns.

长期数据表明，iptacopan在阵发性夜间血红蛋白尿症中能够持久控制溶血，并维持正常或接近正常的血红蛋白水平，且未出现新的安全问题。

We believe that these data support iptacopan as a potential therapy option, suggesting that we are in a new treatment era for paroxysmal nocturnal haemoglobinuria.

我们相信这些数据支持iptacopan作为一种潜在的治疗选择，表明我们正处于阵发性夜间血红蛋白尿症治疗新时代。

funding

Novartis.

诺华制药。