Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
Lancet Neurol. 2024 Oct;23(10):1013-1024. doi: 10.1016/S1474-4422(24)00309-0.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP.
ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia-Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed.
Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0-71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25-0·61]; p<0·0001). 31 (27·9% [19·6-36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3-63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group).
ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options.
argenx.
慢性炎症性脱髓鞘性多发性神经病（CIDP）是一种自身免疫性疾病，影响外周神经系统，可导致严重的肌肉无力和感觉障碍残疾。约三分之一的患者对现有治疗方法没有反应，许多部分反应的患者仍存在神经功能损害，这突显了需要有效的替代治疗方法。Efgartigimod alfa 是一种人 IgG1 抗体 Fc 片段，已在全身性重症肌无力患者中显示出疗效和安全性。我们评估了皮下注射 Efgartigimod PH20 在 CIDP 成人患者中的安全性、耐受性和疗效。
ADHERE 是一项多阶段、双盲、安慰剂对照试验，从亚太、欧洲和北美 146 个临床地点招募了 CIDP 患者。有临床意义恶化证据的参与者进入为期 12 周的每周皮下注射 1000mg Efgartigimod PH20 的开放性试验阶段（阶段 A）。那些经证实临床改善（治疗应答者）的参与者进入随机撤药阶段，接受每周皮下注射 1000mg Efgartigimod PH20 或安慰剂治疗，最长 48 周（阶段 B）。通过交互式反应技术对参与者进行随机分组（1:1），并根据他们在阶段 A 期间的调整后的炎症性神经病病因和治疗（aINCAT）评分变化以及他们在筛选前 6 个月内最近使用的 CIDP 药物进行分层。研究者、临床研究组织和参与者对治疗情况均不知情。阶段 A 的主要终点是确认的临床改善（aINCAT 下降≥1 分、炎症 Rasch 构建整体残疾量表增加≥4 分[百分位数指标]或握力增加≥8kPa，在 4 次注射和连续 2 次就诊后），评估对象为阶段 A 安全性人群。阶段 B 的主要终点是复发风险（首次 aINCAT 增加≥1 分的时间），评估对象为修改后的意向治疗人群。ADHERE 在 ClinicalTrials.gov（NCT04281472）和 EudraCT（2019-003076-39）上注册，并已完成。
2020 年 4 月 15 日至 2023 年 5 月 11 日期间，有 629 名患者接受了筛查，其中 322 名（114 名女性，208 名男性）进入了阶段 A，其中 214 名（66%，95%CI61.0-71.6）患者经确认临床改善。在阶段 B 中，221 名患者被随机分配（79 名女性，142 名男性；111 名接受皮下注射 Efgartigimod PH20，110 名接受安慰剂）。与安慰剂相比，皮下注射 Efgartigimod PH20 显著降低了复发风险（风险比 0.39 [95%CI0.25-0.61]；p<0.0001）。接受皮下注射 Efgartigimod PH20 的 31 名（27.9% [19.6-36.3]）患者发生了复发，而接受安慰剂的 59 名（53.6% [44.3-63.0]）患者发生了复发。在阶段 A 中，204 名（63%）参与者出现了治疗后出现的不良事件（TEAE），21 名（7%）参与者出现了严重的 TEAEs。在阶段 B 中，71 名（64%）接受皮下注射 Efgartigimod PH20 的患者和 62 名（56%）接受安慰剂的患者出现了 TEAEs，6 名（5%）接受皮下注射 Efgartigimod PH20 的患者和 6 名（5%）接受安慰剂的患者出现了严重的 TEAEs。有 3 名患者死亡：2 名在阶段 A（1 名与治疗无关，1 名可能与治疗有关），1 名在阶段 B（安慰剂组）。
ADHERE 表明，在对治疗有反应的 CIDP 患者中，皮下注射 Efgartigimod PH20 可降低与安慰剂相比的复发风险。需要进一步的研究来提供关于 Efgartigimod alfa 的长期效果的数据，以及它与目前可用的治疗选择相比的情况。
argenx。
