Nerve Growth Factor Antagonists: Is the Future of Monoclonal Antibodies Becoming Clearer?
Nerve Growth Factor Antagonists: Is the Future of Monoclonal Antibodies Becoming Clearer?
复制标题
神经生长因子拮抗剂：单克隆抗体的未来变得更清晰了吗？
DOI：
10.1007/s40265-017-0781-6
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发表时间：
2017-09-01
期刊：
影响因子：
11.5
通讯作者：
Kostine, Marie
中科院分区：
文献类型：
--
作者：
Bannwarth, Bernard;Kostine, Marie
尽管对既有效又安全的止痛药的需求尚未得到满足，但在过去的二十年里，几乎没有新的止痛药被批准。鉴于神经生长因子（NGF）在产生和维持广泛的疼痛状态中的主要作用的实验和临床证据，人源化抗神经生长因子单克隆抗体（抗NGF mAb）的临床开发引起了特别的兴趣。然而，美国食品和药物管理局（FDA）在2010年底暂停了抗NGF mAb的临床研究，首先是因为报告了严重的关节相关不良事件，然后是因为交感神经系统安全性问题。tanezumab和fasinumab的开发计划在FDA于2015年3月解除其控制后恢复，而其他抗NGF mAb则被其赞助商放弃。本文根据已完全发表的研究数据和网站上的公共信息，对抗神经生长因子药物的镇痛功效和安全性进行了最新综述，并讨论了这些药物在治疗慢性疼痛方面未来可能发挥的作用。抗神经生长因子单克隆抗体的疗效是高度可变的，这取决于所研究的慢性疼痛状况。在膝关节和/或髋关节有症状的骨关节炎患者中获得了最一致和令人信服的结果。相反，非特异性下背痛和周围神经性疼痛的研究产生了混合的结果。最后，没有确凿的证据表明抗神经生长因子单克隆抗体在癌症疼痛和泌尿系统慢性盆腔疼痛综合征中的有效性。治疗后出现的不良事件在抗NGF mAb中相似，因此提示了“类别特异性效应”。虽然大多数患者耐受抗神经生长因子剂，神经感觉症状频繁发生，一些患者发展新的或恶化的周围神经病变。然而，最大的安全问题是快速破坏性关节病，导致关节置换手术。迄今为止，关节相关副作用的病因及其病理生理学尚未明确阐明。然而，已经确定了一些风险因素，如较高剂量的抗神经生长因子单克隆抗体和较长的药物暴露，同时使用非甾体抗炎药和预先存在的软骨下功能不全骨折。综上所述，目前的数据表明，低剂量抗NGF单克隆抗体可能在某些慢性疼痛疾病，特别是症状性骨关节炎的选定患者中表现出有利的风险-获益比。
Although there is an unmet need for pain medications that are both effective and safe, virtually no novel analgesics have been approved over the past two decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, the clinical development of humanised anti-nerve growth factor monoclonal antibodies (anti-NGF mAbs) aroused particular interest. However, the US Food and Drug Administration (FDA) placed a clinical hold on anti-NGF mAb clinical studies in late 2010, first because of reports of serious joint-related adverse events, and afterwards because of sympathetic nervous system safety concerns. The development programmes of tanezumab and fasinumab resumed after the FDA lifted its hold in March 2015, whereas other anti-NGF mAbs were dropped by their sponsors. This article provides an updated review on the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies and public information from websites, and discusses the possible future role of these agents in managing chronic pain. The efficacy of anti-NGF mAbs was highly variable depending on the chronic pain condition studied. The most consistent and convincing results were obtained in patients with symptomatic osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain and peripheral neuropathic pain generated mixed results. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in cancer pain and urological chronic pelvic pain syndromes. Treatment-emergent adverse events were similar across anti-NGF mAbs, thus being suggestive of 'class-specific effects'. Although most patients tolerated anti-NGF agents well, neurosensory symptoms occurred frequently, and some patients developed new or worsened peripheral neuropathies. However, the most problematic safety issue was rapidly destructive arthropathies, leading to joint replacement surgery. To date, the aetiologies of joint-related side effects and their pathophysiology have not been clearly elucidated. However, some risk factors have been identified, such as higher doses of anti-NGF mAbs and longer drug exposure, concurrent nonsteroidal anti-inflammatory drug use and pre-existing subchondral insufficiency fractures. Taken together, the present data suggest that low-dose anti-NGF mABs may exhibit a favourable risk-benefit ratio in selected patients with certain chronic pain conditions, especially symptomatic osteoarthritis.