Service de Rhumatologie, Groupe Hospitalier Pellegrin, 33076, Bordeaux Cedex, France,
Drugs. 2014 Apr;74(6):619-26. doi: 10.1007/s40265-014-0208-6.
It is unanimously accepted that there is an unmet need for pain medications that are both effective and safe. Unfortunately, no really novel analgesics have been approved over the past three 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, drug discovery efforts focusing on the development of anti-NGF agents have aroused particular interest. Several humanized anti-NGF monoclonal antibodies (mAbs) have entered clinical trials as potential analgesics. In this respect, tanezumab is at an advanced stage of clinical development while fulranumab, fasinumab and ABT-110, previously known as PG110, are in early phases of clinical development. This Current Opinion article aims at describing the rationale for targeting NGF for pain, reviewing the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies, conference abstracts, and the US Food and Drug Administration (FDA) website, and discussing the possible future of these agents in managing chronic pain. Anti-NGF mAbs produced significant pain relief and functional improvement in patients with osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain generated mixed results; overall, this condition appeared to be less responsive to anti-NGF agents than osteoarthritis. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in some types of chronic visceral or neuropathic pain. Furthermore, these studies raised safety concerns about anti-NGF mAbs. As a class, these drugs may cause or worsen peripheral neuropathies. But the most problematic issue-which prompted the FDA to place studies of these compounds on clinical hold in 2010-was rapid joint destruction leading to joint replacement surgery. The aetiologies of these side effects have been much debated and their pathophysiology is poorly understood. After an Arthritis Advisory Committee meeting held in March 2012, pharmaceutical companies negotiated with the FDA on the conditions for restarting clinical studies. Although the FDA lifted its clinical hold, there remain many unresolved issues about the long-term efficacy and safety of anti-NGF mAbs. While acknowledging that the future of these drugs is unforeseeable, it appears that they may not be the safe and effective painkillers that have been awaited for decades.
人们普遍认为，需要开发既有效又安全的疼痛治疗药物。遗憾的是，在过去的三十年中，没有真正新颖的镇痛药获得批准。鉴于神经生长因子（NGF）在产生和维持广泛的疼痛状态方面具有重要作用的实验和临床证据，因此，专注于开发抗 NGF 药物的药物发现工作引起了特别的关注。几种人源化抗 NGF 单克隆抗体（mAb）已作为潜在的镇痛药进入临床试验。在这方面，tanezumab 处于临床开发的后期阶段，而 fulranumab、fasinumab 和 ABT-110（以前称为 PG110）处于临床开发的早期阶段。本文旨在描述针对 NGF 治疗疼痛的基本原理，根据已发表的研究、会议摘要和美国食品和药物管理局（FDA）网站的数据，综述抗 NGF 药物的镇痛疗效和安全性，并讨论这些药物在治疗慢性疼痛方面的未来可能。抗 NGF mAb 可显著缓解膝和/或髋关节炎患者的疼痛并改善其功能。相反，在非特异性下腰痛的研究中得出了混合结果；总体而言，这种疾病对抗 NGF 药物的反应似乎不如骨关节炎敏感。最后，没有确凿的证据表明抗 NGF mAb 对某些类型的慢性内脏或神经性疼痛有效。此外，这些研究引起了对抗 NGF mAb 安全性的担忧。作为一类药物，这些药物可能导致或加重周围神经病变。但最成问题的问题-这促使 FDA 于 2010 年暂停了这些化合物的临床研究-是快速的关节破坏导致关节置换手术。这些副作用的病因引起了广泛的争论，其病理生理学尚未得到很好的理解。在 2012 年 3 月举行的关节炎咨询委员会会议之后，制药公司与 FDA 就重新开始临床研究的条件进行了谈判。尽管 FDA 解除了临床搁置，但关于抗 NGF mAb 的长期疗效和安全性仍存在许多未解决的问题。虽然承认这些药物的未来是不可预测的，但它们似乎不会成为人们期待了几十年的安全有效的止痛药。
