Bélanger Patrice, West Christine R, Brown Mark T
Pfizer Inc, CA USA.
Pfizer Inc, CT USA.
J Toxicol Sci. 2018;43(1):1-10. doi: 10.2131/jts.43.1.
Therapeutic agents commonly used in the management of chronic pain have limited effectiveness and may be associated with issues of dependence and tolerability. Thus, a large unmet medical need exists for the development of safe and effective therapeutics for treatment of chronic pain. A novel approach includes identification of intracellular signals involved in the pain transduction pathway, such as nerve growth factor (NGF). Monoclonal antibodies targeting NGF, such as tanezumab, fulranumab and fasinumab, have been investigated for the treatment of chronic pain conditions. Due to unexpected joint adverse events in clinical studies and concerns about sympathetic nervous system toxicity in animals, these agents were placed on 2 separate partial clinical holds, which were subsequently lifted after rigorous evaluations were conducted to understand how inhibition of NGF impacts safety. To share learnings regarding the rigorous evaluation of clinical and nonclinical safety data which contributed to the removal of these partial clinical holds, this article reviews the rationale for developing agents that target NGF as potential treatments for chronic pain, describes nonclinical and clinical studies of these agents, and describes strategies used to evaluate whether inhibition of NGF has negative effects on joint or sympathetic nervous system safety.
常用于慢性疼痛管理的治疗药物效果有限，且可能存在依赖性和耐受性问题。因此，开发安全有效的慢性疼痛治疗药物存在巨大的未满足医疗需求。一种新方法包括识别疼痛传导途径中涉及的细胞内信号，如神经生长因子（NGF）。针对NGF的单克隆抗体，如他尼珠单抗、氟罗珠单抗和法西珠单抗，已被研究用于治疗慢性疼痛病症。由于临床研究中出现意外的关节不良事件以及对动物交感神经系统毒性的担忧，这些药物被置于两项单独的部分临床搁置状态，随后在进行了严格评估以了解NGF抑制如何影响安全性后解除搁置。为分享有关严格评估临床和非临床安全性数据从而促成解除这些部分临床搁置的经验教训，本文回顾了开发靶向NGF的药物作为慢性疼痛潜在治疗方法的基本原理，描述了这些药物的非临床和临床研究，并描述了用于评估NGF抑制是否对关节或交感神经系统安全性有负面影响的策略。
