Bullock Amy, Kaul Inder, Li Sigui, Silber Christopher, Doherty James, Kanes Stephen J
Sage Therapeutics, Inc., Cambridge, MA, United States of America.
Kaul Consulting, LLC, Concord, MA, United States of America.
J Neurol Sci. 2021 Feb 15;421:117277. doi: 10.1016/j.jns.2020.117277. Epub 2020 Dec 20.
Parkinson's disease (PD) is characterized by both motor and nonmotor deficits. Among cardinal symptoms of this disorder, tremor is the least responsive to dopamine replacement therapy and is often undertreated. Zuranolone (SAGE-217) is an investigational oral neuroactive steroid (NAS) gamma-aminobutyric acid A (GABA) receptor-positive allosteric modulator (PAM) that has been investigated for its safety and efficacy in patients with PD. In the current open-label study, zuranolone capsules (20 to 30 mg) were administered for 7 days in 14 patients (mean age, 65.1 years; mean time since PD diagnosis, 9 years). The primary efficacy endpoint was reduction in tremor symptoms, as assessed by change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II/III Tremor Scores on Day 8. Additional endpoints included improvements in overall motor symptoms, and motor and nonmotor aspects of daily living. Adverse events (AEs) were also monitored. The MDS-UPDRS Part II/III Tremor Score improved by 40% (P < 0.0001) from baseline on Day 8. The motor score, and nonmotor experiences of daily living (nM-EDL), and motor experiences of daily living (m-EDL) scores (MDS-UPDRS Parts I and II, respectively), also improved on Day 8. No serious AEs were reported, and no patients discontinued treatment. The most common AEs were dizziness, sedation, and somnolence. Zuranolone was generally well tolerated and improved tremor symptoms in patients with PD who were on stable doses of concurrent dopaminergic agents. These data support the further investigation of NAS GABA receptor PAMs as adjunctive treatments for tremor in patients with PD.
帕金森病（PD）的特征是存在运动和非运动功能障碍。在这种疾病的主要症状中，震颤对多巴胺替代疗法的反应最小，且常常治疗不足。祖拉诺龙（SAGE-217）是一种正在研究中的口服神经活性甾体（NAS）γ-氨基丁酸A（GABA）受体正性变构调节剂（PAM），已针对其在帕金森病患者中的安全性和疗效进行了研究。在当前的开放标签研究中，14例患者（平均年龄65.1岁；自帕金森病诊断以来的平均时间为9年）服用祖拉诺龙胶囊（20至30毫克），持续7天。主要疗效终点是震颤症状的减轻，通过第8天运动障碍协会统一帕金森病评定量表（MDS-UPDRS）第二部分/第三部分震颤评分相对于基线的变化来评估。其他终点包括总体运动症状以及日常生活的运动和非运动方面的改善。还监测了不良事件（AE）。第8天，MDS-UPDRS第二部分/第三部分震颤评分较基线提高了40%（P<0.0001）。运动评分、日常生活非运动体验（nM-EDL）评分和日常生活运动体验（m-EDL）评分（分别为MDS-UPDRS第一部分和第二部分）在第8天也有所改善。未报告严重不良事件，也没有患者停止治疗。最常见的不良事件是头晕、镇静和嗜睡。祖拉诺龙总体耐受性良好，可改善稳定服用多巴胺能药物的帕金森病患者的震颤症状。这些数据支持进一步研究NAS GABA受体PAMs作为帕金森病患者震颤的辅助治疗方法。
