J&J’s Esketamine for Depression Faces an FDA Panel Next Week

强生抗抑郁药 Esketamine 疑似致幻,下周将面临 FDA 的调查

2019-02-10 09:39:08 BioSpace


On Feb. 12, a U.S. Food and Drug Administration (FDA) advisory committee will debate whether to recommend Johnson & Johnson’s esketamine spray for major depression. It may be an uphill battle, although any positive results in this extremely difficult-to-treat patient population will no doubt be taken into account. Esketamine is related to ketamine, a well-known party drug. Esketamine nasal spray is being developed by Janssen Research & Development, a J&J company. Esketamine is a glutamate receptor modulator that they believe restores synaptic connections in brain cells in individuals with major depressive disorder. Esketamine also appears to induce a dreamlike sensation in some users, which has the agency concerned, although the probability of abuse seems low. “Ketamine abuse is relatively uncommon in the general population,” agency staff wrote in a report ahead of the meeting. However, there are concerns that patients receiving the drug in a doctor’s office might experience the euphoria and dissociation as they leave. It takes about 90 minutes for those “high” symptoms to resolve. There are also concerns about elevated blood pressure. On September 21, 2018, Janssen announced results from a Phase III trial of the esketamine spray that was disappointing. It failed to show statistical significance for the primary endpoint, change in a depression severity rating scale score from baseline to four weeks, for the 84 mg dose plus an oral antidepressant compared to oral antidepressant and placebo. However, analyses of the primary endpoint and key secondary endpoints favored the esketamine plus oral antidepressant groups over the control group. At the time, Husseini K. Manji, Janssen Research & Development’s Global Head, Neuroscience Therapeutic Area, stated, “Together with the recently announced results from four other Phase III studies, these data provide continued support for a positive benefit-risk assessment for esketamine nasal spray as a potentially novel treatment approach for patients living with treatment-resistant depression. One-third of patients with major depressive disorder do not respond to existing therapies, and they need new treatment options.” Earlier trials showed some benefit in patients who had failed at least two prior treatments. In one of the trials, about 69 percent of the study group responded to the drug after 4 weeks compared to 52 percent in the intranasal placebo group. And 52.2 percent of the esketamine group achieved remission compared to only 31 percent of the placebo group at Week 4. The company’s New Drug Application (NDA) was accepted on Sept. 4., 2018. It is based on five pivotal Phase III trials—three short-term studies, one withdrawal maintenance of effect study, and one long-term safety study. The studies defined treatment-resistant depression as patients who didn’t respond to two or more antidepressants of adequate dose and duration. The FDA staff report also noted there were six deaths in patients taking esketamine in the trial, three of which were suicide. Since those patients had treatment-resistant severe depression, that’s unlikely to be a side effect of the drug itself. Reviewers wrote, “Given the small number of cases, the severity of the patients’ underlying illness, and the lack of a consistent pattern among these cases, it is difficult to consider these deaths as drug-related.” Janssen has a target action date for the drug of March 4. It had received Breakthrough Therapy designation for treatment-resistant depress in addition to depressed people at risk of suicide. Data from a study in suicidal patients is expected this year.
2月12日, 美国食品和药物管理局(FDA) 咨询委员会将 讨论 是否推荐 强生公司的艾蒿胺喷雾治疗严重抑郁症。这可能是一场艰苦的战斗,尽管这种极难治疗的患者群体的任何积极结果无疑都会被考虑在内。 Esketamine与氯胺酮有关,氯胺酮是一种众所周知的派对药物。Esketamine鼻喷剂由 J&J公司Janssen Research&Development开发。Esketamine是一种谷氨酸受体调节剂,他们认为可以恢复重度抑郁症患者脑细胞的突触连接。 尽管滥用的可能性似乎很低,但依此使用该药物,一些用户似乎也会引起一种梦幻般的感觉。“在一般人群中,氯胺酮滥用相对不常见,”该机构工作人员在会 前提交的一份报告中写道 。 然而,有人担心在医生办公室接受药物的患者可能会在离开时感受到兴奋和分离。这些“高”症状需要大约90分钟才能解决。还有人担心血压升高。 在2018年9月21日,Janssen 宣布 了一项令人失望的esketamine喷雾III期试验的结果。对于84mg剂量加口服抗抑郁药与口服抗抑郁药和安慰剂相比,它未显示主要终点的统计学显着性,从基线到4周的抑郁严重性评定量表评分的变化。 然而,对主要终点和关键次要终点的分析有利于对照组的艾氯胺酮加口服抗抑郁药组。 当时 ,Janssen研究与发展部全球负责人,神经科学治疗领域的Husseini K. Manji表示,“连同其他四项III期研究最近公布的结果,这些数据为esketamine的正面利益风险评估提供了持续的支持。鼻喷雾作为一种潜在的新型治疗方法,适用于患有抗抑郁治疗的患者。三分之一的重度抑郁症患者对现有疗法没有反应,他们需要新的治疗方案。“ 早期试验 显示,至少两次治疗失败的患者有一些好处。在其中一项试验中,约有69%的研究组在4周后对该药物有反应,而鼻内安慰剂组为52%。52.2%的艾氯胺酮组达到缓解,而第4周只有安慰剂组的31%。 该公司的新药申请(NDA)于2018年9月4日被接受。它基于五个关键的III期试验 - 三项短期研究,一项效果研究的退出维持和一项长期安全性研究。 这些研究将治疗抵抗性抑郁症定义为对两种或多种剂量和持续时间足够的抗抑郁药无反应的患者。 美国食品和药物管理局的工作人员报告还指出,在试验中服用艾氯胺酮的患者中有6人死亡,其中3人是自杀。由于这些患者具有治疗抵抗性严重抑郁症,因此不太可能是药物本身的副作用。评论者写道,“鉴于病例数量较少,患者潜在疾病的严重程度,以及这些病例之间缺乏一致的模式,很难将这些死亡视为与药物相关的。” Janssen有一个针对3月4日药物的目标行动日期。除了有自杀风险的抑郁症患者外,它还获得了治疗抵抗抑郁症的突破性治疗指定。预计今年有关自杀患者的研究数据。