Rapid Onset and Sustained Efficacy of Onfasprodil (MIJ821), a Novel NR2B Negative Allosteric Modulator, in Patients With Treatment-Resistant Depression: A Phase 2, Randomized, Placebo-Controlled, Proof-of-Concept Study.

IF 4.6 2区医学 Q1 PSYCHIATRY

Journal of Clinical Psychiatry Pub Date : 2025-08-06 DOI:10.4088/JCP.23m15246

Richard C Shelton, Robert E Litman, Howard Hassman, David P Walling, Salvador Ros Montalbán, Joan Salvà-Coll, John Zajecka, Oleksandr Sverdlov, Baltazar Gomez-Mancilla, Mark P Healy, Y Gopi Shanker, Maria Berkheimer, Thomas Faller, Florian von Raison, Carmen Serban, Jang-Ho Cha, S Nassir Ghaemi

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引用次数: 0

Abstract

Background: Onfasprodil (MIJ821) is a highly potent and novel selective NR2B subunit negative allosteric modulator. This phase 2, randomized, placebo-controlled, proof-of-concept study evaluated efficacy and safety of onfasprodil in patients with treatment-resistant major depression (TRD).

Methods: Adults with TRD who did not respond to ≥2 antidepressants were randomized (3:3:3:3:6:4) to receive a 40-minute intravenous infusion of onfasprodil 0.16 mg/kg weekly (n = 11), onfasprodil 0.16 mg/kg biweekly (n = 10), onfasprodil 0.32 mg/kg weekly (n = 10), onfasprodil 0.32 mg/kg biweekly (n = 9), placebo weekly (n=20), or ketamine 0.5 mg/kg weekly (n= 10) for 6 weeks. Primary end point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score at 24 hours. Secondary end points were change in MADRS score at 48 hours and at final follow-up at 6 weeks. Safety and tolerability were assessed during the study.

Results: Of 70 randomized patients, 53 (75.7%) completed the study. At 24 hours, adjusted mean differences versus placebo for pooled onfasprodil 0.16 mg/kg, 0.32 mg/kg, and ketamine groups were -8.25 (P = .001), -5.71 (P = .019), and -5.67 (P = .046), and at 48 hours, -7.06 (P = .013), -7.37 (P = .013), and -11.02 (P = .019), respectively. At Week 6, adjusted arithmetic mean MADRS difference between ketamine and placebo was -5.24 (80% CI, -10.42 to -0.06; P= .0974). At Week 6, the difference versus placebo on MADRS was -5.78 (P= .0427) for pooled 0.16 mg/kg and -4.24 (P= .1133) for pooled 0.32 mg/kg groups. The commonest treatment-emergent adverse events in the onfasprodil groups were dizziness (14.3%), transient amnesia (14.3%), and somnolence (11.4%). It had overall a good safety profile and was well tolerated.

Conclusion: Onfasprodil appeared to be effective and well-tolerated across all dosing regimens in patients with TRD and demonstrated rapid onset of action (24 hours) with evidence of antidepressant effects to be maintained at Week 6, particularly for the lower-dose group.

Trial Registration: ClinicalTrials.gov identifier: NCT03756129.

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新型NR2B阴性变构调节剂Onfasprodil （MIJ821）在治疗抵抗性抑郁症患者中的快速起效和持续疗效：一项随机、安慰剂对照、概念验证的2期研究

背景：Onfasprodil （MIJ821）是一种高效的新型选择性NR2B亚基负变构调节剂。这项随机、安慰剂对照、概念验证的2期研究评估了onfasprodil对难治性重度抑郁症（TRD）患者的疗效和安全性。方法：对≥2种抗抑郁药物无反应的TRD成人随机（3:3:3:3:6:4）接受静脉滴注onfasprodil 0.16 mg/kg /周（n= 11）、onfasprodil 0.16 mg/kg /周（n= 10）、onfasprodil 0.32 mg/kg /周（n= 10）、onfasprodil 0.32 mg/kg /周（n= 9）、安慰剂（n=20）或氯胺酮0.5 mg/kg /周（n= 10），持续6周。主要终点为24小时Montgomery-Asberg抑郁评定量表（MADRS）评分与基线的变化。次要终点是48小时和6周最终随访时MADRS评分的变化。在研究期间评估了安全性和耐受性。结果：70例随机患者中，53例（75.7%）完成了研究。在24小时时，与安慰剂相比，合并onfasprodil 0.16 mg/kg、0.32 mg/kg和氯胺酮组的校正平均差异分别为-8.25 （P = 0.001）、-5.71 （P = 0.019）和-5.67 (P = 0.046)，在48小时时，分别为-7.06 （P = 0.013）、-7.37 （P = 0.013）和-11.02 （P = 0.019）。在第6周，氯胺酮和安慰剂的校正算术平均MADRS差异为-5.24 (80% CI, -10.42至-0.06；P = .0974)。在第6周，与安慰剂相比，合并0.16 mg/kg组的MADRS差异为-5.78 (P= 0.0427)，合并0.32 mg/kg组的MADRS差异为-4.24 （P= 0.1133）。在非法普罗地尔组中，最常见的治疗不良事件是头晕（14.3%）、短暂性遗忘（14.3%）和嗜睡（11.4%）。总的来说，它具有良好的安全性和耐受性。结论：在TRD患者的所有给药方案中，Onfasprodil似乎都是有效且耐受性良好的，并且表现出快速起效（24小时），有证据表明抗抑郁作用在第6周保持，特别是对于低剂量组。试验注册：ClinicalTrials.gov标识符：NCT03756129。

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来源期刊

Journal of Clinical Psychiatry 医学-精神病学

CiteScore

7.40

自引率

1.90%

发文量

审稿时长

3-8 weeks

期刊介绍： For over 75 years, The Journal of Clinical Psychiatry has been a leading source of peer-reviewed articles offering the latest information on mental health topics to psychiatrists and other medical professionals.The Journal of Clinical Psychiatry is the leading psychiatric resource for clinical information and covers disorders including depression, bipolar disorder, schizophrenia, anxiety, addiction, posttraumatic stress disorder, and attention-deficit/hyperactivity disorder while exploring the newest advances in diagnosis and treatment.