Wang Gang, Aguado Mario, Spear Matthew A, Alphs Larry, Chen Crystal, Huang Holly, Lu Xiao-Xiong, Doostzadeh Julie, Wu Shaohui, Wang Shikai, Patel Ashok, Nemeroff Charles B, Wang Zhiqiang, Li Anning, Luo Wen
Beijing Anding Hospital, Capital Medical University, Beijing, China.
SG Research, Miami, Florida.
JAMA Psychiatry. 2025 Sep 10. doi: 10.1001/jamapsychiatry.2025.2416.
This study represents a first successful use of a genetic biomarker to select potential responders in a prospective study in psychiatry. Liafensine, a triple reuptake inhibitor, may become a new precision medicine for treatment-resistant depression (TRD), a major unmet medical need.
To determine whether ANK3-positive patients with TRD benefit from a 1-mg and/or 2-mg daily oral dose of liafensine, compared with placebo, in a clinical trial.
DESIGN, SETTING, AND PARTICIPANTS: A novel pharmacogenomic biomarker, ANK3, was discovered as a predictor of liafensine's efficacy retrospectively. In this biomarker-guided, randomized, double-blind, placebo-controlled, phase 2b clinical trial conducted at 58 sites from July 2022 through March 2024, 1967 patients were assessed for eligibility and 189 ANK3-positive patients with TRD were randomized. Key exclusion criteria included specified disorders, concomitant medications, or organ dysfunction. Investigators, patients, raters, and sponsors were blinded to ANK3 status and treatment. Data analysis was performed from March 26 to April 23, 2024.
Patients were randomized 1:1:1 to once-daily oral liafensine, 1 mg; once-daily oral liafensine, 2 mg; or oral placebo once daily.
The primary outcome was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to day 42.
Of the 189 ANK3-positive patients with TRD who were randomized, 188 received study drug (mean [SD] age, 43.2 [14.8] years; 119 [63.3%] female), and 186 had at least 1 dose of study drug and 1 postrandomization efficacy evaluation. The mean (SE) MADRS score change in these patients was -15.4 (0.9) for liafensine (including both 1- and 2-mg doses) vs -11.0 (1.3) for placebo (mean treatment difference, -4.4; 95% CI, -7.6 to -1.3; P = .006). Statistically significant improvements were also seen in all secondary end points. Adverse events were tolerable, with low rates of meaningful events. Adverse events leading to discontinuation of treatment occurred in 5 patients (4.0%) receiving liafensine and 9 (14.1%) receiving placebo.
Liafensine was efficacious and well tolerated in ANK3-positive patients with TRD, with clinically meaningful and statistically significant improvements over placebo suggesting ANK3 as a predictive genetic biomarker for liafensine. This represents a first successful prospective genetic biomarker-guided trial in psychiatry.
ClinicalTrials.gov Identifier: NCT05113771.
本研究首次成功地在精神病学前瞻性研究中使用基因生物标志物来选择潜在的反应者。三联再摄取抑制剂利芬色林可能成为治疗抵抗性抑郁症（TRD）这一重大未满足医疗需求的新型精准药物。
在一项临床试验中，确定与安慰剂相比，每日口服1毫克和/或2毫克利芬色林的剂量，是否使ANK3阳性的TRD患者受益。
设计、地点和参与者：一种新型药物基因组生物标志物ANK3，是通过回顾性研究发现的利芬色林疗效预测指标。在这项由生物标志物引导、随机、双盲、安慰剂对照的2b期临床试验中，于2022年7月至2024年3月在58个地点进行，对1967名患者进行了资格评估，189名ANK3阳性的TRD患者被随机分组。主要排除标准包括特定疾病、合并用药或器官功能障碍。研究人员、患者、评估者和申办者对ANK3状态和治疗均不知情。数据分析于2024年3月26日至4月23日进行。
患者按1:1:1随机分组，每日口服1毫克利芬色林；每日口服2毫克利芬色林；或每日口服一次安慰剂。
主要结局是蒙哥马利-阿斯伯格抑郁评定量表（MADRS）总分从基线到第42天的变化。
在189名随机分组的ANK3阳性TRD患者中，188名接受了研究药物治疗（平均[标准差]年龄为43.2[14.8]岁；119名[63.3%]为女性），186名至少接受了1剂研究药物并进行了1次随机分组后的疗效评估。这些患者中，利芬色林组（包括1毫克和2毫克剂量）的MADRS评分平均（标准误）变化为-15.4（0.9），而安慰剂组为-11.0（1.3）（平均治疗差异为-4.4；95%置信区间为-7.6至-1.3；P = 0.006）。在所有次要终点也观察到了具有统计学意义的改善。不良事件是可耐受的，有意义事件的发生率较低。导致治疗中断的不良事件在接受利芬色林治疗的5名患者（4.0%）和接受安慰剂治疗的9名患者（14.1%）中发生。
利芬色林在ANK3阳性的TRD患者中有效且耐受性良好，与安慰剂相比有临床意义且具有统计学意义的改善，表明ANK3可作为利芬色林的预测性基因生物标志物。这是精神病学中首次成功的前瞻性基因生物标志物引导试验。
ClinicalTrials.gov标识符：NCT05113771。
