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The recently discovered genetic biomarker ankyrin-3 (ANK3) was found to be successful in guiding a clinical trial of liafensine for treatment-resistant depression. Presence of gene ANK3 was found to be predictive of positive response to liafensine in patients with treatment-resistant depression. This phase 2b trial is the first successful prospective genetic biomarker-guided clinical trial in psychiatry.1
The ENLIGHTEN clinical trial, sponsored by Denovo Biopharm, included 189 adult patients who tested positive for the ANK3 gene and had treatment-resistant depression (TRD), ultimately demonstrated a 4.4 point improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores as compared with placebo.
The study selected participants with the ANK3 gene who also had TRD, to assess the gene as a predictor of liafensine’s efficacy in this TRD population. The trial was a randomized, double-blind phase 2b trial in which patients were randomly assigned to received 1mg liafensine, 2 mg liafensine, or placebo once-daily orally for 6 weeks.
Eligibility criteria were meeting the DSM-V criteria for major depressive disorder and the criteria for TRD from the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. Inclusion criteria were failure of at least 2 antidepressants in different classes and having a Hamilton Depression Rating Scale of at least 21 (moderate severity). Participant exclusion criteria included specific disorders, organ dysfunction, and concomitant medications.
Liafensine was well tolerated in patients with the ANK3 gene and TRD and met primary and secondary endpoints. The study met its primary endpoint of MADRS score change from start to day 42, showing an improvement of 4.4 points (95% CI, −7.6 to −1.3; P = .006) for a combined group of the 1 mg and 2 mg liafensine groups. The 1 mg and 2 mg groups individually also showed significant MADRS score improvement. MADRS was evaluated at baseline and days 7, 14, 28, and 42. Secondary endpoints were also met, with Clinical Global Impression Severity and Improvement scores change of -0.4 and 2.3, respectively, for the combined 1 and 2 mg liafensine group compared with placebo. The most common treatment-emergent adverse effects were nausea (16 patients [12.9%]), headache (15 patients [12.1%]), and constipation (13 patients [10.5%]). Adverse events leading patients to discontinue participation occurred in 5 patients receiving liafensine (4%) and 9 patients receiving placebo (14.1%). There were 8 serious treatment-emergent adverse effects were reported in 5 patients: 3 (2.4%) with liafensine and 2 (3.1%) with placebo. One death was reported in the 2 mg liafensine group, with unknown cause and undetermined relationship to study drug; authors noted “the site personnel noticed that the patient did not return for follow-up and later found an obituary with no cause of death provided and no other information available.”1
Liafensine is a triple reuptake inhibitor, targeting membrane transporters of serotonin, norepinephrine, and dopamine; there may be a mechanistic link between liafensine and ANK3, as the gene product links the cytoskeleton to membrane transporters. The ANK3 gene is a scaffolding protein expressed in the nervous system, which plays an important role in neuronal signaling through modulation of cell membrane proteins. ANK 3 has been linked to psychiatric diseases, including depression. Dosage comparison results were consistent with previous studies on selective serotonin reuptake inhibitors which show a trend of flat dose-response curves for efficacy but increasing medication discontinuation due to adverse effects at higher doses.3 Because of this, further studies on liafensine will use the 1 mg administration.
“The morbid safety issues associated with the drugs currently used to treat TRD, or many frequent with SSRIs and SNRIs, either were not observed or were reported with low incidence in liafensine-treated patients. In particular, data from liafensine studies do not indicate abuse liability, sedation, dissociative symptoms, respiratory depression, metabolic dysfunction, weight gain, or notable sexual dysfunction,” added the investigators of the study.1
Statistically significant and clinically meaningful improvements in the treatment group vs placebo suggest ANK3 may be a predictive biomarker for liafensine response. Previous studies had shown no significant efficacy of liafensine in patients who were not biomarker indicated.2 Wang et al noted that the study “indicates that 1 drug is not optimal for all patients with such diverse genetic backgrounds, and it raises a concern there might not be a single-gene biomarker that can predict drug efficacy in depression like those companion diagnostics approved in oncology. However, this work suggests that a single locus, if identified correctly, could be successfully used to predict antidepressant response, which represents major progress in advancing precision medicine in psychiatry.”1
References
1. Wang G, Mario A, Spear MA, et al. ANK3 as a novel genetic biomarker for liafensine in treatment-resistant depression: the ENLIGHTEN randomized clinical trial.JAMA Psychiatry. 2025.
2. Luo W, Wang G, Whitaker JW, et al. Discovery of a novel pharmacogenomic biomarker on ANK3 gene for liafensine, a triple reuptake inhibitor for treatment-resistant depression.Research Square. Preprint. 2025.
3. Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173(2):174-183.
