Safety and Tolerability of Dexmecamylamine (TC-5214) Adjunct to Ongoing Antidepressant Therapy in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

Abstract

Safety and tolerability are important considerations when selecting patients' treatment for major depressive disorder. We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine (TC-5214), adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder and who had an inadequate response to antidepressants. This 52-week, double-blind, placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine. Patients were randomized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI. The patient population comprised inadequate responders from 2 Phase III acute dexmecamylamine studies (NCT01157078 [study 002], NCT01153347 [study 004]) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding randomization. Safety and tolerability were assessed by monitoring adverse events, vital signs, and physical and laboratory parameters. Descriptive statistical analyses were performed on most efficacy-related end points. Sustained efficacy was analyzed using logistic regression. Overall, 813 patients were randomized (610 received dexmecamylamine, 203 received placebo). In total, 82.4% and 84.6% of patients, respectively, experienced an adverse event. Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation (19.6% vs 6.0%), dizziness (12.0% vs 7.0%), and dry mouth (9.7% vs 5.0%). Back pain (2.8% vs 8.5%), weight increase (4.4% vs 7.0%), and fatigue (5.6 % vs 7.5%) occurred more frequently in placebo-treated patients. No notable differences were observed between dexmecamylamine and placebo for any secondary end point. In this long-term study, safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine.

Functioning outcomes with adjunctive treatments for major depressive disorder: a systematic review of randomized placebo-controlled studies

“…Only one of the included studies was a long-term study, and, over 52 weeks, adjunctive dexmecamylamine did not show a notable difference to adjunctive placebo on the SDS total. 41 However, dexmecamylamine failed as an adjunctive agent in MDD, having shown no differences to placebo on the primary efficacy outcome in four acute studies, 39 , 40 and thus no benefit on the SDS might be expected.…”

Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression

“…However, a positive allosteric modulator of α7nAChR, JNJ-39393406, failed to improve depressive symptoms in patients [ 97 ]. Mecamylamine, a nicotinic antagonist acting via α7 and β2 subunits, improved depression symptoms when used as adjunct to ongoing antidepressant therapy in a smaller patient cohort, but this effect was not confirmed in following study with larger cohort [ 51 , 98 , 99 ]. Future clinical studies with negative allosteric modulators, having effect on α7nAChR similar to that of HNK, or with HNK itself should test their potential therapeutic potential.…”

Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression

“…18 However, in phase 3 clinical trial, TC-5214 as an adjunctive therapy in patients with major depressive disorder (MDD), who were inadequate responders to SSRI or serotonin-norepinephrine reuptake inhibitors (SNRIs), failed to meet the primary efficacy endpoint. 19 Possible reasons for failure were reported as a higher placebo effect, combination treatment, and nonselectivity of TC-5214. Apart from TC-5214, other reported α4β2 nAChR ligands such as TC-2216, 20 varenicline, 21 sazetidine-A, 22 sazetidine-A-isoxazole analogue (I), 23 and cyclopropyl sazetidine analogue (II) 24 showed antidepressant activity in preclinical models of depression (Figure 1) showing the potential of α4β2 nAChR ligands in treating depression.…”

“…It also showed improvement on other secondary measures . However, in phase 3 clinical trial, TC-5214 as an adjunctive therapy in patients with major depressive disorder (MDD), who were inadequate responders to SSRI or serotonin-norepinephrine reuptake inhibitors (SNRIs), failed to meet the primary efficacy endpoint . Possible reasons for failure were reported as a higher placebo effect, combination treatment, and nonselectivity of TC-5214.…”