Background: Major depressive disorder (MDD) is a leading cause of disability, morbidity, and mortality, with approximately 264 million people worldwide and 21 million adults in the U.S. reporting symptoms of depression. Despite available treatments, a significant unmet need remains, as many patients do not adequately respond to first-line pharmacotherapies and often experience side effects. Current antidepressants also do not adequately treat anhedonia, a core clinical feature of MDD that affects approximately 70% of patients and is associated with more severe depressive symptoms. New targeted therapies are needed to treat MDD, including symptoms of anhedonia, while also improving tolerability over current antidepressants. Kappa opioid receptors (KORs) are novel targets for anhedonia that are abundantly expressed in brain circuits regulating reward, motivation, stress, and anxiety. KOR activation is a strong negative modulator of multiple neurotransmitters, including dopamine, and results in dysphoria. Conversely, KOR antagonists are believed to restore the regulation of multiple neurotransmitters including dopamine in reward processing pathways, which play an important role regulating mood, cognition, reward, and behavior. Navacaprant (NMRA-140, BTRX-335140) is a novel, potent, and highly selective KOR antagonist with no agonist activity at mu, kappa, or delta opioid receptors. Navacaprant is in development as monotherapy to treat the symptoms of MDD.

Methods: This 8-week, randomized, double-blind, placebo-controlled Phase 2 clinical trial evaluated the efficacy and safety of navacaprant vs placebo in adults with MDD and symptoms of anhedonia and anxiety. Participants that met the blinded-rule list with a 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 14-30, a Hamilton Anxiety Rating Scale (HAM-A) score of ≥8, and a Snaith-Hamilton Pleasure Scale (SHAPS) score of ≥26 were randomized 1:1 to navacaprant (80 mg) or matched placebo taken orally once-daily. The primary efficacy endpoint was the change from baseline (CFB) to Week 8 in HAMD-17 score. Secondary endpoints included CFB to Week 4 in HAMD-17 score and CFB to Weeks 4 and 8 in SHAPS score. The primary efficacy analysis was conducted using mixed models repeated measures (MMRM). Since ≥10% of subjects had missing data, a prespecified Last Observation Carried Forward (LOCF) analysis of covariates (ANCOVA) was used for the primary and secondary endpoints and prespecified subgroups. To evaluate the efficacy of navacaprant in patients with moderate-to-severe MDD, who comprise the most common population in clinical trials, a prespecified subgroup analysis was performed on the primary efficacy endpoint by stratifying results according to baseline HAMD-17 score of ≥22. Safety was assessed during the 8 weeks of treatment and a 4-week safety follow-up.

Results: 204 patients from 31 US sites were randomized (102 in each group) and included in the safety population. In the efficacy population (n = 88 navacaprant, n = 83 placebo), which included patients with baseline HAMD-17 scores as low as 14, statistically significant separation of navacaprant from placebo on HAMD-17 score was detected at Week 4 (least squares mean difference, LSMD [SE], MMRM -2.7 [0.90], P = 0.003) but not Week 8 (-1.7 [1.08], P = 0.121) which was the primary endpoint. In the prespecified LOCF analysis, a statistically significant improvement was detected for navacaprant 80 mg over placebo for both Week 4 (LSMD [SE], LOCF -2.9 [0.88], P = 0.002) and Week 8 (-2.2 [0.98], P = 0.024). For symptoms of anhedonia, navacaprant showed a significant improvement over placebo at both Week 4 and Week 8 (SHAPS: LSMD [SE], LOCF -2.8 [0.96], P = 0.004; and -3.4 [1.10], P = 0.002, respectively).

In the prespecified subgroup analysis of patients with moderate-to-severe MDD (baseline HAMD-17 ≥22, n = 53 navacaprant, n = 47 placebo), a statistically significant difference at Week 4 and Week 8 favoring navacaprant was detected for depression (HAMD-17: LSMD [SE], LOCF -3.0 [1.20], P = 0.015; and -2.8 [1.33], P = 0.037, respectively). For anhedonia, a trend was observed at Week 4 (SHAPS: LSMD [SE], LOCF -2.4 [1.31], P = 0.071) and a statistically significant difference was observed at Week 8 (LSMD [SE], LOCF -4.8 [1.35], P = 0.001).

Navacaprant was generally safe and well tolerated. The incidence of treatment-emergent adverse events (TEAEs) was lower in the navacaprant group compared with placebo (35.3% vs 44.1%). Most TEAEs were mild to moderate, with the most common TEAEs being headache (4.9% both groups), nausea (4.9% navacaprant, 1.0% placebo), and COVID-19 (3.9% navacaprant, 2.9% placebo). Discontinuations due to TEAEs were less frequent in the navacaprant group (1.0%) than in the placebo group (11.8%). There was no observed weight gain and no spontaneous reports of sexual dysfunction reported in those receiving navacaprant. No serious TEAEs were reported in the navacaprant group vs 1.0% in the placebo group (1 suicide attempt). No evidence of suicidal behavior was reported in the navacaprant group.

Conclusions: Navacaprant resulted in statistically and clinically significant reductions in symptoms of depression and anhedonia compared with placebo following 8 weeks of treatment in patients with moderate-to-severe MDD. Navacaprant was generally safe and well tolerated, with low rates of discontinuation due to TEAEs. These findings support the further development of navacaprant as an antidepressant monotherapy.

Keywords: Major Depressive Disorder, Anhedonia, Navacaprant, Antidepressant, Kappa Opioid Receptor Antagonist

Disclosure: Almatica Pharma, Biohaven, BioXcel Therapeutics, Boehringer-Ingelheim, Brii Biosciences, Clexio Biosiences, COMPASS Pathways, Delix Therapeutics, Douglas Pharmaceuticals, Eleusis, EMA Wellness, Engrail Therapeutics, Levo Therapeutics, Liva Nova, Merck, Perception Neurosciences, Praxis Precision Medicines, Neumora Therapeutics, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, Sunovion, XW Pharma: Consultant (Self). Boehringer-Ingelheim, Neurocrine, Sage Therapeutics: Grant (Self).