Navacaprant: A Hot Topic at the ACNP 2023 Annual Meeting

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CONFERENCE REPORTER

Among the “hot topics” at the American College of Neuropsychopharmacology 2023 Annual Meeting is navacaprant—a novel, oral, once-daily, highly selective kappa opioid receptor antagonist that is currently in phase 3 development as a monotherapy for major depressive disorder (MDD). Sanjay Mathew, MD, professor at Baylor College of Medicine, led the discussion.

MDD affects 264 million individuals worldwide, and 21 million individuals in US, shared Mathew, demonstrating the need for novel therapeutics like navacaprant. There is a significant unmet need for patients who do not respond to standard SSRIS or antidepressants. Furthermore, anhedonia—another hot topic of the day—affects 70% of patients and is associated with more severe depressive symptoms and functional impairment.¹

“Kappa opioid receptors are novel targets for anhedonia that are abundantly expressed in brain circuits regulating reward, motivation, stress, and anxiety,” said Mathew. “Monitoring the kappa opioid receptor system is a well characterized pathway that results from several decades of preclinical studies supporting its potential to modulate depression and anxiety.”

Kappa opioid receptor antagonists may potentially restore the regulation of multiple neurotransmitters, like dopamine, in reward processing pathways. This monotherapy, navacaprant, has 300-fold selectivity for kappa over mu opioid receptors and no agonist activity at kappa, mu, or delta opioid receptors.²

Mathew shared phase 2 data, which evaluated the impact of navacaprant compared with placebo on MDD and anhedonia symptoms, as well as anxiety, following 8 weeks of double-blind treatment, measured by the HAMD-17 Scale. The study was initiated shortly before the pandemic in December 2019. The initial study inclusion was mild-to moderate MDD (BL HAMD-17 of 14-22), but was eventually amended to enroll patients with moderate-to-severe MDD. The participants’ mean age was 42. Of the participants, 70.5% were female, 61.4% were White, 34.1% were Black, and 4.5% were Asian.

“645 participants were screened and 441 screen failed. The randomization in the safety population was 102 per arm,” said Mathew.

The efficacy population narrowed down even further, consisting of 83 participants in the placebo group, and 88 participants in the navacaprant group. Of those 88, 72 participants completed the study in navacaprant group.

The primary endpoint was change from baseline to week 8 in HAMD-17; the secondary endpoint was baseline change to week 4.

Navacaprant demonstrated benefit in the total population, as well as a statistically significant and clinically meaningful improvement in depression symptoms at week 4; however, navacaprant did not achieve statistical significance compared with placebo at week 8.

The most common adverse events included headache (5%) and nausea (5%). Those receiving navacaprant reported fewer adverse events than those receiving placebo (35.3% versus 44.1%).

“The next step is to pursue a phase 3 development program, which is underway with 3 placebo, large scale programs for monotherapy,” said Mathew.

References

1. Cao B, Zhu J, Zuckerman H, et al. Pharmacological interventions targeting anhedonia in patients with major depressive disorder: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry. 2019;92:109-117.

2. Limoges A, Yarur HE, Tejeda HA. Dynorphin/kappa opioid receptor system regulation on amygdaloid circuitry: implications for neuropsychiatric disorders. Front Syst Neurosci. 2022:16:963691.