Aticaprant

Aticaprant (LY-2456302, CERC-501, JNJ-67953964) is a potent, selective, orally bioavailable antagonist of the kappa-opioid receptor (KOR) with a binding affinity (Ki) of 0.81 nM, approximately 30-fold selectivity over the mu-opioid receptor (Ki = 24.0 nM), and approximately 190-fold selectivity over the delta-opioid receptor (Ki = 155 nM). The compound belongs to the aminobenzyloxyarylamide chemical class and was designed at Eli Lilly Research Laboratories as a clinically viable therapeutic targeting the endogenous dynorphin/KOR neuromodulatory system, a pathway implicated in the pathophysiology of stress-induced anhedonia, dysphoria, and addictive behaviors. In contrast to earlier KOR antagonists such as JDTic and nor-binaltorphimine, which exhibit ultra-long-duration receptor inactivation persisting for weeks after a single dose, aticaprant produces short-acting, reversible KOR blockade with an elimination half-life of 30 to 40 hours, enabling conventional once-daily oral dosing and predictable pharmacokinetic management.

The preclinical pharmacology of aticaprant was characterized in the seminal Rorick-Kehn et al. (2014) report, which demonstrated that oral administration selectively and potently occupied central KOR in vivo (ED50 = 0.33 mg/kg) without evidence of mu- or delta-opioid receptor occupancy at doses up to 30 mg/kg. In rodent behavioral models, aticaprant produced antidepressant-like effects in the mouse forced swim test, enhanced the efficacy of imipramine and citalopram, reduced ethanol self-administration in alcohol-preferring (P) rats, and reversed unpredictable chronic mild stress-induced anhedonia in C57BL/6J mice, as measured by sucrose preference, nest building, and forced swim endpoints. Positron emission tomography (PET) imaging in humans confirmed near-complete saturation of brain KOR at a 10 mg oral dose (94% receptor occupancy at 2.5 hours post-dose), with sustained occupancy (82% at 24 hours for a 25 mg dose), supporting the translational pharmacology from preclinical models to human central nervous system target engagement.

Clinical development of aticaprant has proceeded through multiple sponsors. Eli Lilly conducted the initial Phase 1 single- and multiple-ascending dose studies (Lowe et al. 2014), establishing safety, tolerability, and the absence of clinically significant interactions with ethanol. Cerecor Inc. acquired the compound in 2015 and initiated early clinical studies in mood and substance use disorders. Janssen Pharmaceuticals (Johnson and Johnson) acquired the compound in 2017 and advanced it through Phase 2 and Phase 3 programs for adjunctive treatment of major depressive disorder (MDD) in patients with inadequate response to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The Phase 2 randomized, double-blind, placebo-controlled study (Jacobsen et al. 2024) in 181 participants with MDD and moderate-to-severe anhedonia demonstrated a statistically significant reduction of 2.1 points on the Montgomery-Asberg Depression Rating Scale (MADRS) for aticaprant 10 mg versus placebo (p = 0.04), with favorable tolerability and no new safety signals. However, the compound did not separate from placebo on secondary measures of anhedonia (Snaith-Hamilton Pleasure Scale), global illness severity (CGI-S), anxiety (HAM-A), or patient-reported depression outcomes.

Janssen subsequently initiated the VENTURA Phase 3 program comprising five pivotal trials in MDD with anhedonia. On 6 March 2025, Johnson and Johnson announced discontinuation of the VENTURA program due to insufficient efficacy in the target population, while noting that the compound remained safe and well tolerated with no new safety signals detected. The most common treatment-emergent adverse events in clinical trials were headache (11.8% versus 7.1% placebo), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). Johnson and Johnson has indicated that it will explore future development opportunities for aticaprant in other areas of high unmet need. The compound is not approved by any regulatory authority for any indication. This monograph reviews the chemistry, synthesis, receptor pharmacology, pharmacokinetics, preclinical and clinical evidence base, sourcing and quality considerations, reconstitution and handling, stack interactions, adverse-event profile, and a comparative assessment of five KOR antagonist candidates against aticaprant on five competency standards.