Immediate Impact

On March 6, 2025, Johnson & Johnson (J&J) announced that they discontinued their phase 3 VENTURA trial, which evaluated the drug aticaprant as an adjunctive treatment for patients with major depressive disorder (MDD). While aticaprant was shown to be safe and well-tolerated in patients, the trial ultimately found that the treatment lacked efficacy in addressing the symptoms of MDD.

VENTURA Study Summary

VENTURA was a 54-week clinical trial involving 840 adults (aged 18 to 74) with MDD. Participants took aticaprant daily alongside their existing depression medications.

The study assessed the percentage of participants with suicidal thoughts or behaviors and monitored changes in their depression symptom scores over time. Additionally, the trial evaluated the drug’s impact on sexual dysfunction and weight gain, medication side effects that commonly result in treatment discontinuation among MDD patients.

With the development of aticaprant, J&J aimed to provide a treatment option with improved efficacy, safety, and tolerability compared to current antidepressants. Despite the conclusion of the VENTURA trial, J&J intends to investigate future opportunities for development due to the drug's promising mechanism.

About Aticaprant

Aticaprant is designed to block kappa opioid receptors (KORs), targeting pathways that influence mood and behavior. This mechanism is similar to that of Neumora’s navacaprant, which also failed to meet its efficacy goals.

Dr Clayton –

Importance to Science: 5
Importance to the Molecule: 7
Importance to the Medication Class: 8

Aticaprant 10 mg daily is a KOR antagonist with 30-fold greater selectivity for the Kappa receptor vs the Mu receptor (1/10 the Kappa receptor selectivity of navacaprant, which may limit dosing) that was evaluated as an adjunctive treatment to standard-of-care oral antidepressants in patients with moderate to severe MDD. 

I also reviewed the placebo-controlled RCT 6-week published phase 2 study (Schmidt ME, et al. Neuropsychopharmacology. 2004;49:1437-1447.) in which efficacy was demonstrated vs placebo for MDD (p=0.044, effect size 0.23) with better but insignificant outcomes in patients with Snaith-Hamilton Pleasure Scale scores at baseline greater than the median baseline score. There was a placebo run-in period in the randomized controlled trial of up to 3 weeks (28% placebo responders as determined by a reduction >30% in the Montgomery-Åsberg Depression Rating Scale total score), which has not been found to meaningfully reduce placebo-response rates in the enriched population. 

The results of the open-label study lack demonstrated efficacy per suicidal ideation/behavior ratings and the depression symptom severity scale. They also showed that the medication was safe and well-tolerated, but specific percentages of adverse events were not reported in the press release. Patients taking aticaprant may be at increased risk of addiction given navacaprant and aticaprant 30:1 ratio vs 300:1 ratio, respectively, for the Kappa receptor:Mu receptor sensitivity, especially if the dose needs to be increased for efficacy. It is unclear how well sites were managed to limit placebo response. Anhedonia effects were not reported. Potential areas of unmet need include MDD with anxious distress and depression associated with chronic pain. I would not look at fibromyalgia, as opioid agonists are not helpful in this population. 

The negative findings suggest the need to reassess dosing, as the industry underdoses to keep adverse events low. There is a need to find the ineffective dose, minimal therapeutic dose, and maximum tolerated dose, especially for adjunctive treatment. The high placebo response rates suggest poor site selection/monitoring (it only takes a few sites with high placebo response rates to tip the balance against the drug). Pharmaceutical companies, rather than contact research organizations, may need to be the final monitors of site-specific placebo-response rates across trials in current studies to inform the selection of sites in future trials. The potential for addiction risk appears higher for aticaprant than navacaprant due to the selectivity ratio in Kappa vs Mu opioid receptors. Studies may have been loaded with patients with anhedonia (which may be more difficult to treat) or with emotional blunting from the standard-of-care antidepressant medication (mistaken for anhedonia), which remained constant across the trial. (They might be able to tease this out with the Oxford Depression Scale). The meaning of sex differences is unclear without information about reproductive status in women (eg, premenopausal, perimenopausal, postmenopausal) or use of age as an initial proxy. Sex differences may actually be related to dosing (too low in men).

Dr DeBattista –

Importance to Science: 7 
Importance to the Molecule: 5 
Importance to the Medication Class: 6 

This phase 3 study appears to have been stopped quite early. I do not think it was anywhere near completing enrollment. Without a toxicity signal, I would speculate that an interim analysis showed no chance of meeting its primary endpoint. Like navacaprant, this study followed weak phase 2 results. At least it appears safe for study in other potential indications (eg, substance use disorders, negative symptoms, anxiety, etc).

I would give this a 7/10 in importance because the study, along with the Neumora data, makes it unlikely that other KOR antagonists will be studied for the treatment of MDD or, more specifically, anhedonia. In terms of how negatively important this is to the molecule, I would give it a 5. The molecule itself was well tolerated and might seek other indications. I would give it a 6/10 in importance to the class (ie, Kappa opioid). The study is a blow to KOR antagonists in general because depression was considered the most likely indication. However, there are other stress-related disorders, including anxiety, PTSD, and substance use disorders, that could be future indications. 

Dr Thase –

Importance to Science: 5 
Importance to the Molecule: 9 
Importance to the Medication Class: 9 

There are a lot of putative targets for novel antidepressants, and that’s why my rating for science is less than for the other 2 parameters. Although there are some interesting mini signals hidden within the J&J aticaprant dataset, this is pretty much the death knell for this compound and the class.

Dr Mattingly –

Importance to Science: 7 
Importance to the Molecule: 8
Importance to the Medication Class: 8

This negative phase 3 adjunctive MDD trial result is worrisome, especially coming on the heels of the negative phase 3 KOASTAL-1 trial for Navacaprant. This trial is limited by the adjunctive nature of an active comparator. As the second Kappa opioid molecule to fail in recent MDD trials, this is worrisome for this molecule and the class of Kappa opioid molecules for MDD.