Trial evaluates purine P2X7 receptor antagonist JNJ-54175446 in patients with major depressive disorder

By Neha MathurJul 31 2023Reviewed by Sophia Coveney

In a recent study published in Translational Psychiatry, researchers investigated the safety and pharmacokinetics of JNJ-54175446 in a double-blind, multicenter, randomized controlled trial (RCT) in the Netherlands and Germany.

The study population comprised 69 major depressive disorder (MDD) patients who suffered a single episode or recurrent MDD episodes whose Inventory of Depressive Symptomatology Clinician (IDS-C) rating was under 30 at screening (baseline). 

They received a single dose of 600 mg of JNJ-54175446, followed by daily doses of 150 mg of JNJ-54175446.

Additionally, this study involved total sleep deprivation (TSD) as an exploratory proof-of-concept intervention to induce acute mood improvements in the study population before or after JNJ-54175446 or placebo administration, which helped the researchers examine its potential effects on mood and mood-related symptoms. The team subjected all patients to 36 hours of TSD.

Background

Microglial cells of the central nervous system (CNS) and monocytes express adenosine triphosphate (ATP)-gated P2X ion channels, including purine P2X7 receptor (P2X7R). Under non-stress conditions, ATP has a low affinity for P2X7R; however, during oxidative stress, inflammation, or cellular injury, ATP activates P2X7Rs, leading to IL-1β release in the CNS. P2X7–IL-1β pathway plays a primary role in neuroinflammation.

Studies have shown that IL-1β concentrations are high in patients with recurrent and persistent mood disorders. Thus, antidepressant drugs, especially cytokine inhibitors, can help improve mood in MDD patients. Researchers hypothesized that P2X7R antagonists might work as a mood disorders treatment in MDD patients who suffer from disease recurrence due to chronic stress.

JNJ-54175446 is a high affinity, CNS-penetrant P2X7R antagonist. In preclinical experiments, CNS-penetrant high affinity and selective P2X7R antagonists have been shown to cause effects such as a reduction of ex-vivo lipopolysaccharide (LPS)-induced IL‐1β release in rat microglia and human monocytes, and the blocking of benzyl (Bz)‐ATP-induced IL‐1β release in rat brains.

In human trials, JNJ-54175446 demonstrated blood-brain barrier (BBB) penetration. A positron emission tomography (PET) scan showed that a five to 300 mg dose of JNJ-5417544 was safe and well tolerated. Yet, it remains elusive how JNJ-54175446 helps regulate mood in a relevant clinical population.

About the study

In the present study, researchers randomized patients in a 3:3:2 ratio, with early start Group A receiving JNJ-54175446 throughout a 10-day treatment period. Group B patients received a placebo for one to three days followed by JNJ-54175446 between days four and 10. Group C received only a placebo throughout the 10 days.

The study population comprised male and female patients aged 18 to 64, with body mass index (BMI) between 18 and 32 kg/m^2, who had MDD without psychotic features. They were either medication-free or had received one selective serotonin reuptake inhibitor (SSRI) between six weeks and six months. 

Results and conclusion

Even though 69 patients received at least one dose of JNJ-54175446, only 64 patients completed the study, of which 62.3% were females and 37.7% were males. The average age of the patients was 38.6 years, and their mean BMI was 25.13 kg/m².

All the study participants had similar demographic and baseline characteristics. The treatment phase was completed by 23 of 26 patients in Group A, 24 of 26 patients in Group B, and all 17 patients in the placebo group. 

In Group A, two treatment-emergent adverse events (TEAEs), severe headache, and abdominal pain possibly related to JNJ-54175446 led to study discontinuation. Likewise, in Group B, two TEAEs led to study discontinuation, of which only moderate-intensity chills and nausea were likely related to JNJ-54175446. 

The most commonly reported adverse events (AEs) were headache, nausea, dysgeusia, and vomiting, all of which occurred shortly after the JNJ-54175446 administration as an oral suspension. However, JNJ-54175446 treatment resulted in no serious or persistent AEs, or death.

Overall, 600 mg JNJ-54175446 doses, followed by 150 mg JNJ-54175446 doses, were safe and well tolerated in MDD patients. Its pharmacokinetics in MDD patients were comparable to healthy volunteer studies, which justified their similar AE profile.

TSD improved depressive symptoms on self-reported and clinician-rated rating instruments. Indeed, JNJ-54175446 did not produce rapid antidepressant effects or markedly improve mood after TSD, and that effect did not change throughout the study. 

Overall, there were no differences in levels of IL-1β in peripheral blood in response to JNJ-57417446 treatment vs. placebo, suggesting that multiple IL-1β-releasing pathways do not involve P2X7 receptors.

However, JNJ-57417446 decreased ex vivo IL-1β release by LPS-stimulated peripheral white blood cells in the presence of BzATP, proving its pharmacological activity in the blood and the CNS.

It also blunted the reduction of anhedonia in MDD patients after TSD. The potential mood-stabilizing effects of JNJ-54175446 on hedonic capacity warrant further investigation.