Two Phase 2 Trials Fail to Demonstrate Cognitive Benefits in Schizophrenia Despite Different Mechanisms

Two major phase 2 clinical trials investigating novel approaches to treat cognitive impairment associated with schizophrenia (搜索)搜索该疾病 (CIAS) have failed to demonstrate efficacy, underscoring the persistent challenges in developing treatments for this significant unmet medical need. The studies tested different mechanisms targeting NMDA receptor (搜索)搜索该靶点 dysfunction, a key hypothesis in CIAS pathophysiology.

Basmisanil Study Results

The first trial evaluated basmisanil查看药品详情, a selective GABAA α5 negative allosteric modulator, in a 24-week placebo-controlled study of 213 patients with CIAS. The study, conducted between November 2016 and December 2019, randomized patients to receive 80 mg basmisanil, 240 mg basmisanil, or placebo twice daily. Recruitment into the 80 mg group was stopped after a planned futility analysis.

The primary endpoint was the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score, evaluated in 153 patients in the efficacy analysis population (76 placebo, 77 basmisanil查看药品详情 240 mg). Twenty-four weeks of treatment with basmisanil was well tolerated but failed to improve cognitive or functional measures overall or in any stratified subgroups.

The study incorporated novel design features to address potential sources of heterogeneity, including stratification by cognitive trajectories and age, as well as repeated administration of the MCCB test battery during screening to minimize practice and learning effects. Despite these methodological improvements, no practice or learning effects were observed at week 12, and the treatment showed no benefit.

ERUDITE Trial Findings

The second study, called ERUDITE, examined luvadaxistat查看药品详情 (NBI-1065844查看药品详情/TAK-831查看药品详情), a D-amino acid oxidase (搜索)搜索该靶点 (DAAO) inhibitor that modulates glutamatergic neurotransmission by elevating D-serine levels. This phase 2, randomized, double-blind, placebo-controlled trial enrolled 203 patients across 55 sites in Europe and the USA between December 2021 and October 2024.

Participants were randomized 2:1:1 to receive once-daily placebo, luvadaxistat查看药品详情 20 mg, or luvadaxistat 50 mg for 12 weeks. The study included a 2-week placebo run-in period to evaluate compliance and symptom stability. The efficacy analysis set included 173 participants (85.2%), with 161 completing the study.

For the primary endpoint of change in Brief Assessment of Cognition in Schizophrenia (搜索)搜索该疾病 (BACS) composite score from baseline to Day 98, there was no statistically significant effect. The least-squares mean difference from baseline was −0.7 (95% CI: −2.8, 1.4; p = 0.75) for luvadaxistat查看药品详情 20 mg and −0.5 (95% CI: −2.7, 1.6; p = 0.69) for luvadaxistat 50 mg compared with placebo.

Similarly, no significant changes were observed in the key secondary endpoint of Schizophrenia (搜索)搜索该疾病 Cognition Rating Scale (SCoRS) interviewer total score, with differences of −0.2 (95% CI: −2.2, 1.7; p = 0.40) for 20 mg and −0.6 (95% CI: −2.5, 1.2; p = 0.25) for 50 mg compared to placebo.

Safety Profiles

Both compounds demonstrated acceptable safety profiles. In the basmisanil查看药品详情 study, 24 weeks of treatment was well tolerated without significant safety concerns. In the ERUDITE trial, treatment-emergent adverse events were reported in approximately one-third of participants across all groups, with most events being mild or moderate in severity. Serious adverse events were uncommon, occurring in no more than 3% of participants in any group, and no deaths were reported.

Clinical Context and Implications

CIAS represents a core feature of schizophrenia (搜索)搜索该疾病, contributing significantly to functional deficits including difficulties in independent living, employment, and social relationships. It is considered a strong predictor of long-term functional disability, yet no currently approved pharmacological treatments exist for this condition.

The failure of these trials adds to a growing list of unsuccessful attempts to treat cognitive symptoms in schizophrenia (搜索)搜索该疾病. As of November 2025, only two compounds have advanced to phase 3 trials for CIAS—encenicline查看药品详情 (an α7 nicotinic acetylcholine receptor (搜索)搜索该靶点 agonist) and iclepertin查看药品详情 (a glycine transporter-1 (搜索)搜索该靶点 inhibitor)—and neither demonstrated positive results.

Study Design Challenges

Both studies highlighted important considerations for future CIAS trials. The ERUDITE investigators noted that population heterogeneity and variability in cognitive performance prior to randomization may have affected results. There were no inclusion criteria for enrichment based on cognitive performance other than investigator judgment, and observed discrepancies in baseline cognition across randomized groups highlighted the variability among participants.

The studies also revealed the potential impact of concomitant medications. In ERUDITE, a wide range of antipsychotic treatments was allowed without considering anticholinergic burden, which may have impacted cognitive performance. The use of concomitant anticholinergic medications was permitted with dosing and timing restrictions, and differences in background medication use across treatment groups could have contributed to outcome variability.

Future Directions

Despite these setbacks, researchers emphasize the continued need to address CIAS as a treatment target. The cross-study insights from these trials may help refine future clinical trial designs, including participant enrichment based on cognitive performance and mitigating the impact of differences in background medication use.

The development of luvadaxistat查看药品详情 has been discontinued following these results. However, ongoing exploratory analyses from the ERUDITE study may offer additional insights to inform future research approaches targeting CIAS, as the field continues to grapple with the complexity of developing effective treatments for cognitive deficits in schizophrenia (搜索)搜索该疾病.