RECENT ADVANCES IN TARGET ENGAGEMENT STUDIES IN SCHIZOPHRENIA

N-methyl-D-aspartate-type glutamate receptors (NMDAR) modulators and other glutamatergic compounds have been assessed in phase II/III clinical trials for schizophrenia symptoms with mixed success1. Two recent examples of high-profile failures are POMA, an agonist of metabotropic (mGluR2/3) glutamate, and bitopertin, a glycine-transport inhibitor (GTI), both of which failed in pivotal clinical trials. A major barrier to effective treatment development is the absence of validated measures for target engagement that can identify effective compounds and guide dose selection. We discuss several recent/ongoing studies2-6 utilizing auditory learning induced plasticity, MMN and ketamine- induced pharmacoBOLD (phBOLD) as target engagement.

In Study 1, we assessed target engagement and the optimal dose (80 vs.100 vs. 120 mg/kg) of the NMDAR modulator D-serine combined with 3 sessions of an auditory plasticity program in Sz. Target engagement was assessed with plasticity improvement, MMN and Beta oscillations. In Study 2, we investigate the dose-response of ketamine in healthy volunteers, using phBOLD as a prelude to potential future target engagement studies with mGluR2/3 agonists (TS-134) in schizophrenia. In our previous work, we chose a single dose of ketamine that produced a highly robust (0.23 mg/kg, d=5.4) which have been near the peak of the dynamic range for BOLD activity. In Study 2, we assessed lower ketamine doses, predicting that doses that produce a more moderate phBOLD response may be optimally sensitive to the effects of glutamatergic agents. The primary goal was to determine the lowest dose that will generate an effect size of 1.5.

In Study 1, 45 schizophrenia subjects were randomized. Across all 3 visits, there was a statistically significant treatment effect for plasticity improvement (p=0.014). Significant plasticity improvement was seen in the 80/100 mg/kg dose-cohorts, starting with the 1st visit (10-13.9%, all p<0.001, all d>0.67). By contrast, placebo-treated participants showed non-significant changes across all visits (4-5%, n.s.).

Target engagement was demonstrated by a larger MMN pitch (p=0.049, d=1.0) and larger Beta event related desynchronization (p=0.025) for the 100 mg/kg dose-cohort without safety concerns. In Study 2, we assessed 4 doses. phBOLD data for the 0.04, 0.06 and 0.08 mg/kg cohorts, along with a previously collected 0.23 mg/kg. This data supports an “optimal” dose of 0.086 mg/kg to generate an effect size of 1.5. In an ongoing study, we randomize to a low, medium or high (0.086, 0.125 or 0.23 mg/kg) dose pre/post 4 days of TS-134/placebo.

Study 1 findings support engagement of the NMDAR system by D-serine, as measured by behavioral plasticity and MMN. Sustained effects will be assessed in an ongoing R33. In Study 2, preliminary results support a ketamine dose response for pharmacoBOLD, and viability as a target engagement biomarker. Results are supportive of dose- dependent target engagement for specific compounds, de-risking larger, longer studies for clinically relevant outcomes, further exemplified by studies of luvadaxistat and CVN-058. Active questions include the relationship between these surrogate biomarkers and clinical response, the use of ketamine as a model, expansion to related compounds and the pluses/minuses of specific techniques.

1. Javitt DC, Kantrowitz JT. The glutamate/N-methyl-d-aspartate receptor (NMDAR) model of schizophrenia at 35: On the path from syndrome to disease. Schizophr Res Apr 2022;242:56-61.

2. Sehatpour P, Iosifescu DV, De Baun HM, et al. Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine. Biol Psychiatry Jul 15 2023;94(2):164- 173.

3. Govani V, Shastry AM, Iosifescu DV, et al. Augmentation of learning in schizophrenia by d-serine and auditory remediation is related to auditory and frontally-generated biomarkers: A randomized, double- blind, placebo-controlled study. Schizophr Res Sep 8 2023;260:205-208.

4. Donde C, Kantrowitz JT, Medalia A, et al. Early auditory processing dysfunction in schizophrenia: Mechanisms and implications. Neurosci Biobehav Rev May 2023;148:105098.

5. Sehatpour P, Javitt DC, De Baun HM, et al. Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058. Neuropsychopharmacology Feb 2022;47(3):711-718.6. Kantrowitz JT, Grinband J, Goff DC, et al. Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers. Neuropsychopharmacology Oct 2020;45(11):1842-1850.