Discussion
RECRUITMENT, CORTEX, CEREBELLAR FUNCTION
Although it showed a trend to enhance but had no statistically significant effect on the primary endpoint, EBC, luvadaxistat significantly improved MMN and showed a trend toward improving ASSR, in both cases at 50 mg, but not with 500 mg. Luvadaxistat did not affect P300 or BACS at either dose. An important caveat in this study is the small sample size, so these results should be taken as exploratory in nature.All changes in estimates in a favorable direction for MMN and ASSR occurred with the lower luvadaxistat 50 mg dose and were not observed with the higher 500 mg dose. This observation may be due to an inverted-U dose-response, and it is consistent with results from a parallel phase 2 study (INTERACT), in which 12 weeks of treatment with luvadaxistat 50 mg, but not luvadaxistat 500 mg, resulted in cognitive improvement [DAAO is highly expressed in the cerebellum, yet the main observation in this study is driven by MMN, a measure typically showing the largest response in the cerebral cortex. Given that we observed D-serine increases in plasma, and in CSF in a previous phase 1 study, it is possible that DAAO inhibition in the cerebellum yields enough increase in D-serine levels that reach NMDAR in other parts of the brain. Alternatively, an indirect impact of cerebellar function on MMN and other cortical ERPs cannot be ruled out [Because MMN and ASSR are strongly correlated with cognitive performance [There are some limitations with these results, however. The sample size was small, as recruitment was impacted by the COVID-19 pandemic. The placebo effects on MMN were different for the cohorts receiving 50 mg vs 500 mg. Yet, even with such small sample sizes there were nominally significant differences, so the data can be interpreted as reliable. Our use of one-sided p values is not standard and could be viewed as a limitation; however, this approach was set a priori as we hypothesized a MMN change in one direction. In addition, the difference in placebo effects between groups emphasizes the relevance and need of within subject comparisons with variable measures such as these ERPs.A key learning from our study is that functional biomarkers should be used in early clinical development to de-risk later stages in drug development for psychiatry. The INTERACT study tested luvadaxistat 50 mg and 500 mg on the basis of what we knew about D-serine elevations from phase 1 studies, and 500 mg was hypothesized to be the effective dose because it was at the plateau of D-serine elevation, without our knowing the functional impact of such elevation. The current study demonstrates the benefit of knowledge gained in early functional biomarker studies. Neurocircuitry-related assessments remain a necessary and underutilized approach in drug development. Functional biomarker data can be used in the design of later-stage studies, including doses and objectives to be tested, leading to a more efficient drug-development process.