Effects of N-methyl-d-aspartate receptor modulation on brain glutamate, functional connectivity, and clinical...

This exploratory, 2-site phase 2 clinical trial investigated whether neuroimaging biomarkers could demonstrate the analgesic potential of NYX-2925, a novel N-methyl-d-aspartate receptor modulator, in women with fibromyalgia.

Twenty-two participants completed sequential 2-week treatment periods: placebo, 20 mg NYX-2925, and 200 mg NYX-2925. Resting state functional connectivity magnetic resonance imaging and proton magnetic resonance spectroscopy were performed during the second week of each period.

The 200 mg dose produced statistically significant improvements in pain, fatigue, fibromyalgia severity, and function compared with placebo. Neuroimaging revealed that NYX-2925 reduced glutamate and glutamine/total creatine ratios in the dorsal anterior cingulate cortex at rest (P = 0.032) and in the posterior insular cortex after evoked pain (P = 0.039). Notably, higher baseline pain-evoked glutamate and glutamine levels in the pIns predicted greater reductions in experimental pain sensitivity at both the 20 mg (r = 0.55; P = 0.029) and 200 mg (r = 0.51; P = 0.046) doses. The 20 mg dose also reduced resting state connectivity between the dorsal anterior cingulate cortex and both primary somatosensory cortex (P = 0.030 family-wise error) and precuneus (P = 0.031 family-wise error). NYX-2925 demonstrated good tolerability and safety.

These exploratory findings suggest that NYX-2925 modulates excitatory neurometabolic activity and functional connectivity in pain-processing networks, with modest accompanying clinical improvement. A subsequent larger randomized trial did not confirm clinical benefit, so the present results should be regarded as hypothesis-generating and require independent replication. We discuss the value, and the limits, of neuroimaging measures for mechanistic drug development and personalized pain medicine.