Multi-Modal Correlation Analyses From a Phase 2, Open-Label Study of NE3107 in Patients With Cognitive Decline Due to Degenerative Dementias
Joseph Palumbo1, Jeffrey Zhang2, Kennedy Mahdavi3, Victoria Venkatraman3, Sergio Becerra3, Jonathan Haroon3, Kaya Jordan3, Elisabeth Rindner3, Jean R. Surya3, Taylor Kuhn3, Bijan Pourat4, Sheldon Jordan3
1BioVie Inc., 2Princeton Pharmatech LLC, 3The Regenesis Project, 4Cedar Sinai Medical Center
Objective:
To determine correlations among changes in inflammatory markers, improvements in neuropsychological health, changes in brain metabolism and functional connectivity, and changes in patients’ daily abilities after NE3107 treatment.
Background:
Lowering chronic neuroinflammation may slow Alzheimer’s disease (AD) progression. An exploratory, 3-month, phase 2 trial of NE3107, an oral, anti-inflammatory molecule, enrolled 23 patients, 17 with mild cognitive impairment (MCI) to mild dementia [Mini-Mental State Examination (MMSE) scores ≥20] and 6 patients with moderate dementia (MMSE scores <20). In patients with MMSE ≥20, NE3107 treatment was associated with significant improvements in cognitive performance, including the AD assessment Scale-Cognitive Subscale 12 (ADAS-Cog12), trending improvements in biomarker levels, including tumor necrosis factor-α (TNF-α), significant improvements in the Global Rating of Change (GRC), and enhanced neurophysiological health. We assessed correlations between the anti-inflammatory effects and meaningful clinical outcomes.
Design/Methods:
Eligible patients had a Clinical Dementia Rating score of 0.5 (MCI) or 1 (mild dementia). Clinicians, patients, and caregivers completed a GRC at study completion. Correlations between changes from baseline in cognitive function (ADAS-Cog12) and the key inflammatory biomarker (TNF-α) or patient global impression (GRC) were determined. Hypothesis-based examination of metabolic and functional brain imaging was initiated.
Results:
Patients had a mean age of 71.6 (SD=9.63) years and 15 (65%) were females. In patients with MMSE ≥20, reductions in TNF-α significantly correlated with improvements in ADAS-Cog12 scores (r=0.7; p=0.0077). Improvements in cognition, based on changes in ADAS-Cog12, significantly correlated with clinician-observed improvements in GRC outcomes (r=−0.52; p<0.05). Neuroimaging data suggest correlations with other study outcomes.
Conclusions:
Correlations among improved cognitive function, reduced inflammation, and changes in the clinician-observed GRC (overall impression of patient’s abilities) were consistent with the hypothesized activities of NE3107. Preliminary examination of metabolic and functional brain imaging supports hypothesis-based directional changes in accordance with the expected mechanism of action.