Positive Phase 1 Data on Gut-Targeting Therapy in Neurodegenerative Diseases Announced
Because its gut-acting and gut-restricted, the safety profile of DGX-001 was considered advantageous in comparison to traditional neuropsychiatric therapies.
Titus Plattel, MSc
Viage Therapeutics recently announced positive findings from a phase 1 study assessing its lead clinical stage candidate, DGX-001, a first-in-class oral drug that targets the gut-brain axis, in healthy volunteers. Based on the findings, the company is planning to commence a phase 2 development program assessing the agent in mildly cognitive forms of Alzheimer disease (AD) and Parkinson disease (PD).1
All told, findings from the double-blind, placebo-controlled single-ascending dose (SAD) and multiple-ascending dose (MAD) study highlighted DGX-001’s safe and tolerable profile that was consistent with previous preclinical studies. Comprised of 68 healthy individuals, DGX-001 showed potential signals of clinical activity, including its potential to improve cognitive and executive functions, as measured through quantitative electroencephalogram changes.
"Results from the Phase 1 study provide a compelling safety profile and support further exploration of the therapeutic potential of DGX-001 in cognitive disorders," Titus Plattel, MSc, president at Viage Therapeutics, said in a statement.1 "We are excited to make our first-in-class oral drug candidate available to patients as we initiate the Phase 2 clinical program and in parallel discuss steps to file an investigational new drug application with the FDA."
DGX-001 is designed to modulate the vagus nerve through specific receptor interactions on enteroendocrine cells in the gut, resulting in a regulation of brain cell activity. The planned phase 2 program will initially aim to improve cognitive impairment across several different diseases, representing a transdiagnostic study design, which may ultimately enable indications beyond neurology and psychiatry, the company noted.
The study is conducted in 3 parts: Part 1 consisting of SAD cohorts, Part 2 consisting of MAD cohorts, and Part 3 consisting of 1 high-dose cohort who also underwent a stress exposure resilience panel. This panel is based on a sleep-deprivation model believed to mimic cognitive impairment in patients with neurodegenerative diseases. The primary outcome measures included treatment-emergent adverse events (TEAEs), severity of TEAEs, safety laboratory tests, ECG testing, and urinalysis findings.
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Previous research has shown that changes in certain metabolic processes, including the metabolism and transport of cholesterol, have been associated with AD. A notable 2018 paper by Rima Kaddurah-Daouk, PhD, et al. found that individuals with AD had significantly lower amounts of liver-produced bile acids (Bas) but higher amounts of bacterially produced secondary Bas in their blood. These secondary BAs were significantly associated with cognitive decline.2
A follow-up analysis of the same participants showed that altered ratios of primary and secondary BAs in the blood correlated with brain changes associated with AD. Specifically, an elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: OR, 7.932 [95% CI, 1.673-37.617; P = .03; ALT: OR, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio; ß = –0.465 [SE, 0.180]; P = .02 for memory composite score; ß = –0.679 [SE, 0.215]; P = .006 for executive function composite score; ALT: ß = 0.397 [SE, 0.128]; P = .006 for memory composite score; ß = 0.637 [SE, 0.152]; P <.001 for executive function composite score).3
Additional findings from that study showed that lower levels of ALT were associated with increased amyloid-ß deposition, and reduced brain glucose metabolism (ß = 0.096 [SE, 0.030]; P = .02) and greater atrophy. These results were, the authors knowledge, the first to show an association of peripheral markers of liver functioning with central biomarkers associated with AD.
