Nrf2/Bach1 Program
// Nrf2/Bach1 Program
Overview
vTv Therapeutics has identified multiple classes of novel, non-electrophilic small molecules that can modulate both nuclear factor erythroid 2-related factor 2 (Nrf2) and BTB and CNC homology 1 (Bach1), an antioxidant response element (ARE) transcriptional repressor, resulting in potent activation of the Nrf2 pathway. Activation of the Nrf2 pathway not only alleviates oxidative stress but also regulates inflammatory responses, thereby helping to prevent tissue damage. Among the molecules identified by vTv, HPP971 is the most extensively studied.
// Nrf2/Bach1 Program
Clinical and Nonclinical Studies
HPP971 was evaluated in Phase 1 single-ascending dose and multiple-ascending dose studies in healthy participants, where it was well tolerated.
Pre-clinical pharmacodynamic data showed induction of Nrf2/Bach1 target genes across multiple organs, including the kidney, liver, lung, heart, and brain, as well as across diverse cell types (e.g., normal human lung fibroblasts, vascular smooth muscle cells, renal proximal tubule epithelial cells, human umbilical vein endothelial cells, astrocytes and diseased cells). Efficacy and proof of concept have been observed in multiple disease-relevant animal models including liver disease (NASH), neurodegenerative disorders (e.g., Parkinson’s disease, traumatic brain injury, Alzheimer’s disease), bone loss (e.g., osteoarthritis), and other indications.
Mechanism of Action
Activation of the Nrf2 pathway has historically relied on molecules containing reactive, electrophilic groups, which may be associated with safety and tolerability issues. In contrast, modulation of the Nrf2/Bach1 pathway by vTv’s non-electrophilic compounds in vitro and in vivo has shown suppression of both oxidative stress and inflammation. These effects are mediated through increased expression of antioxidant proteins, elevation of cellular glutathione levels, increased production of anti-inflammatory cytokines, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional activity, and polarization of macrophages toward the anti-inflammatory M2 phenotype.