Nrf2/Bach1 Program
// Nrf2/Bach1 Program
Overview
vTv Therapeutics has identified multiple classes of novel, first-in-class 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 is expected to not only alleviate oxidative stress but also regulate inflammatory response which could ultimately help reduce tissue damage. Among the molecules identified by vTv, HPP971 is the most advanced, having been investigated in Phase 1 clinical studies, while numerous other compounds with different pharmacodynamic and pharmacokinetic profiles such as HPPD (HPP8668) and HPPE (HPP3033), are in preclinical development.
// Nrf2/Bach1 Program
Clinical and Nonclinical Studies
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.
HPP971 was evaluated in Phase 1 single-ascending dose and multiple-ascending dose studies in healthy participants, where it was well tolerated.
HPPD (HPP8668) has been evaluated in pre-clinical studies in the Townes Sickle Cell Disease mouse model which showed that HPPD induced fetal hemoglobin (HbF) in a time- and dose-dependent manner, with effects comparable to or exceeding hydroxyurea, the current standard HbF-inducing therapy. In addition to HbF induction, HPPD showed reductions in oxidative stress and sickled red blood cells, supporting its potential as a disease-modifying oral therapy with a differentiated mechanism of action. HPPD has received Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of Sickle Cell Disease.
HPPE (HPP3033) has shown robust neuroprotective activity in preclinical models of neurodegenerative diseases, reducing neurodegeneration, oxidative stress, and neuroinflammation. In Parkinson’s disease models, HPPE preserved dopaminergic neurons, reduced oxidative stress and neuroinflammation, and provided benefit when administered after the onset of disease pathology. These findings support modulation of the NRF2/BACH1 pathway as a promising therapeutic strategy for neurodegenerative disorders characterized by oxidative stress, inflammation, and progressive neuronal loss.
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.