Nivalis Therapeutics developed a portfolio of novel disease modifying therapies designed to preserve intracellular GSNO (S-nitrosoglutathione) levels. GSNO is a molecule with cell signaling effects implicated in the pathophysiology of cystic fibrosis (CF) and other respiratory diseases. Nivalis’ lead candidate, cavosonstat (N91115), was evaluated in a phase 2 trial in patients with the F508del mutation, the most common disease-causing mutation in CF.
Alpine Immune Sciences is seeking opportunities to continue the development of cavosonstat (N91115) and the Nivalis clinical candidates and platform through out-licensing. If you are interested in cavosontat and related intellectual property, please contact us.
Nivalis developed a broad portfolio of proprietary, investigational small molecule inhibitors of the S-nitrosoglutathione reductase (GSNOR) protein which have been shown in preclinical studies to increase CFTR activity as well as decrease airway inflammation.
Nivalis’ drug candidate portfolio consists of multiple compounds which are designed for oral, intravenous (IV), or inhaled administration.
Lead Clinical Candidate
Cavosonstat (N91115), is an investigational small molecule that has the potential to address a defect in CFTR, resulting from mutations in the CFTR gene, the underlying cause of CF. Nivalis believed cavosonstat is a first-in-class CFTR stabilizer that modulates CFTR activity through a novel mechanism of action potentially complementary to existing and future CFTR modulators.
Cavosonstat is the only clinical stage product candidate Nivalis was aware of designed to stabilize CFTR inside the cell and at the cell surface. Nivalis has preclinical data demonstrating the stabilizing effect of cavosonstat increases and prolongs CFTR activity when added to other CFTR modulators.
GSNO and GSNOR
Endogenous S-nitrosoglutathione (GSNO) plays a critical role in modulating protein function through the transfer of nitric oxide to a protein thiol group, or S-nitrosation. Although administering GSNO directly has shown potential as a therapeutic intervention in preclinical models of cystic fibrosis and other diseases, it is limited as a chronic therapy for several reasons including difficulty in formulation and administration.
Depleted GSNO levels are believed to contribute to loss of airway function and pathology in CF lung disease due to dysregulated S-nitrosation. The S-nitrosation of certain proteins has been shown to modulate CFTR activity and decrease inflammation in preclinical human airway and animal models of disease. These targeted effects have been demonstrated to modify certain molecular chaperones, such as Hsp70/Hsp90 organizing protein or HOP which affect trafficking and stability of the F508del CFTR protein.
GSNO concentrations are regulated by GSNO reductase (GSNOR) an enzyme that breaks down GSNO. GSNOR, through its regulation of GSNO levels, plays a key role in pulmonary, gastrointestinal, and cardiovascular physiology and pathophysiology.
The Nivalis drug development strategy was based on the premise inhibiting of GSNOR should increase intracellular levels of GSNO by preventing its degradation, particularly in the setting of cystic fibrosis and other diseases with decreased levels of GSNO and/or increased GSNOR.