Alpine/Nivalis Transaction

On April 18, 2017, Alpine and Nivalis announced a transaction combining the companies.

On July 24, 2017, this transaction was completed with Alpine Immune Sciences, Inc. beginning trading July 25, 2017 on the NASDAQ National Market under the ticker “ALPN”.

Alpine’s primary focus is developing novel protein‐based therapies using our variant immunoglobulin domain (vIgD™) platform technology. The vIgD platform is designed to create novel therapeutics that modulate multiple therapeutic targets, including many present in the immune synapse. Our vIgDs are developed via a unique process known as directed evolution which can produce proteins capable of either enhancing or diminishing an immune response, creating a platform applicable to both oncology and inflammatory diseases. For more information on Alpine’s vIgD platform, see the Our Science page.

As part of the transaction, Alpine obtained all rights to Nivalis’ GSNOR platform and related intellectual property. Described briefly to the right, Alpine seeks to outlicense this technology to an interested party. For more information on Nivalis’ GSNOR platform licensing opportunities, please contact us using the link below.

Nivalis Therapeutics

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 Platform

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.

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Selected data on Nivalis platform

Enhanced F508del-CFTR Modulation with the S-nitrosoglutathione Reductase Inhibitor N91115 in addition to CFTR Corrector and Potentiation (poster)

The Pharmacokinetics of N91115 in Cystic Fibrosis Patients (poster)

Safety and Pharmacokinetics of N91115 in Patients with Cystic Fibrosis Homozygous for the F508del-CFTR Mutation (poster)

A Novel Therapeutic Target in Asthma: Translational Evidence for Inhibition of S-Nitrosoglutathione Reductase (GSNOR)(poster)

Safety, Tolerability, and Pharmacokinetics of the Oral S-Nitrosoglutathione Reductase Inhibitor N91115: A Multiple Ascending-Dose Study in Healthy Subjects (poster)

Safety, Tolerability, and Pharmacokinetics of the Intravenous S-Nitrosoglutathione Reductase Inhibitor N6022: An Ascending-Dose Study in Subjects Homozygous for the F508del-CFTR Mutation (poster)

Pharmacological Correction and Acute Inhibition of GSNOR Results in Improved In Vitro CFTR Function (poster)

Primary airway epithelial cells expanded with feeder cells and ROCK inhibitor for screening novel GSNOR inhibitors and CFTR correctors (poster)

Identification of Novel, Efficacious F508del‐CFTR Correctors to Treat Cystic Fibrosis (poster)

Next Generation F508del CFTR Correctors Using a YFP-Based High Throughput Screening Assay (poster)

Intestinal Current Measurement to Assess Modulation of F508del-CFTR Function by GSNOR Inhibitor Treatment In Vivo (poster)

A Novel GSNOR Inhibitor with Potent Bronchodilatory Effects and CFTR Potentiation Activity (poster)

S-Nitrosoglutathione Reductase Inhibitors Modulate F508-del CFTR Protein Levels and Chloride Secretion In Vitro
(poster)

Small Molecule Inhibitors of GSNOR Possess Anti-Inflammatory and Bronchodilatory Actions in Mouse Models of Inflammatory Lung Disease and Modulate CFTR Function in F508del-CFTR Mice (poster)

S-Nitrosoglutathione Reductase Inhibitors for the Prevention and Treatment of Experimental Colitis (poster)

Structure-Activity Relationships of Pyyrol-Based S-Nitrosoglutathione Reductase Inhibitors — Carboxamide Modification (poster)

Heterozygous Deletion S-Nitrosoglutathione Reductase in Mice Does Not Increast Nitrosative Inactivation of O6-Alkylguanine-DNA Alkyltransferase or Diethylnitrosamine-Induced Hepatocarcinogenesis (poster)

Oral S-Nitrosoglutathione Reductase Inhibitors Attenuate Pulmonary Inflammation and Decrease Airspace Enlargement in Experimental Models of COPD (poster)

Inhibition of the Enzyme S-Nitrosoglutathione Reductase Does Not Cause Mechanism-Based Toxicity (poster)

Discovery of S-Nitrosoglutathione Reductase (GSNOR) Inhibitors as Potential Agents to Treat Asthma and Related Diseases (poster)

Pharmacological Inhibition of S-Nitrosoglutathione Reductase Improves Endothelial Vasodilatory Function in Rats in vivo (journal article)

ADH IB Expression, but Not ADH III, Is Decreased in Human Lung Cancer (journal article)

Mechanism of Inhibition for N6022, a First-in-Class Drug Targeting S-Nitrosoglutathione Reductase (journal article)

Structure–Activity Relationship of Pyrrole Based S-Nitrosoglutathione Reductase Inhibitors: Carboxamide Modification (journal article)

Preclinical 28-Day Inhalation Toxicity Assessment of S-Nitrosoglutathione in Beagle Dogs and Wistar Rats (journal article)

Discovery of Potent and Novel S-Nitrosoglutathione Reductase Inhibitors Devoid of Cytochrome P450 Activities (journal article)

Structure-Activity Relationships of Pyrrole-Based S-Nitrosoglutathione Reductase Inhibitors: Pyrrole Regioisomers and Propionic Acid Replacement (journal article)

Discovery of S-Nitrosoglutathione Reductase Inhibitors: Potential Agents for the Treatment of Asthma and Other Inflammatory Diseases (journal article)

Questions on licensing this technology?