Nivalis Therapeutics, Inc., a Boulder, Colorado-based clinical stage pharmaceutical company, announced that the first patient has been dosed in the Phase 2 clinical trial of its lead investigational drug, N91115, a stabilizer of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
The purpose of this double-blind, randomized, placebo-controlled, parallel group study is to investigate the efficacy and safety of N91115 in adult patients with CF who have two copies of the F508del-CFTR mutation and are being treated with the CF drug Orkambi (lumacaftor/ivacaftor).
The clinical trial, “Study of N91115 in Patients With CF Homozygous for the F508del-CFTR Mutation (SNO-6)” (NCT02589236), is currently recruiting participants. It is set to conclude in July 2016.
According to Nivalis, N91115 works through a novel mechanism of action, called S-nitrosoglutathione reductase (GSNOR) inhibition, that is presumed to modulate the unstable and defective CFTR protein responsible for CF. GSNOR inhibition restores GSNO levels, thereby modifying the chaperones responsible for CFTR protein degradation. In preclinical studies, N91115 was shown to increase the function of F508del-CFTR, the mutant protein that is estimated to be present in almost 90 percent of CF patients. This stabilizing effect was shown to increase and prolong the function of the CFTR protein and may lead to an increase in net chloride secretion — an effect both complementary and agnostic to other CFTR modulators, like Orkambi.
Nivalis (formerly known as N30 Pharma) recently completed a Phase 1 dose-escalation trial of orally administered N91115 in healthy volunteers. No dose-limiting toxicities were identified by the trial’s data monitoring committee.
“We are pleased to initiate the Phase 2 study as planned to evaluate clinical utility of N91115 in patients with CF, and we expect to report results from the study in the second half of next year,” says Jon Congleton, president and chief executive officer of Nivalis in a release. “N91115 has a novel mechanism of action that stabilizes the CFTR protein, and we are optimistic about its potential ability to improve lung function in people with CF.”
“Based on preclinical and Phase 1b data, we are encouraged that a therapeutic approach including N91115 as a stabilizer of the CFTR protein may help improve clinical outcomes,” says Scott H. Donaldson, MD, principal investigator of the study and associate professor of medicine at the University of North Carolina at Chapel Hill’s Marsico Lung Institute. “Importantly, N91115 has the potential to become part of a new multi-mechanism approach to treating CF.”
According to the Cystic Fibrosis Foundation, an estimated 30,000 children and adults in the United States and 70,000 people worldwide have CF, a life-threatening, genetic disease that primarily affects the lungs and digestive system. CF is characterized by a defect in the chloride channel of human cells known as the “cystic fibrosis transmembrane conductance regulator,” or CFTR — critical for adequate hydration of the lungs and other organs of the body. The defect is caused by a mutation of the F508del-CFTR gene. Researchers have identified more than 1,800 mutations in the CF gene, and it is estimated that approximately 48 percent of CF patients in the U.S. have two copies of the F508del-CFTR mutation, with an additional 39 percent having one copy.
As a consequence of this mutation, CF patients produce a defective form of CFTR protein that fails to adequately transport fluid. With N91115, Nivalis Therapeutics aims to increase CFTR function and restore proper hydration to critical organs, particularly the lungs.
Nivalis Therapeutics, Inc.
Cystic Fibrosis Foundation