Nivalis Therapeutics, Inc., announced that a Phase 2 clinical study of its lead investigational drug N91115 has begun treating its first patient. Nivalis, a pharmaceutical company focused on cystic fibrosis (CF) treatments, developed N91115 as a stabilizer of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The drug is being studied to evaluate its potential, when added to Orkambi™ (lumacaftor/ivacaftor), in treating CF patients who have two copies of the F508del mutation.
“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,” Jon Congleton, president and CEO of Nivalis, said in a press 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.”
A Phase 1 clinical trial of N91115 included a dose-escalation safety study in healthy volunteers (Phase 1a) and a safety study in CF patients with two F508del mutation copies (Phase 1b). The results showed that N91115 increased the function of F508del-CFTR, the mutant protein that is estimated to be present in approximately 86% of CF patients in the U.S. and Europe.
“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,” said Scott H. Donaldson MD, the study’s lead investigator and associate professor of medicine at the University of North Carolina. “Importantly, N91115 has the potential to become part of a new multi-mechanism approach to treating CF.”
N91115 works through a novel mechanism, called S-nitrosoglutathione reductase (GSNOR) inhibition. This mechanism is thought to modulate the unstable and defective CFTR protein that causes CF. GSNOR inhibition restores GSNO levels, thus changing the chaperones responsible for CFTR protein degradation. In preclinical trials, the stabilizing effect was seen to increase and prolong CFTR protein function, and could augment net chloride secretion. This effect is both complementary and agnostic to other CFTR modulators, like Orkambi.
The 12-week trial is a double-blind, randomized, placebo-controlled, parallel group study, planned to evaluate the efficacy and safety of two doses of N91115, 200mg and 400mg, administered twice a day to 135 adult CF patients homozygous for the F508del-CFTR mutation and currently being treated with Orkambi.
The primary efficacy outcome is the absolute change from baseline in percent predicted in forced expiratory volume in 1 second (FEV1). Secondary outcomes include changes in the sweat chloride, the CFQ-R Respiratory Symptom scale and Body Mass Index (BMI). More information, including conditions for possible enrollment, are available on the study’s webpage, at ClinicalTrials.gov/NCT02589236. Results are expected in July 2016.
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