Nivalis Therapeutics, Inc., a pharmaceutical company focused on developing treatments for patients with cystic fibrosis (CF), recently announced positive topline data from its Phase 1b trial assessing N91115, 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. Results from the clinical trial showed favorable tolerability, safety and pharmacokinetics of the drug in CF adults patients who have two copies of the F508del-CFTR mutation.
N91115 is a first-in-class CFTR stabilizer that modulates CFTR activity through a novel mechanism of action that aims to be complementary to existing and future CFTR modulators. In Nivalis’ randomized, placebo-controlled, double-blind, parallel group clinical trial, a total of 51 adults with a diagnosis of CF were assigned at random to receive a drug placebo or N91115 at 50, 100 or 200 mg doses twice per day for a period of 28 days. Primary study endpoints were the tolerability, safety, and pharmacokinetic profile of N91115. Secondary endpoints of the study were the determination of doses for the Phase 2 study and the exploration of pharmacodynamic indicators of the disease’s biological activity. During the study, an independent Data Monitoring Committee monitored the patients’ safety.
Results from the study showed that at the examined dose range, the drug was well tolerated and is safe in adult CF patients. In terms of pharmacokinetic profile, the results revealed that N91115 completely reached the dose selection rationale and the targeted blood levels. The results also showed a tendency for a modest decline in sweat chloride at the highest dose analyzed, which may indicate a threshold effect for CFTR modulation.
During the North American Cystic Fibrosis Conference (NACFC) (October 8-10), which will take place in Phoenix, Arizona, the company will present the full data of the Phase 1b clinical study.
“These data provide important insight about the safety, pharmacokinetics and pharmacodynamics of N91115,” said Scott H. Donaldson MD, principal investigator of the study and Associate Professor of Medicine at the University of North Carolina. “We are encouraged by the exploratory sweat chloride levels, a key measure of the function of the CFTR protein, observed in the 200 mg treatment group, which supports further study of the potential of N91115 as a CFTR modulator.”
Based on the trial results, a Phase 2 clinical trial is planned to examine 200 mg twice per day and a higher N91115 dose. The assumed new mechanism of action of N91115 S-nitrosoglutathione reductase (GSNOR) inhibition is different from other CFTR modulators and in pre-clinical trials has been found to improve the CFTR function when added to potentiators and correctors.
“These results represent a significant milestone in our efforts to further understand the clinical utility of N91115 in patients with the most common and complex form of cystic fibrosis,” said Jon Congleton, president and chief executive officer of Nivalis. “We look forward to initiating our Phase 2 study later this year evaluating the safety and efficacy of N91115 when added to Orkambi™.”
The Phase 2 clinical trial to examine N91115 added to Orkambi in CF patients who carry two copies of the F508del genetic mutation will be reviewed and is expected to start during the last trimester of 2015. Results are expected during the second semester of 2016.
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