Boulder, Colorado based Nivalis Therapeutics, Inc. a clinical stage pharmaceutical company focused on treating people with cystic fibrosis (CF), is reporting positive topline results from a Phase 1b clinical study evaluating its Cystic Fibrosis drug candidate N91115 — a novel stabilizer of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The clinical trial demonstrated favorable safety, tolerability and pharmacokinetics in adult CF patients with two copies of the F508del-CFTR mutation, and no dose limiting toxicities were observed.
In the randomized, double-blind, placebo-controlled, parallel group study, 51 adult CF patients were randomly assigned to receive either a placebo or N91115 at doses of 50, 100 or 200 mg administered twice daily for 28 days. The study’s primary objective was to evaluate the safety, tolerability and pharmacokinetic profile of N91115, with secondary objectives including dosage determination the forthcoming Phase 2 clinical trial and exploration of biological activity pharmacodynamic markers. Trial participant safety was monitored by an independent Data Monitoring Committee.
Nivalis Therapeutics (formerly N30 Pharmaceuticals), a clinical-stage pharma company focused on translating bench-side science into patient benefit, is developing a novel class of disease modifying therapies that are designed to preserve intracellular GSNO (S-nitrosoglutathione), an endogenous molecule with cell signaling effects that are implicated in the pathophysiology of cystic fibrosis (CF).The Company’s lead candidate, N91115 initially targets patients with the F508del mutation, the most common disease causing mutation in CF.
Nivalis reports that the trial showed N91115 to be safe and well tolerated over the dose range studied, with the drug’s pharmacokinetic profile fully achieved within the targeted blood levels and dose selection rationale. While not powered to demonstrate statistically significant clinical efficacy, the company notes that a trend toward a modest reduction in sweat chloride at the highest dose studied was observed that may suggest a threshold effect for CFTR modulation (placebo difference -5.2 mmol/L, 95% CI -11.7, 1.4, p = 0.11).
Healthy subjects demonstrated linear increases in N91115 PK exposure levels with increases in dose. The six female subjects with CF included in this study had a mean age of 25.2 years (range 18-37 years) and a baseline mean percent predicted FEV1 of 72.8% (range 51% to 98%). At steady state, on Day 14, plasma N91115 concentrations peaked rapidly with a median Tmax of 2 hours (versus 1 hour in healthy subjects). The investigators conclude that the rate of absorption of N91115 is slightly slower in CF patients with a longer Tmax and a lower Cmax, but the overall exposure as measured by AUC is similar, and that N91115 was well tolerated in CF patients homozygous for F508del-CFTR. When administered at a dose of 50 mg twice daily for 14 days, N91115 is safe and well-tolerated in subjects with CF, and no dose adjustments are required. More detail on the trial results is available at: http://www.nivalis.com/Content/docs/posters/2015-10-07-NACFC-PK-Poster.pdf
Full results of the Phase 1b trial will be presented in an oral presentation and posters at the North American Cystic Fibrosis Conference(NACFC) being held this week from October 8-10, 2015 in Phoenix, Arizona. Sponsored by the Cystic Fibrosis Foundation, the NACFC is the largest forum of its kind to advance research for the treatment and cure of CF.
“These data provide important insight about the safety, pharmacokinetics and pharmacodynamics of N91115, says 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 upon this early signal of CFTR activity and the absence of dose limiting toxicities, the researchers say 200 mg twice daily and a higher dose of N91115 are planned for the upcoming Phase 2 study. The presumed novel mechanism of action of N91115 S-nitrosoglutathione reductase (GSNOR) inhibition is distinct from other CFTR modulators and has been shown to improve the function of CFTR when added to correctors and potentiators in pre-clinical studies.
“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,” says 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 study, in which N91115 will be added to Orkambi (lumacaftor 200 mg/ivacaftor 125 mg) — another new Cystic Fibrosis drug approved by the FDA in July — in people with CF who have two copies of the F508del mutation, is subject to regulatory review and is planned to be initiated in the fourth quarter of 2015 with data available in the second half of 2016.
Cystic Fibrosis (CF) is a life-shortening genetic disease that affects an estimated 70,000 people worldwide, including approximately 65,000 in the United States and Europe. It is the most common fatal genetic disease in Caucasians. There is no known cure for CF and the predicted median age of survival in the United States is approximately 41 years, although some persons with CF are reaching the half-century mark in recent years.
CF prevalence of is expected to increase at an average annual rate of 0.8% between now and 2023, with the main growth driver being increased life expectancy due to better disease modifying therapies that extend life. CF patients typically require lifelong treatment with multiple daily medications and frequently require hospitalization and potentially lung transplants.
The disease is caused by mutations in the gene that encodes CFTR, a chloride channel that regulates the movement of salt and water into and out of cells in organs such as the lungs, pancreas and gastrointestinal tract. The F508del mutation is the most common cause of CF. People who have two copies of the F508del mutation, one inherited from each parent, account for approximately half of the CF population in the U.S. CF occurs only in patients with two defective copies, or alleles, of the CFTR gene. In CF patients, defective CFTR cannot perform its normal function, which results in the buildup of thick mucus in several vital organs. Lung disease is the most critical manifestation of CF, characterized by airway obstruction, infection and inflammation that allows bacteria to grow unfettered and impairs the lungs’ immune system.
More than 90 percent of all CF patients die of respiratory failure. In the pancreas, damage caused by CF leads to diabetes and the buildup of mucus prevents the release of digestive enzymes that help the body break down food and absorb important nutrients. In the gastrointestinal tract, the thick mucus contributes to further impairment of nutrient absorption — leading to chronic malnutrition.
When Nivalis began operations in 2008, its initial focus was on administering exogenous GSNO as a potential therapeutic agent in asthma and CF. The company completed Phase 1 testing of an inhaled formulation of GSNO, and also applied for, and was granted, Orphan Drug designation related to the potential use of GSNO to treat CF in the United States.
Evaluation of GSNO as a potential therapeutic intervention resulted in identification of novel small molecule inhibitors of GSNOR, the enzyme that breaks down naturally occurring GSNO in the human body. These small molecule inhibitors provided advantages as drug candidates, compared to the direct administration of GSNO, because GSNO is limited by route of administration, instability, and lack of intracellular penetration. In 2010, Nivalis’s development efforts were redirected from GSNO to their GSNOR inhibitors and their discovery efforts focused on optimizing and evaluating drug candidates for oral dosing and expanding our portfolio of GSNOR inhibitors.
GSNO belongs to a class of compounds known as S-nitrosothiols or SNO — the body’s most abundant low molecular weight SNO that is formed from glutathione and nitric oxide. SNOs are normally present in the human lung but are depleted in the lungs of patients with CF. These depleted levels are due in part to increased breakdown of GSNO by the enzyme GSNO reductase (GSNOR).
Nivalis says that in preclinical studies GSNO has been shown to increase the trafficking and maturation of the defective F508del-CFTR protein in airway cells from CF patients. Restoration of intracellular levels of GSNO may therefore represent a novel therapeutic strategy in CF. Consistent with this hypothesis, inhibition of GSNOR with N91115 significantly increased and prolonged the function of F508del-CFTR in airway cells from CF patients when added to a CFTR corrector and potentiator.
Consequently, Nivalis’s drug development strategy is based on the premise that GSNOR inhibition will result in an increase in intracellular levels of GSNO by preventing its degradation, particularly in the setting of cystic fibrosis and other diseases that have decreased levels of GSNO and/or increased GSNOR. Nivalis also plans to utilize its proprietary S-nitrosoglutathione reductase (GSNOR) inhibitor portfolio to develop therapeutics for other diseases.
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Nivalis Therapeutics, Inc.
U.S. Food and Drug Administration (FDA)
University of North Carolina