Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR

  • J Cyst Fibros. 2017 May;16(3):371-379. doi: 10.1016/j.jcf.2017.01.009.
Scott H Donaldson  1 ,  George M Solomon  2 ,  Pamela L Zeitlin  3 ,  Patrick A Flume  4 ,  Alicia Casey  5 ,  Karen McCoy  6 ,  Edith T Zemanick  7 ,  Arun Mandagere  8 ,  Janice M Troha  8 ,  Steven A Shoemaker  8 ,  James F Chmiel  9 ,  Jennifer L Taylor-Cousar  10
Affiliations
  • 1. Cystic Fibrosis Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected].
  • 2. Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, AL, USA.
  • 3. Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 4. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
  • 5. Department of Medicine, Division of Respiratory Diseases, Boston Children's Hospital, Boston, MA, USA.
  • 6. Ohio State University, Nationwide Children's Hospital, Columbus, OH, USA.
  • 7. Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
  • 8. Nivalis Therapeutics Inc., Boulder, CO, USA.
  • 9. Department of Pediatrics, Case Western Reserve University School of Medicine and Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
  • 10. Department of Internal Medicine, Pulmonary Division, National Jewish Health, University of Colorado Health Sciences Center, Denver, CO, USA; Department of Pediatrics, Pulmonary Division, National Jewish Health, University of Colorado Health Sciences Center, Denver, CO, USA.
PMID: 28209466 DOI: 10.1016/j.jcf.2017.01.009
Abstract

Background: Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.

Methods: A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects.

Results: Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28.

Conclusions: The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.

Keywords
CFTR stabilizer; Cystic fibrosis; GSNOR, F508del-CFTR; Homozygous; Modulator.
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