P098 Metabolic and excretion profiles of the FAIR therapeutics CFTR modulators nesolicaftor, posenacaftor and dirocaftor in humans (healthy volunteers)

• Published in: Journal of cystic fibrosis Vol. 24; p. S97
• Main Authors: Cipriani, A., Beekman, J., van der Ent, K., Charitou, P.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.06.2025
• Subjects: Pulmonary/Respiratory
• ISSN: 1569-1993
• DOI: 10.1016/j.jcf.2025.03.116

Clinical studies of CFTR modulators have mainly targeted F508del CFTR and gating mutations, covering 85% of CF patients. However, the remaining 15% with rare CFTR mutations lack targeted therapies. FAIR Therapeutics is developing a triple combination therapy, including nesolicaftor (NES/FT-428), posenacaftor (POS/FT-801), and dirocaftor (DIR/FT-808). This study assessed the metabolism of these modulators in healthy subjects to understand their ADME profiles. Each modulator, radiolabeled with [14C], was orally administered to eight healthy male subjects. Plasma, urine, and feces concentrations were measured using LC-MS/MS. Dosages were 50 mg NES, 600 mg POS, and 300 mg DIR, with approximately 100 µCi/kg radioactivity. •NES: 95% of the dose was recovered, with a t1/2 of 15.4 hours. Urinary excretion was dominant (83.18%), with fecal excretion at 12.11%. One major metabolite (37.5%) and four minor metabolites were identified.•POS: 89.7% recovery, with a t1/2 of 24.8 hours. Fecal excretion was predominant (83.2%), with minor urinary excretion (6.54%). One major and six minor metabolites were detected.•DIR: 96% recovery, with a t1/2 of 19.4 hours. Fecal excretion was predominant (93.86%), with minimal urinary excretion (2.17%). Three major and three minor metabolites were identified. The metabolism of NES, POS, and DIR showed high recovery and prolonged half-lives (15–25 hours). NES is mainly excreted via urine, while POS and DIR are excreted through feces.