First-in-Man Safety, Tolerability, and Pharmacokinetics of a Novel and Highly Selective Inhibitor of Matrix Metalloproteinase-12, FP-025: Results from Two Randomized Studies in Healthy Subjects

  • Clin Drug Investig. 2021 Jan;41(1):65-76. doi: 10.1007/s40261-020-00981-9.
Khalid Abd-Elaziz  1 ,  Christine Voors-Pette  2 ,  Kang-Ling Wang  3  4 ,  Sandy Pan  5 ,  Yisheng Lee  6 ,  John Mao  6 ,  Yuhua Li  6 ,  Benjamin Chien  6 ,  David Lau  6 ,  Zuzana Diamant  2  7  8  9
Affiliations
  • 1. Department of Clinical Pharmacology, QPS-Netherlands, Groningen, The Netherlands. [email protected].
  • 2. Department of Clinical Pharmacology, QPS-Netherlands, Groningen, The Netherlands.
  • 3. General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 4. School of Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 5. QPS Taiwan, Taipei City, 115, Taiwan.
  • 6. Foresee Pharmaceuticals Co. Ltd, Taipei City, 115, Taiwan.
  • 7. Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands.
  • 8. Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden.
  • 9. Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
PMID: 33331980 DOI: 10.1007/s40261-020-00981-9
Abstract

Background and objectives: Matrix Metalloproteinases (MMPs) are proteases with different biological and pathological activities, and many have been linked to several diseases. Targeting individual MMPs may offer a safer therapeutic potential for several diseases. We assessed the safety, tolerability, and pharmacokinetics of FP-025, a novel, highly selective oral matrix metalloproteinase-12 inhibitor, in healthy subjects.

Methods: Two randomized, double-blind, placebo-controlled studies were conducted. Study I was a first-in-man study, evaluating eight single ascending doses (SADs) (50-800 mg) in two formulations: i.e., neat FP-025 in capsule (API-in-Capsule) and in an amorphous solid dispersion (ASD-in-Capsule) formulation. In Study II, three multiple ascending doses (MADs) (100, 200, and 400 mg, twice daily) of FP-025 (ASD-in-Capsule) were administered for 8 days, including a food-effect evaluation.

Results: Ninety-six subjects were dosed. Both formulations were well tolerated with one adverse event (AE) reported in the 800 mg API-in-Capsule SAD group and seven AEs throughout the MAD groups. The exposure to FP-025 was low with the API-in-Capsule formulation; it increased dose-dependently with the ASD-in-Capsule formulation, with which exposure to FP-025 increased in a greater-than-dose-proportional manner at lower doses (≤ 100 mg) but less proportionally at higher doses. The elimination half-life (t1/2) was between 6 (Study I) and 8 h (Study II). Accumulation of FP-025 was approximately 1.7-fold in the MAD study. Food intake delayed the rate of absorption, but without effect in the extent of absorption or bioavailability.

Conclusion: FP-025 was well tolerated and showed a favorable pharmacokinetic profile following ASD-in-Capsule dosing. Efficacy studies in target patient populations, including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, are warranted.

Trial registration number: www.clinicaltrials.gov : NCT02238834 (Study I); NCT03304964 (Study II). Trial registration date: Study I was registered on 12 September 2014 while study II was registered on 9 October 2017.

Products