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.

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.

Identification of small molecule modulators of HIV-1 Tat and Rev protein accumulation.

BACKGROUND: HIV-1 replication is critically dependent upon controlled processing of its RNA and the activities provided by its encoded regulatory factors Tat and Rev. A screen of small molecule modulators of RNA processing identified several which inhibited virus gene expression, affecting both relative abundance of specific HIV-1 RNAs and the levels of Tat and Rev proteins. RESULTS: The screen for small molecules modulators of HIV-1 gene expression at the post-transcriptional level identified three (a pyrimidin-7-amine, biphenylcarboxamide, and benzohydrazide, designated 791, 833, and 892, respectively) that not only reduce expression of HIV-1 Gag and Env and alter the accumulation of viral RNAs, but also dramatically decrease Tat and Rev levels. Analyses of viral RNA levels by qRTPCR and RTPCR indicated that the loss of either protein could not be attributed to changes in abundance of the mRNAs encoding these factors. However, addition of the proteasome inhibitor MG132 did result in significant restoration of Tat expression, indicating that the compounds are affecting Tat synthesis and/or degradation. Tests in the context of replicating HIV-1 in PBMCs confirmed that 791 significantly reduced virus replication. Parallel analyses of the effect of the compounds on host gene expression revealed only minor changes in either mRNA abundance or alternative splicing. Subsequent tests suggest that 791 may function by reducing levels of the Tat/Rev chaperone Nap1. CONCLUSIONS: The three compounds examined (791, 833, 892), despite their lack of structural similarity, all suppressed HIV-1 gene expression by preventing accumulation of two key HIV-1 regulatory factors, Tat and Rev. These findings demonstrate that selective disruption of HIV-1 gene expression can be achieved.