Safety, Pharmacokinetics, and Pharmacodynamics of the ADAMTS‐5 Inhibitor GLPG1972/S201086 in Healthy Volunteers and Participants With Osteoarthritis of the Knee or Hip

Abstract

GLPG1972/S201086 is a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5) inhibitor in development as an osteoarthritis disease-modifying therapy. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics (turnover of plasma/serum ARGS-aggrecan neoepitope fragments [ARGS]) of GLPG1972 in 3 randomized, double-blind, placebo-controlled phase 1 trials. Study A, a first-in-human trial of single (≤2100 mg [fasted] and 300 mg [fed]) and multiple (≤1050 mg once daily [fed]; 14 days) ascending oral (solution) doses, investigated GLPG1972 in healthy men (N = 41; NCT02612246). Study B investigated multiple ascending oral (tablet) doses of GLPG1972 (≤300 mg once daily [fed]; 4 weeks) in male and female participants with osteoarthritis (N = 30; NCT03311009). Study C investigated single (Japanese: ≤1500 mg; White: 300 mg [fasted]) and multiple (Japanese, ≤1050 mg once daily; White, 300 mg once daily [fed]; 14 days) ascending oral (tablet) doses of GLPG1972 in healthy Japanese and White men (N = 88). The pharmacokinetic profile of GLPG1972 was similar between healthy participants and participants with osteoarthritis, with low to moderate interindividual variability. GLPG1972 was rapidly absorbed (median time to maximum concentration, 4 hours), and eliminated with a mean apparent terminal elimination half-life of ≈10 hours. Steady state was achieved within 2 days of dosing, with minimal accumulation. Steady-state plasma exposure after 300 mg of GLPG1972 showed no or minor differences between populations. Area under the plasma concentration-time curve (56.8-67.6 μg • h/mL) and time to maximum concentration (4 hours) were similar between studies. Urinary excretion of GLPG1972 (24 hours) was low (<11%). Multiple dosing significantly reduced ARGS levels vs baseline at all time points for all doses vs placebo. GLPG1972 was generally well tolerated at all doses.

Discovery of Isoindoline Amide Derivatives as Potent and Orally Bioavailable ADAMTS-4/5 Inhibitors for the Treatment of Osteoarthritis

“…GLPG1972 was well tolerated at all doses (up to 2100 mg once daily) in phase I clinical trials. 26 Thus, despite the slightly higher activity of 18 in inhibition of MMP2, MMP8, and MMP12 when compared to GLPG1972, the imperfect protease selectivity from inhibition of MMP12/8/2 does not raise safety and toxicity "red flags" on compound 18.…”

“…However, GLPG1972 did not meet its primary clinical endpoints in phase II clinical studies. Both GLPG1972 and ADAMTS-5 nanobody therapies were well tolerated and generally safe. , …”

“…Both GLPG1972 and ADAMTS-5 nanobody therapies were well tolerated and generally safe. 26,27 It is essential to distinguish the inhibition of ADAMTS-4/5 from other metzincin superfamily members, e.g., other ADAMTS family members, ADAMs (a disintegrin and metalloproteinases) and MMPs (matrix metalloproteinases). Nonselective MMP inhibitors resulted in several side effects, such as musculoskeletal syndrome (MSS), which hampered their clinical success in the treatment of OA disease.…”

Exploring Future Horizons in Osteoarthritis Relief: Unveiling the Potential of Slow-Acting Drugs and Innovative Medications

“…Research on another proteinase known as aggrecanase (specifically ADAMTS5) as a potential contributor to the progression of osteoarthritis (OA) led to the exploration of GLPG1972/S201086, a drug acting as an ADAMTS5 inhibitor. In a phase I clinical trial, this drug demonstrated a favorable safety profile and effectively decreased aggrecanase activity [33]. However, the results from the phase II clinical trial, published in 2023, revealed that there was no significant reduction in cartilage loss compared to the placebo group [34].…”

Osteoarthritis, part of life or a curable disease? A bird's‐eye view

“…The enzyme A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) is involved in the degradation of aggrecan, which is a critical proteoglycan and building block of cartilage. ADAMTS-5 induces cartilage degradation and has been reported to be highly expressed in patients with OA [97,98]. There have been several attempts in preclinical models to inhibit ADAMTS-5, but often with safety concerns.…”