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Editors Selection IGR 14-3

Medical Treatment: Investigational new drugs

Comment by Fotis Topouzis on:

67228 A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of 2 and 4 Weeks of Twice-Daily Ocular Trabodenoson in Adults with Ocular Hypertension or Primary Open-Angle Glaucoma, Myers JS; Sall KN; DuBiner H et al., Journal of Ocular Pharmacology and Therapeutics, 2016; 32: 555-562

Find related abstracts

Adenosine and its receptors seem to play a role in modulating IOP. Specifically, selective A1 receptor agonism has been shown to lower IOP. The lowering of IOP is due to increasing conventional outflow by increasing the secretion of matrix metalloproteinase-2 (MMP-2). MMP-2 digests hydrolyzed collagen type IV a major component of extracellular matrix (ECM) in the trabecular meshwork&trademark;. Trabodenoson is a highly selective adenosine mimetic targeting A1 receptor with a potential to lower IOP via a novel mechanism of action: by increasing outflow facility at the trabecular meshwork thus increasing the outflow of aqueous humor via the conventional pathway. In this multi-center, randomized, double-masked, placebo-controlled, dose-escalation Phase-2 Study, Jonathan Meyers and co-authors assess trabodenoson's safety, tolerability, and IOP lowering efficacy in subjects with ocular hypertension (OHT) or primary open-angle glaucoma (POAG).

Trabodenoson represents a potential new class of IOP lowering drug therapy with a novel mechanism of action.

Patients received unilateral topical twice daily trabodonoson (50, 100, or 200 mcg) or placebo for 14 days, or 500 mcg trabodenoson or placebo for 28 days. Intraocular pressure (IOP) was assessed using Goldmann tonometry. Trabodenoson was well tolerated and produced a dose-dependent IOP reduction. IOP reduction in 500 mcg group were significantly greater than placebo at all-time points at Day 28. The Day 28 IOP lowering was significantly greater than at Day 14 indicating increased efficacy with longer treatment, and that reaching a pharmacodynamics steady state requires at least four weeks of therapy. In addition, an increase in IOP lowering efficacy was seen with increasing dose, with no apparent plateau in the dose-efficacy responses up to the highest dose tested. This suggests that higher dose could provide with further IOP lowering. This may need to be investigated in a future trial. However, higher dose should also be evaluated for safety and tolerability. Trabodenoson represents a potential new class of IOP lowering drug therapy with a novel mechanism of action.

With the balance of ECM deposition by TM cells, and its digestion and removal by MMPs, trabodenososn's mechanism of action is very interesting and relevant to outflow pathophysiology associated with OHT and POAG. In addition, this mechanism of action may be complementary with the mechanisms of action of other classes of medications currently in use. However, clinical evaluation in Phase 3 trials and with higher doses of trabodenoson and longer follow-up are needed.

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