Trabodenoson is a potential new therapy for ocular hypertension (OHT) and primary open-angle glaucoma (POAG) that restores a more natural state in the eye by mimicking the action of adenosine. Trabodenoson selectively binds to the adenosine A1 receptor, resulting in intracellular signaling that increases expression, secretion and activation of several MMPs, including MMP-2, by TM cells. This, in turn, remodels the extracellular matrix, restores mechanosensitivity of the trabecular meshwork (TM) cells, and increases outflow facility through the TM, resulting in a lowering of IOP. This mechanism mimics the adenosine-mediated control of IOP that is utilized by the healthy eye.
Trabodenoson was engineered by Inotek to be highly selective for the A1 receptor with no significant binding to other adenosine receptors such as A2A, A2B, and A3. It is believed that that this high selectivity may underlie its favorable safety/tolerability profile.
Trabodenoson has high lipid solubility which results in high ocular penetration, allowing it to reach target tissues with topical administration. In addition, it exhibits high tissue compatibility with the often sensitive tissues in the front of the eye which may reduce the risk of side effects.
This is a more physiologic and natural approach that has the advantage of preserving oxygen- and nutrient-rich aqueous humor flow to the TM, and resets the system to a lower chronic IOP level that may improve the ability to respond to acute IOP changes.
Current commonly prescribed therapies for POAG do not target the dysfunctional trabecular meshwork. They work by reducing aqueous humor production1 (eg, beta blockers, carbonic anhydrase inhibitors, alpha agonists), or by diverting aqueous humor flow away from the TM toward the unconventional/uveoscleral pathway (prostaglandins).2 Traditional glaucoma surgery and trabecular stents also divert humor flow away from the TM to increase outflow facility. Many of these approaches are non-physiologic and less natural, and may harm the TM by shunting the flow of oxygen- and nutrient-rich aqueous away from it.
This diagram depicts that in patients with glaucoma, the TM is characterized by reduced outflow facility due to increased flow resistance.
This is a potential new approach to effectively lower IOP in patients with OHT and POAG with minimal to no side effects.
Trabodenoson is currently in Phase 3 development in what Inotek calls the MATrX program. MATrX-1, the first pivotal Phase 3 clinical trial in patients with ocular hypertension (OHT) and primary open-angle glaucoma (POAG) has recently completed, and will be followed by a second pivotal trial, MATrX-2, and a long term safety trial, MATrX-3. In Phase 2 trials, treatment with trabodenoson demonstrated a clinically significant reduction in IOP, and a favorable local and systemic safety and tolerability in subjects with OHT or POAG. Notably, in our Phase 2 Dose Ranging Trial, efficacy continued to improve up to the highest dose tested, indicating that higher doses may be more efficacious. The data also showed continued improvement in IOP-lowering efficacy with longer duration of therapy. Based on these results, higher doses of trabodenoson are being evaluated in MATrX-1 with the goal of identifying the dose with the optimal clinical profile for subsequent MATrX trials and NDA submission for approval.
Trabodenoson is an investigational compound and is not yet approved by the FDA.