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ACN-1052 for Glaucoma

Glaucoma remains one of the leading causes of blindness worldwide, afflicting approximately 70 million people.  Elevated Intraocular Pressure (IOP) has been demonstrated as a major risk factor for the development and progression of glaucoma, through a number of well-conducted, prospective, randomized clinical trials that have provided overwhelming evidence that IOP reduction effectively slows the rate of development or progression of visual loss caused by glaucoma.  However, available pharmacological and surgical therapies have limited efficacy and significant side effects. 

One-third of patients have persistent high IOP fluctuations despite best medical therapy.  Topical prostaglandin analogs are the currently preferred first-line agents for most patients with glaucoma.  However, not all patients respond to prostaglandin treatment, and side effects include iritis, cystoid macular edema and permanent change of eye color.  More than 25% of patients treated with prostaglandins have persistent high IOP fluctuations, particularly African-Americans.  Topical ocular drug bioavailability is notoriously poor due to the multiple barriers to drug entry involving nasolacrimal drainage, epithelial drug transport and vasculature clearance.

Delivery of an eye drop poses significant problems for many individuals and effectiveness of ocular medications are substantially limited by patient compliance.  Only two-thirds of patients are able to reliably get the medication onto the ocular surface.  Videotaped studies show that 17-25% of patients are unable to get a drop in their eye, with older patients having the most difficulty.  Elderly patients can reliably take a pill, yet effective, safe and well tolerated oral medications for glaucoma are lacking.

Product Overview

Adenosine A3 receptor (A3AR) antagonists are a novel oral treatment for glaucoma.  Acorn Biomedical is developing first-in-class compounds targeting the A3AR, which modulate the production of aqueous humor in the mammalian eye.  The A3AR subtype is the most recently characterized member of the adenosine receptor family.  Adenosine levels have been found to be elevated in the aqueous humor of ocular hypertensive patients, and A3ARs are substantially upregulated on nonpigmented ciliary epithelial (NPE) cells in patients with pseudoexfoliation syndrome.  The A3AR holds promise in glaucoma because knockout of the A3AR reduces IOP in the living mouse and A3AR antagonists have been shown to reduce IOP in rodents, rabbits, and both normal and glaucomatous monkey.  A3AR antagonists physiologically decrease inflow of aqueous humor by inhibiting Cl- channels of the NPE at the aqueous surface.  It has also been observed that antagonists of A3AR are neuroprotective to oxygen and glucose deprived hippocampal tissue.  A3AR are present on retinal ganglion cells and antagonists of the A3AR have the potential to be neuroprotective in patients with glaucoma.  Currently, none of the existing medical or surgical therapies protect the retina from degeneration in glaucoma. 

Development of a therapeutic A3AR antagonist has thus far been impeded by the lack of cross-species affinity and specificity.  Various A3AR antagonists had been identified, yet none exhibited similar levels of specificity and selectivity for both the rodent and human A3AR, precluding nomination as therapeutic candidates. 

ACN-1052 is the first orally bioavailable, potent, selective, and specific A3AR antagonist with single digit nM affinity for both the human and rat A3AR.  The pharmacodynamics of ACN-1052 has been extensively studied in preclinical models. ACN-1052 substantially reduced IOP within minutes after topical addition with a duration of effect outlasting prostaglandins, β-blockers and alpha agonists.  With repeat administration, ACN-1052 produced a prolonged and sustained effect reducing intraocular pressure.

Upon oral administration of ACN-105, the reduction in IOP was substantially greater than that achieved with ocular administration, with IOP dropping to near venous pressure within 2 hours of dosing.  The reduction in IOP achieved with oral ACN-1052 was nearly 2-fold lower than that achieved with ocular Xalatan, Timolol or Alphagan.  The combination of ACN-1052 with Xalatan produced a significant synergistic effect further reducing IOP.  ACN-1052 has been well tolerated when administered by the ocular, intramuscular and oral routes.

These data indicate the ability of ACN-1052 to be readily absorbed following oral administration, penetrate the eye and provide a long duration of inhibition of the A3AR and substantial IOP reduction.  The synergistic effect of ACN-1052 with an outflow modulating agent, such as a prostaglandin, provides the therapeutic opportunity to dampen the diurnal IOP spikes that have been shown to accelerate the rate of vision loss in glaucoma patients.