OT-730: A Safer Beta-Blocker for Glaucoma without Systemic Side-Effects

(Currently in Preclinical Development)

OT-730 is a small molecule oculoselective beta-blocker for reducing the elevated intraocular pressure associated with glaucoma, a disease that affects 2.2 million Americans. It represents an entirely new class of beta blocker drugs - oculoselective agents. Applied topically via eye drop, this oculoselective beta blocker is active in the eye, yet rapidly metabolizes into inert compounds in the bloodstream. It represents a potentially significant clinical advance for an effective and safe anti-glaucoma medication.

About Glaucoma

Glaucoma is one of the leading causes of blindness in the world today. About 4 million Americans each year are prescribed pharmaceuticals to lower intraocular pressure (IOP).

Glaucoma is a disease characterized by damage to the optic nerve (which relays images from the eye to the brain). In the most common form of glaucoma, abnormally high pressure caused by fluid in the eye damages the optic nerve, resulting in distorted and compromised fields of vision and, ultimately, blindness.

The most prevalent symptom of glaucoma is a narrowing of the field of vision, starting with the loss of peripheral sight. The most common form of the disease is open-angle glaucoma, where symptoms appear in the space in the front of the eye, the anterior chamber. A clear aqueous fluid flows continuously into and out of the anterior chamber, nourishing nearby tissues. This fluid leaves the chamber at the angle where the cornea and iris meet. When the fluid reaches the angle, it leaves the eye through a spongy meshwork that operates like a drain. If fluid passes too slowly or is obstructed, it accumulates and creates pressure inside the eye. This increased pressure has the potential to damage the optic nerve and result in vision loss.

Despite the current availability of a number of therapies, including eye drops, ointments, pills, and surgery, there is still a significant unmet need for a safer and more effective treatment option for glaucoma.

The class of drugs known as beta-adrenergic antagonists (beta-blockers) has been a first-line therapy for the treatment of glaucoma for many years. Prior to ocular use, this class of drugs was first developed for non-ophthalmologic indications owing to the capability to bind with cellular receptors in the heart and blood vessels. Beta-blockers are highly effective at slowing the production of aqueous fluid, thereby lowering intraocular pressure (IOP). However, the first generation of ophthalmic beta-blockers, while effective in reducing IOP, produce unwanted and potentially dangerous systemic side effects as they drain from the eye into the systemic circulation. Therefore, prior to the Othera’s formation, the scientific founders of Othera initiated research efforts to discover a new generation of oculoselective beta-blockers to better control where and for how long they would act in the body, thus improving the overall safety profile.

OT-730 in Glaucoma

Building on this early research, Othera developed OT-730, a compound currently in preclinical development for the treatment of glaucoma. This novel compound has the potential to produce the desired reduction in IOP in the eye, without causing the systemic side effects associated with current beta-blocker therapies. OT-730 is a proprietary pro-drug that is converted by enzymes in the cornea into a metabolite, a novel small molecule antagonist of beta receptors for reducing the elevated intraocular pressure associated with glaucoma. While OT-730’s metabolite is active in ocular tissues, animal studies indicate that it is rapidly converted to inactive compounds in the blood steam, thus limiting the side effects throughout the rest of the body.

In preclinical experiments, Othera directly compared the systemic side effects of OT-730 to timolol, a traditional beta blocker. Animals were first dosed with an agent that activates beta-receptors in the heart and blood vessels, causing a decrease in blood pressure and an increase in heart rate. The animals were administered OT-730, timolol or placebo by eye drop. Timolol caused severe decrease in the heart rate and blood pressure due to potent systemic beta-blocking activity. In contrast, OT-730 had the same systemic effect as placebo, indicating the drug does not exhibit this undesired interaction with beta receptors in the heart and lungs.

Othera is currently developing an eye drop formulation of OT-730 in preparation for filing an Investigational New Drug Application (IND) and initiation of human clinical trials by mid-2008.