Glaucoma is a disease of the eye in which damage to the optic nerve leads to progressive, irreversible vision loss. It is associated with a number of risk factors, the most prominent of which is high intraocular pressure (IOP).

Physiology of the Eye

The eye can be thought of as if it were a fibrous sack which must stay “inflated” with a fluid, known as aqueous humor, at the proper pressure in order to maintain its shape and effectively convey light to the retina where the light stimulus is then relayed to the brain and converted into a visual image. To maintain the eye’s pressure – and therefore its shape – and as a means to provide nutrients to eye tissue, aqueous humor is constantly produced inside the eye by a tissue known as the ciliary body. The ciliary body sits just behind the iris, which is the colored part of the eye. Aqueous humor flows forward through a hole in the center of the iris, called the pupil, and down into the angle defined by the front of the iris and the back of the cornea, which is the clear covering on the front of the eye. This angle is the same angle referred to in Primary Open Angle Glaucoma, or POAG, the most common form of glaucoma. Below is a diagram identifying certain parts of the eye, including the ciliary body, iris and the angle defined by the front of the iris and the back of the cornea:
Human Eye: Internal structures (transverse view)

In this angle, around the outer rim of the iris, is the trabecular meshwork, a natural, pressure-regulating drainage system. Approximately 70% of the aqueous humor leaving a healthy, well-functioning eye exits through the trabecular meshwork, and flows into a drainage canal known as Schlemm’s canal, which empties into a venous drainage system. The remaining approximately 30% of aqueous humor leaves the eye through a secondary pathway called the uveoscleral pathway which, unlike the trabecular meshwork, is pressure-insensitive. The diagram below shows the location of the trabecular meshwork and uveoscleral pathway, the two pathways for aqueous humor to leave the eye.
Trabecular Meshwork and Aqueous Humor Dynamics


Development of High IOP and its Effects in Glaucoma

In a typical patient afflicted with glaucoma, not enough aqueous humor exits the eye, and the pressure within the eye increases. This excess pressure squeezes the retina, the layer of tissue covering the inside of the back half of the eye that converts light into nerve impulses. For people to “see,” these impulses – the visual signal – must be relayed through the optic nerve to the brain for processing. Cells in the retina require nutrients and oxygen that are delivered via blood vessels entering and exiting the eye through the same opening as the nerve fibers carrying the visual signal. However, when IOP is too high, it becomes difficult to pump blood enriched in oxygen and nutrients into the retina. The diagram below shows eye anatomy and how elevated pressure can impair nerve tissue in the retina and optic nerve head.
Effects of Chronic Increased IOP on the Retina and Optic Nerve Head
Human Eye: Internal structures (transverse view)


Deprivation of blood supply to the retina may damage Retinal Ganglion Cells (RGCs), a specialized type of nerve cell distributed throughout the retina. RGCs have long tails called axons that extend to the brain to carry the visual image, and in fact the optic nerve is nothing more than a bundle of these axons extending to the vision processing center of the brain. When an RGC dies, one of the connections between the retina and brain is lost, and, like most cases when a nerve is damaged or severed (e.g. spinal cord injury), there is no current way to repair the damage. As a result, some portion of vision is permanently lost. Therefore, the root cause of vision loss in glaucoma is not high IOP per se, but rather the impact of high IOP on the retina, and specifically on the RGCs.

Impact of Adenosine A1 receptor subtype activation on IOP

In 1995, a study was published describing how adenosine agonists could lower IOP by activating adenosine A1 receptors, in a preclinical model1. Subsequently, in 2001, a study published by the University of Pennsylvania School of Medicine confirmed that stimulation of the A1 receptor lowered IOP, but that stimulating A2a or A3 receptor subtypes, increased IOP2.

Based on these observations, preclinical testing by Inotek scientists began with the goal of understanding the effect of IOP lowering of our highly selective A1 mimetics. The most advanced of the small molecules to come from these efforts is trabodenoson (formerly known as INO-8875) which has now, in human clinical trials, been shown to have a robust IOP-lowering effect.

Based on the observations, preclinical testing began so as to understand the effect of IOP lowering of the highly selective A1 mimetics created by Inotek scientists. The most robust of these small molecules being trabodenoson (formerly known as INO-8875) which has now, in human clinical trials, been shown to have a robust IOP-lowering effect.

1J Pharmacol Exp Ther. 1995 Apr;273(1):320-6. Adenosine receptor activation modulates intraocular pressure in rabbits. Crosson CE

2Br J Pharmacol. 2001 Sep;134(2):241-5. A(1)-, A(2A)- and A(3)-subtype adenosine receptors modulate intraocular pressure in the mouse. Avila MY1, Stone RA, Civan MM.