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New class of glaucoma therapeutics a reason for cautious optimism
ROCK inhibitors and adenosine agonists seem to act at the site of aqueous flow dysfunction, but these agents are still in development.
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A new class of glaucoma drugs in the late stages of development may offer the potential to enact treatment at the critical point of aqueous humor drainage, but much work still needs to be done to clarify the exact mechanism of action and safety.
Research is ongoing on Rho-kinase inhibitors and adenosine agonists, both of which are believed to positively affect the trabecular meshwork, making the region more amenable to aqueous outflow. Earlier this year, Santen Pharmaceuticals announced that it had reached an agreement to license Clinical Data’s adenosine A2A agonist compound ATL313 for further development.
In a press release announcing the deal, Santen officials said that encouraging preclinical testing of the selective adenosine agonist warranted further investigation as a topical ophthalmic treatment. The compound is also being investigated as a potential B-cell cancer therapy.
“We are encouraged by the results of our work with Clinical Data’s adenosine compounds to date and based on continued positive findings from further studies, plan to file an IND for ATL313 in the shortest possible time or hopefully in a year,” Akira Kurokawa, president and CEO of Santen, said in the release.
Work on Rho-kinase (ROCK) inhibitors is more nascent. In 2001, researchers at Duke University, sponsored by the Foundation Fighting Blindness, Glaucoma Foundation of American Health Assistance Foundation and the National Institutes of Health, published results from an in vitro study showing that a compound, dubbed Y-27632, caused changes in cell shape and decreases in actin stress fibers, focal adhesions and protein phosphotyrosine staining in human cell trabecular meshwork and Schlemm’s canal.
In particular, Schlemm’s canal permeability increased as much as 80% in the study. Testing in enucleated porcine eyes demonstrated an increase of aqueous outflow between 40% and 80%, an effect the researchers attributed to widening of the extracellular spaces.
“Physiological and pharmacological agents that influence Rho/Rho kinase-mediated signaling pathways represent a potential therapeutic means to treat elevated ocular pressure in glaucoma patients,” the study authors said.
Since that study, several ROCK inhibitors have been explored in the published literature in animal and cell studies.
A new class
The field of glaucoma has not seen a new class of drugs since prostaglandin analogues were introduced more than a decade ago. While acknowledging that much research still needs to be done, some glaucoma experts are already anticipating how new therapeutics could affect clinical practice.
In particular, the mechanism of action offered by either ROCK inhibitors or adenosine agonists would seem to offer an advantage over current mechanisms, in that their activity is at the site of problematic anatomy. Other classes of glaucoma drugs, although effective, act by increasing or decreasing inflow or outflow mechanisms at tissue sites surrounding the trabecular meshwork. Both ROCK inhibitors and adenosine agonists appear to expand the capability of flow to the anterior chamber, potentially minimizing the effect of synechiae in obstructing flow mechanisms.
 Douglas J. Rhee |
“This will give us not just another drug, but a novel class. Having one more class in medication, there’s a potential there for fewer patients needing surgery,” OSN Glaucoma Board Member Douglas J. Rhee, MD, said in an interview.
But even though the potential for new classes of medication is exciting, the core issue of compliance remains in glaucoma, Dr. Rhee said. The challenge to glaucoma is still actually getting needed medications into the eye.
ROCK inhibitors and adenosine agonists, because they act at the usual site of dysfunction, may bring glaucoma specialists closer to the ideal of getting needed therapies to the at-risk site. – by Bryan Bechtel and Erin L. Boyle
References:
- Rao PV, Deng PF, Kumar J, Epstein DL. Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest Ophthalmol Vis Sci. 2001;42(5):1029-1037.
- Santen press release. Available at: http://www.santen.com/news/20100430.pdf. Accessed Aug. 10, 2010.
- Douglas J. Rhee, MD, can be reached at Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02144; 617-573-3670; fax: 617-573-3707; e-mail: dougrhee@aol.com.
