Bright New Ideas in Glaucoma Treatment

Seven fledging companies are focused on the future of lowering IOP.

BY Gerald Helzner, Senior Editor

Their names may be unfamiliar to you and they may all be categorized as “developmental stage” but a number of new companies believe they may have the next “big idea” in glaucoma therapy. Often backed by venture capital, the innovators and scientists who have committed their talents to these companies recognize that the path from developmental stage to commercial success can be long, difficult and expensive.

Here are seven companies whose leaders believe their concepts have “the right stuff” to make a difference in the future of how glaucoma is treated. Several of these companies made presentations at the Ophthalmology Innovation Summit held recently in conjunction with the annual AAO meeting.

ROCK Inhibitors

Aerie Pharmaceutical, which has already raised $61 million in venture capital funding, owes some of its initial scientific and therapeutic concepts to David L. Epstein, MD, chairman of ophthalmology at Duke University School of Medicine, and Eric J. Toone, PhD, a professor of chemistry at Duke. The current team of in-house Aerie researchers have advanced their work.

Founded in 2005, Aerie is fairly far along in its development of glaucoma therapies focused on Rho kinase (ROCK) inhibitor drugs. ROCK inhibitors are designed to lower IOP by improving the outflow of ocular fluid via the trabecular pathway. Evidence is growing that ROCK inhibitors may be more effective in treating normal-tension glaucoma than existing medications.

Recently, Aerie has reported promising results from phase 2 studies of two of its investigational therapies: AR-13324 as monotherapy and AR-12286 in combination with travoprost. Aerie has other therapeutic concepts for glaucoma in the pipeline.

The company, with locations in Bedminster, N.J., and Research Triangle Park, N.C., says all of its technology is based upon internal research and is protected by a strong intellectual property portfolio.

Aerie’s goals are ambitious. Tom van Haarlem, MD, president and CEO, has stated, “We’re going to hopefully contribute three new options for the treatment of glaucoma. They will involve first- and second-line therapy, as well as monotherapy, adjunctive and fixed-combination therapy.”

‘Localized Drug Action’ Platform

Amakem is a Belgian kinase platform company focusing on ophthalmology and is developing new treatments for serious eye conditions. The company’s lead candidate, AMA0076, is also a ROCK inhibitor that targets glaucoma by improving aqueous outflow through the trabecular meshwork.

Based on Amakem’s “Localized Drug Action” platform, the company describes AMA0076 as “a highly potent ROCK inhibitor that has been designed to allow for high localized dosing in the eye combined with low systemic exposure.” Amakem says AMA0076 is aimed at providing better patient outcomes than other ROCK inhibitor-based treatments now in development because its improved side-effect profile enables higher dosing, leading to better efficacy. Amakem is currently advancing AMA0076 through preclinical development.

AMA0076 has been shown to cause a profound reduction in IOP in several in vivo models of glaucoma. Applied as eyedrops, AMA0076 is designed penetrate the cornea and be rapidly converted into an inactive form that the body eliminates. This unique feature is aimed at preventing offtarget activity and reducing hyperemia and other significant side effects.

“AMA0076 does not cause any significant hyperemia in preclinical models,” Amakem CEO Jack Elands, PhD, said in a recent presentation. “It has a better efficacy than other known ROCK inhibitors or prostaglandins in preclinical models.”

Protein Drugs for the Eye

Based in Cambridge, Mass., Eleven Biotherapeutics is creating a proprietary technology platform focused on developing first-of-a-kind protein therapeutics to treat a variety of diseases. The company has already raised $45 million in venture capital financing.

Eleven’s internal drug development efforts currently focus on ocular therapeutics, which the company considers “a pioneering area for protein drugs.” Eleven says its approach overcomes previous challenges of applying protein drugs to ocular disease “by opening up new therapeutic avenues to address targets that are regulated by proteins and central to ocular diseases.”

Eleven says its AMP-Rx platform allows for the discovery and development of biotherapeutics that can be optimized for ophthalmic applications.

Abbie Celniker, PhD, CEO of Eleven Biotherapeutics, says that by attenuating underlying inflammatory mechanisms, the company’s AMP-Rx therapy can “play a significant role in discovery and developing novel biotherapeutics to treat a number of ophthalmic diseases, such as ocular surface diseases, neurodegeneration associated with glaucoma and dry AMD, uveitis and retinal vasculospathy.”

Eleven recently initiated an 80-patient phase 1b clinical trial for its lead product in the treatment of dry eye disease.

Receptor Subtype Adenosine-mimetic

Founded in 1997, privately held Inotek Pharmaceuticals is based in Lexington, Mass., and primarily focuses on developing novel molecules for treatment of glaucoma and retinal disease. The company has been successful in raising funding via an array of top-tier venture capital investors.

Paul G. Howes, president and CEO of Inotek, says the company’s lead drug candidate, trabodenoson, is “a highly selective α1 receptor subtype adenosine-mimetic that is a potential first-line, best-in-class glaucoma treatment.” Mr. Howes notes that the efficacy of trabodenoson demonstrated to date is similar to prostaglandins and improves with treatment time.

Inotek says a 144-patient comprehensive phase 2 clinical trial evaluating the efficacy and safety of trabodenoson in patients with primary open-angle glaucoma or ocular hypertension has successfully achieved its primary and secondary endpoints. This new data was presented at the Ophthalmology Innovation Summit.

Trabodenoson was found to reduce IOP by approximately 7 mm Hg at 28 days and was safe and well tolerated, with very good ocular tolerability and less eye redness than currently approved glaucoma treatments, according to Inotek. The company reports that efficacy appears to be related to both the dose of the drug as well as the time on treatment, and that the safety profile should allow longer treatment with higher doses in the next planned studies.

Trabodenoson binds to epithelial cells in the trabecular meshwork, upregulating gelatinases that clean out and remodel the meshwork, increasing outflow and restoring a healthier IOP, the company says.

“These phase 2 trabodenoson results are highly encouraging, with the efficacy and safety data suggesting the potential for a glaucoma treatment with a profile superior to currently approved drugs,” says Rudolf A. Baumgartner, MD, Inotek’s chief medical officer. “Additionally, based on pharmacodynamics observed in this study, we are also encouraged by the possibility of once-daily dosing, and look forward to exploring this profile in future trials.”

Jonathan Myers, MD, director of glaucoma fellowship at Wills Eye Institute in Philadelphia, adds, “Trabodenoson is one of the most promising glaucoma drug candidates in development, based on its novel mechanism of action, the safety and efficacy observed to date and the potential for once-daily dosing. It appears that trabodenoson works directly at the site most affected in glaucoma, the trabecular meshwork.” He explains that trabodenoson restores the fluid permeability of the trabecular meshwork. “If these data are borne out in further clinical evaluation, trabodenoson could shift the paradigm of treatment for patients with glaucoma,” Dr. Myers says.

Based on the phase 2 results, Inotek is planning a comprehensive late-stage clinical development program for trabodenoson.

Scaffold-like Micro-stent

Founded in 2007 and based in Irvine, Calif., Ivantis Inc. is venture-capital funded and boasts a blue-ribbon scientific advisory board that includes such leading glaucoma specialists as Ike Ahmed, Reay Brown, Thomas Samuelson, Richard Lewis, Henry Jampel and others of similar stature. The company’s lead product, the Hydrus I Microstent, is a tiny nickel/titanium “scaffold” approximately the size of an eyelash.

Ivantis recently reported that a multicenter, international clinical trial of its Hydrus I Microstent for treatment of primary open-angle glaucoma has shown excellent one-year results.

The 69 patients in the study had been diagnosed with mild to moderate open-angle glaucoma. Study data indicated that IOP was reduced to acceptable levels in 100% of participants after they received minimally invasive stent-implant surgery. In 29 patients, the micro-stent was placed during cataract surgery while the other 40 patients had the Hydrus Microstent placed without cataract surgery to assess whether the device would be effective on its own.

No significant complications occurred in either patient group. At the six-month follow-up, 85% of combined-surgery and 70% of stent-only patients no longer needed eyedrop medications to control their IOP. Reductions in IOP were consistent among all patients and remained stable at the one-year follow up.

Noninvasive IOP Sensor

Established in 2003, Sensimed AG is a Swiss company with its principal focus on design, development and commercialization of integrated micro-systems for medical devices.

Sensimed has developed a patented, non-invasive product for glaucoma management called the Triggerfish Sensor that monitors IOP around the clock. Triggerfish is in the form of a soft, hydrophilic single-use contact lens containing passive and active strain gauges embedded in the silicone to monitor fluctuations in diameter of the corneoscleral junction. The output signal, sent wirelessly to the Triggerfish antenna, correlates directly to fluctuations in IOP.

The patient wears the Triggerfish up to 24 hours and assumes normal activities, including sleep periods. When the patient returns to the doctor, Bluetooth technology transmits the data from the device to the practitioner’s computer for immediate analysis.

“The need for continuous monitoring of glaucoma patients has been recognized for several years,” says Sensimed CEO Jean-Marc Wismer. “Diurnal fluctuations in IOP represent an independent risk factor for glaucoma disease progression despite normal office IOP. A significant percentage of glaucoma patients have intraocular peaks or target pressure breakthroughs at night or early morning. In addition to levels of IOP, key information lies in patterns of IOP. There’s no other device that offers this.”

Sensimed believes the Triggerfish device will contribute to a deeper understanding of glaucoma progression, allowing ophthalmologists to personalize and to optimize the glaucoma patient’s therapeutic care.

CyPass Micro-Stent

Based in Menlo Park, Calif., Transcend Medical is the first ophthalmic company to be spun out of the ForSight startup incubator. Funded by venture capital, Transcend’s lead product is the CyPass Micro-Stent for the treatment of glaucoma, which is currently in clinical trials in the United States and Europe.

The surgeon inserts CyPass Micro-Stent into the eye during routine cataract surgery, just after placement of the IOL. Using specialized instrumentation, the surgeon places the CyPass Micro-Stent in a precise location just below the ocular surface to create a new pathway for fluid drainage, thus reducing IOP. Once in place, the CyPass Micro-Stent is intended to control IOP all day long, which may reduce the risk of glaucoma disease progression.

A presentation at the European Society of Cataract and Refractive Surgeons by Magda Rau, MD, showed the CyPass to be effective as both a stand-alone glaucoma treatment or in a combined procedure with cataract surgery. Both surgical groups achieved significant mean IOP reduction. In the group receiving the stand-alone procedure, the average number of medications declined from 2.4 to 1.4.

CyPass has received the CE mark. In the United States, the COMPASS clinical trial is evaluating the device in a combined glaucoma-cataract procedure.

The Promise and the Reality

The history of developmental-stage companies is that some will succeed, some will be acquired by larger entities and some will eventually fall by the wayside. The companies featured here are all well-funded and each has selected a niche in the area of glaucoma treatment and management that shows potential for successful innovation. It will be interesting to follow these seven companies over the next few years to see how they progress. OM