Medical Device Daily Contributing Writer

CHICAGO — The annual meeting of the American Academy of Ophthalmology (AAO; San Francisco), the largest ophthalmic meeting of the year, took place here in the past few days, with an estimated 26,000 persons from around the world in attendance. The meeting was conducted in conjunction with the Asia-Pacific Academy of Ophthalmology.

Preceding the AAO was the fourth annual Ophthalmology Innovation Summit (OIS), which was organized by International Business Forum (Massapequa, New York). The attendance of nearly 800 persons was very impressive and was substantially above the previous three OIS-AAO gatherings. Attendees came from 36 states in the U. S. and from 23 countries around the world.

The purpose of the OIS conference is to support innovation by facilitating deal-flow and business partnerships between CEOs of young companies, investors, corporate executives, physicians and academic scientists in the field of ophthalmology.

Whereas the OIS held in conjunction with the American Society of Cataract and Refractive Surgeons (ASCRS; Reston, Virginia) focused solely on the medical device world, OIS at AAO also encompasses the pharmaceutical and biotechnology sector of the ophthalmic industry.

In the past decade, there has been a dramatic increase in the sales of drugs to treat age-related macular degeneration (AMD). Marketscope (St. Louis) estimates that 2012 global revenue in AMD drug sales will be about $4.7 billion, with anti-VEGF products representing about 95% of this worldwide total.

Additionally, Marketscope also estimates that there will be nearly 11 million anti-VEGF injections in 2012, up dramatically from less than one million in 2006. Avastin, which is an oncology drug used off label to treat AMD has captured about 63% of these injections in the U.S., compared to 23% for Lucentis. Avastin's sole advantage is that it is approximately $100 per dose, compared to $2000 for Lucentis.

At an AAO press conference, Abdish Bhavsar, MD, a retinal specialist from the Retinal Center (Minneapolis) discussed the recently released two year results of the Comparison of Age-related macular degeneration Treatment Trials (CATT) trial. This trial analyzed the safety and efficacy profiles of Lucentis and Avastin and Bhavsar noted that the two drugs were "equivalent for visual acuity at all time points over a 2-year period." While noting a modest increase in Avastin's adverse events, he noted that this was a not a major issue overall.

Despite the tremendous uptake of anti-VEGF drugs, fostered by their very favorable safety and efficacy profile, a surprising fact is that many patients are not receiving monthly injections, which is what is generally recommended. To wit, an article in the June 2012 issue of the American Journal of Ophthalmology titled "Treatment Patterns for Neovascular Age-related Macular Degeneration: Analysis of 284,380 Medicare Beneficiaries" concluded that " . . . few patients treated with anti-VEGF medications received monthly injections and discontinuation rates were high."

Specifically, the study found that anti-VEGF therapy was discontinued in 53.6% of eyes within one year, and in 61.7% of eyes within 18 months." This lack of "adherence" or compliance is well known within the pharmaceutical industry, with abysmal adherence seen across many drug types. Indeed the 9th edition of a study on patient adherence prepared by the consulting firm Capgemini Group (New York) revealed a shockingly low level of adherence, even for medications to treat diseases like HIV/AIDS and cancer. The former has an adherence rate of 54% while the latter has a 62% rate.

In a presentation at the OIS, CEO Jim Taylor of privately owned, venture-backed company Oraya Therapeutics (Newark, California), discussed his company's proposed solution to help reduce the treatment burden of monthly injections and the high dropout rate for anti-VEGF AMD drug therapy. He noted that there are four categories of commonly adopted adherence interventions strategies: longer acting therapy, combination therapy, easier delivery mechanism and a simplified regimen. Oraya's system, trade named the IRay, appears to fit into two or three of these categories.

Earlier this year, Oraya reported (MDD, May 4, 2012) that its pivotal trial IRay Plus Anti-VEGF Treatment For Patients With Wet AMD (INTREPID) had successfully met its one-year endpoint. INTREPID, which completed enrollment in April 2011 with 230 patients enrolled, was the first sham-controlled double-masked trial to evaluate the effectiveness and safety of a one-time radiation therapy in conjunction with as-needed anti-VEGF injections for the treatment of wet AMD. The multi-national study included sites in Austria, Czech Republic, Germany, Italy and the UK.

The complete results from the INTREPID study, which were presented during the EURETINA Congress in Milan, Italy in September, showed that the small volume doses of radiation were not harmful and that the trial achieved its primary endpoint with a 33% reduction in injections. For the "best responders" there were major benefits: (1) Visual acuity was notably higher in the IRay cohort, specifically the average patient enjoyed a nearly seven letter improvement over sham at one year; (2) The number of anti-VEGF injections required was reduced by an impressive 54% versus the control group.

IRay is a non-invasive, low-voltage, stereotactic radiosurgical device that is designed to deliver a precise dose of radiation noninvasively through the sclera to the macula using a robotic positioning system, a proprietary localizing algorithm and a novel methodology for eye stabilization. Intended as a one-time procedure, the iRay is non-invasive, rapid, comfortable for the patient and easy for a trained operator to perform. The total procedure time typically takes less than 20 minutes, the company said.

Oraya has a CE mark and has begun its commercial rollout in select markets outside the U.S. The company has not yet disclosed its plans for a clinical trial or commercial rollout in the U.S.

Another presenting company at OIS, which bridges both the pharmaceutical and device businesses, was venture-backed Avedro (Waltham, Massachusetts). CEO David Muller, a veteran of the ophthalmic device industry, discussed its corneal cross-linking (CXL) technology, which he described as having "huge potential."

CXL is a technique that uses UV light and a photosensitizing drug (typically riboflavin ophthalmic solution) to strengthen the chemical bonds in the cornea. There are several interesting applications for CXL and one of the most important is to halt corneal ectasia. This condition, which is defined by progressive steepening or bulging of the cornea and the possible loss of vision, is one of the most devastating complications from LASIK and its impact is increasingly being seen in post-LASIK patients.

A second current use for CXL is to treat keratoconus, which is a progressive thinning of the cornea that generally leads to vision loss or distortion.

According to a recent comment from Peter Hersh, MD, Avedro's Medical Monitor and director of the Cornea and Laser Eye Institute (Teaneck, New Jersey), "there are limited treatment options for decreasing the natural progression of keratoconus and ectasia. Cross-linking has the promise of stabilizing these progressive corneal disorders and maintaining patients' visual function over time."

At the AAO's Subspecialty Day titled "Refractive Surgery 2012," a section of the program was devoted solely to CXL. The general consensus there was that CXL is a valuable technique to treat both ectasia and keratoconus. It was approved in Europe several years ago and is now widely used by refractive and corneal specialists. CXL has gained significant traction in those two conditions outside the U.S. with Muller projecting that it will sell about 50,000 kits abroad in 2012.

Muller believes that the "home run" application for CXL will be its use as a concurrent procedure with LASIK. Avedro has dubbed this combination approach as LASIK Xtra and the intended purpose is to restore the cornea's biomechanical integrity following the creation of the LASIK flap and/or excimer laser ablation during LASIK or PRK. He also noted that "LASIK weakens the cornea by up to 30% and cross-linking can strengthen the cornea threefold."

He said that this potential market is the 3.8 million annual LASIK procedures worldwide and he believes that in time Avedro will make significant inroads into this market.

Avedro has been very active on the clinical and regulatory front, with two Phase III studies completed. In March, Avedro reported that it had submitted an NDA to the FDA for its combination system for the treatment of keratoconus and corneal ectasia following refractive surgery. In addition, the company is currently supplying CXL products for 114 approved U.S. clinical sites currently in three additional Phase III studies on the safety and efficacy of accelerated cross-linking.

In 2011, the company's CXL system was granted orphan designation by the FDA for the treatment of keratoconus and corneal ectasia following refractive surgery. If approved, orphan drug status will entitle Avedro to seven years of U.S. marketing exclusivity for these indications.

Final FDA approval of Avedro's CXL system may be several months away, however. MDD sources believe that its NDA application has been delayed at the FDA and therefore the timetable for final approval is unclear.

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