BBI Contributing Writer

WASHINGTON Cosmetic procedures has been by far the fastest-growing segment of the surgery market in the U.S. in the past several years as aging Americans seek to maintain a youthful and attractive appearance. Based upon the number of sessions devoted to refractive surgery at the American Society of Cataract and Refractive Surgery's (ASCRS; Reston, Virginia), annual Symposium on Cataract, IOL and Refractive Surgery, held at the Washington Convention Center in mid-April, ophthalmology clearly is participating in this mega-trend.

The surgical correction of refractive error already has become a huge business for the industry and its physician customers, as the 1.4 million annual laser vision correction (LVC) procedures in the U.S. generate in excess of $2.5 billion in fees to the profession.

While there are clear-cut signs that the LVC market has begun to mature, with estimated procedures in 2005 of about 1.4 million essentially flat compared to 2000, recently approved and emerging technologies appear to have enormous clinical and commercial potential.

Whereas LVC primarily addresses the correction of myopia and, to a lesser extent astigmatism, these new techniques offer hope for the about 90 million aging Americans who will be presbyopic in the next 10 years. The lion's share of these technologies is based on a intraocular lens (IOL) implantation, a skill that has been well-honed over many years by surgeons who remove a cataractous, clouded natural lens and then replace it with an IOL.

In the U.S., there now are five approved refractive IOLs. Publicly traded Advanced Medical Optics (AMO; Santa Ana, California) has three approved lenses, the Array and the recently approved Re-Zoom for multifocality and the phakic (natural lens remains intact) IOL Verisyse for patients with high myopia. AMO also has an option to acquire privately owned Quest Vision Technologies (Tiburon, California), which is in the early stages of developing an accommodative IOL designed to closely resemble the natural lens in design and function.

In late 2003, privately owned, venture capital-backed Eyeonics (Aliso Viejo, California) became the first U.S. company to gain approval for an accommodative, refractive intraocular lens, and recently the industry's dominant player in cataract surgery Alcon (Fort Worth, Texas) gained FDA marketing clearance for its ReSTOR lens.

The approval of the Eyeonics Crystalens culminated about two decades of ardurous and frustrating work to perfect a design that mimics the movement of the natural lens as it shifts back and forth from a reading to distance mode. In spite of the need for very carefully controlled rollout and meticulous physician training, Eyeonics enjoyed strong sales momentum in 2004, as physicians and their patients responded well to its excellent efficacy and safety profile.

Clinical data presented at the ASCRS-sponsored conference was quite favorable, as numerous presenters reported that the Crystalens was performing as well or better than expected. Both John Doane, MD, of Discover Vision Centers (Kansas City, Kansas) and Steven Dell, MD, of Dell Laser Consultants (Austin, Texas) noted that their patients are enjoying outstanding reading and distance vision that has actually improved between year one and year three. Both physicians indicated that more than 95% of the patients enjoy spectacle-free reading and very sharp distance vision. Most importantly, patient satisfaction is extremely high.

The ophthalmic industry's juggernaut, Alcon, with annual global revenue of nearly $4 billion, is now prominently involved in the accommodative IOL market, having gained FDA approval for its ReSTOR IOL in March. This lens has been marketed in Europe since late 2003 and more than 11,000 eyes have been implanted to date. ReSTOR is made from the same acrylic material as its hugely successful Acrysof conventional IOL and is based on a unique design that features apodization, refraction and diffraction qualities. The first term refers to a change in the characteristics of the lens from the center, moving out to the periphery. In particular, the center of this lens provides the patient with near vision, while out in the periphery, distance clarity is provided.

In addition to a plethora of podium papers that were strongly supportive of ReSTOR's performance, Alcon held a press conference during the symposium. CEO Cary Rayment said that it took a decade to develop this lens, with the goal to provide excellent near, intermediate and far vision. It appears that the company has achieved that goal, as 80% of the patients in the FDA pivotal trial were spectacle-free after implantation.

Richard Mackool, MD, a veteran ophthalmologist from the New York Eye & Ear Infirmary (New York), noted that while these results were clearly impressive, an additional 13% of patients could have been spectacle-free if enhancements had been allowed during the trial. In real life, these patients can and likely would opt for a procedure such as laser in situ keratomileusis (LASIK) that could further improve their vision. Most importantly, about 94% of the patients said they were "very satisfied" and would have the procedure again, despite some reported incidence of nighttime glare and halos.

Mackool, who called ReSTOR a "major breakthrough in IOL technology," said he expected to use this product extensively in his practice upon market release in May. His surgical scheduling nurse, Susan Byrne, who received the implant in the pivotal trial, told the audience that it has been a "liberating experience" to get rid of her contact lenses and glasses.

Conventional cataract surgery and IOL implants are reimbursed by Medicare and these IOLs are typically priced in the $100 to $150 range in the U.S. Medicare patients are estimated to account for about 80% of the 2.8 million domestic annual IOL implants, while private-pay, pre-Medicare patients account for the rest.

Taking its cue from the enormous success for consumer-paid LVC procedures, Eyeonics is only selling to the private pay market and Alcon, after considerable soul-searching, has decided to follow the same strategy. Eyeonics priced Crystalens at $800 in the U.S., which will be leapfrogged by Alcon's $895 price tag for ReSTOR. These lenses are not marketed for any Medicare reimbursement and physicians charge the patient for both the full cost of the lens and the surgical fee.

Over the several months leading up to the ASCRS symposium, there had been an intense lobbying effort by the cataract and refractive surgery companies to educate the Centers for Medicare & Medicaid Services (CMS; Baltimore) that these new IOLs are truly for both a therapeutic (cataractous lens) and a refractive (restoring accommodation) purpose. The industry and its supporters wanted to see CMS adopt a policy whereby it would cover the therapeutic aspect of the IOL and the patient would pay for the refractive remainder. That was clearly divergent from its current policies, which treats an IOL as solely a therapeutic device.

John Ciccone, director of communications for ASCRS, said that "Medicare patients should have access to refractive and accommodating IOLs following cataract surgery, and they should be allowed to pay the difference between what Medicare would normally reimburse for a conventional IOL and the cost of the accommodating or refractive lens." That initiative paid off with CMS's announcement last month (see sidebar, next page) that it would allow beneficiaries to pay for the more advanced lenses, in addition to "associated services that exceed the charge for insertion of a conventional IOL following cataract surgery."

The change will have important implications not only for today's refractive IOL contenders but also for the myriad of startups that are diligently working to perfect accommodative IOL technology and garner a share of what promises to be a large and lucrative market.

Domestic sales of refractive IOLS are currently paltry, but rapid growth is expected in the coming years. Ken Taylor, OD, the CEO of Taylor Consulting Group (Marblehead, Massachusetts), a firm specializing in ophthalmic industry analysis, told The BBI Newsletter that he projects that the embryonic refractive IOL market will grow at a robust 45% annual rate in the 2004 to 2009 period.

Taylor added that such a rate would be four to five times the rate of growth of the overall refractive surgery market.

Making strides in presbyopia

The past two decades have featured remarkable progress in cataract surgery technology, as the combination of minimally invasive phaco-emulsification surgery and the availability of foldable intraocular lens (IOL) materials have made cataract surgery and IOL implantation highly predictable, efficacious and very safe. The next frontier for the industry and its highly adoptive physicians is to correct for presbyopia, which represents an enormous opportunity, as an estimated 90 million Americans, or roughly 30% of the population, are expected to be presbyopic within the next decade.

Presbyopia is characterized as a progressive, age-related loss of accommodative amplitude. Progression of presbyopia typically begins in early adulthood in life, culminating in the complete loss of accommodation usually no later than age 50. It is the most prevalent of all ocular afflictions, ultimately affecting 100% of the population during the normal human life span.

The exact causes and mechanisms of presbyopia remain highly controversial in the ophthalmic community and that was well demonstrated at the ASCRS symposium. A common refrain from this meeting was that there is still much to learn about accommodation. As one ophthalmologist told BBI, "we are still a long way from understanding all there is to know about accommodation."

The lack of consensus on what causes presbyopia, plus the highly entrepreneurial and innovative nature of the ophthalmic community, has given rise to a plethora of early stage companies that appear to making impressive strides.

Venture capital-backed Visiogen (Irvine, California) has a developed a novel dual optic system with a plus-powered lens anteriorly and a minus-powered lens posteriorly, joined by a spring. Accommodation is achieved when the two lenses move back and forth with the contractions of the ciliary body in the eye. Ivan Ossma, MD of Bucaramanga, Colombia, reported excellent results on the latest iteration of this silicone lens, trade-named Synchrony, indicating that it can provide about three diopters of accommodation. He told that the audience that this is a "very promising device, it appears safe, effective and should provide ample accommodation for the vast majority of patients."

Visiogen received an investigational device exemption (IDE) from the FDA in late 2004 and is expected to begin its U.S. clinical trials shortly. David Chang, MD, of Altos Eye Physicians (Los Altos, California) will be the medical monitor for this study.

Another exciting, early stage company, presenting for the first time at an ophthalmic meeting, was Acufocus (Irvine, California). Its technology features an ultra-thin, opaque, biocompatible corneal inlay device inserted under a flap in the corneal bed. Daniel Durrie, MD, of Durrie Vision (Overland Park, Kansas), who presented the Acufocus story, described its device in layman's terms as a "doughnut in the eye." Durrie will be the company's medical monitor for its upcoming U.S. clinical trial.

The design is based on a small-aperture optics principle that is not expected to interfere with the normal function of the lens so the patient's distance vision will remain unaffected. This process allows the presbyopic patient to focus on objects that are within an arm's length.

One of the attractive features of the device is the potential that it could be implanted in a patient who previously has laser in situ keratomileusis (LASIK) and now desires a presbyopic correction. Like many other refractive implants, this device has gone through numerous design changes and materials since it was first conceived several years ago. It has now been implanted in 150 eyes in Mexico, Brazil and Turkey, although Durrie only presented data on the latest design, which was implanted in 57 patients.

Clinical results to date, albeit on relatively few eyes and with less than a year follow-up, are clearly exciting, with patients enjoying both excellent near and far vision. During his talk, Durrie quoted one of the luminaries in the ophthalmic surgery field, Jack Holladay, MD, of Holladay LASIK Institute (Bellaire, Texas), who, after carefully examining this technology, said that "this is the most exciting concept I've yet seen for the treatment of presbyopia."

Acufocus will file for an IDE this summer and hopes to begin a multi-center clinical trial in the U.S. later this year. The company recently completed its third round of venture capital financing, led by Pequot Ventures (Westport, Connecticut).

Another fascinating technology in this space is being developed by privately owned, venture capital-backed PowerVision (San Carlos, California). The company is developing a proprietary, microfluidic-controlled accommodating IOL, which uses natural muscular accommodating forces in the eye to transport fluids in the lens. In the eye, the lens goes from thin (unaccommodated) to thick (accommodated) as fluids move from the periphery of the lens through internal fluid channels to a piston-like structure in the center of the lens, pushing it outward. This results in a shape change of the lens, similar to what occurs in the natural lens (changing from thin to thick and back).

The company believes that this approach will enable its IOL to afford an accommodative range of up to 10 diopters, equivalent to the vision of a 25-year-old. This potential accommodation would sharply exceed the products currently commercial available or in clinical development.

In a talk in mid-2004 in the UK, Emanuel Rosen, MD, a well-known ophthalmologist from Manchester, England, said that "truly accommodating IOLs will be those with actual accommodation achieved by change of the curvature of the lens." He went on to say that current generation of multifocal and "pseudo- accommodating" IOLs for presbyopia are only an interim solution. "Pseudoaccommodating" refers to the fact that accommodation occurs by changing the location of a fixed-power lens.

The PowerVision technology was presented at ASCRS by Louis Nichamin, MD of the Laurel Eye Clinic (Brookville, Pennsylvania). Nichamin, who is on the PowerVision scientific advisory board, told BBI: "There is no question in my mind that the future of accommodative IOLs is in shape change." He explained that "we need to emulate Mother Nature and it appears that this lens, in theory, will accomplish that." Finally, he said, "if this lens can do what the company hopes, we will have accomplished the Holy Grail in accommodation."

The industry's leading ophthalmic surgery companies AMO, Alcon and Bausch & Lomb (B&L; Rochester, New York) all are diligently pursuing this major opportunity. AMO recently received FDA approval for its second-generation multifocal lens called Re-Zoom, which will likely supplant its older, less-efficacious, first-generation silicone Array lens. Several papers at ASCRS extolled this product, which is a different material (acrylic) and features some design changes that substantial reduces bothersome nighttime glare and halos.

Last month, AMO exercised an option to buy privately owned Quest Vision Technologies (Tiburon, California), which makes an accommodative IOL designed to closely resemble the natural lens in design and function. The deal came a year after AMO had acquired an option to buy Quest.

Alcon will soon launch its new ReSTOR multifocal IOL, following a very successful ASCRS meeting where more than 20 papers were presented. Alcon CEO Cary Rayment told BBI that his company has several projects to further improve its technology in the refractive market.

B&L also is intending to be a participant in this market, having licensed accommodative technology in mid-2003 from Faezeh Mona Sarfarazi, MD, inventor of a single-piece, molded silicone lens with a dual-optic design. The licensing agreement means Bausch & Lomb will pay research and development costs for the lens, with several milestone-based license fee payments. The company also will pay royalties on product sales upon successful commercialization of the lens. Sarfarazi is considered to be one of the world's experts on accommodation, although her hypothesis is in conflict with other, more widely accepted theories.

Over the past several years, refractive surgery has surged to the forefront of this meeting, usurping the more mature cataract surgery market. The well-established laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) procedures have been supplemented by newer technologies, such as conductive keratoplasty and phakic and refractive intraocular lenses (IOLs) that have generated huge interest and a lucrative revenue stream for the ophthalmic surgery community.

According to the widely quoted market research firm, Marketscope (Manchester, Missouri), excimer laser vision correction (LVC), which dominates today's refractive market, peaked at about 1.4 million procedures in 2000 and then plunged in the economic mailaise that followed the Sept. 11, 2001, terrorist attacks on the U.S. They have gradually recovered and reached nearly 1.4 million in 2004.

Marketscope CEO Dave Harman told BBI that he expects LVC procedures in 2005 to surpass the record number reported in 2000, fueled by rising consumer confidence and greater disposable income. He qualified that statement somewhat, however, noting that the recent slump in the stock market and rising oil prices could dent consumer confidence and slow LVC growth. The more tepid growth of the cataract surgery market primarily reflects the fact that the number of procedures, followed by implantation of an IOL, is growing essentially in line with the increase in the over-65 age category. An estimated 2.8 million cataract procedures and IOL implants were performed in the U.S. in 2004, with about 80% occurring in the Medicare population. As such, this procedure is the most commonly reimbursed one by Medicare, consuming more than half its budget for vision care.

Glaucoma Day debut shows its breadth

One of the most noteworthy changes to this year's program was the debut of Glaucoma Day, the first time that ASCRS has dedicated a full day to this topic. The response to this new program was impressive, with a large ballroom virtually filled to capacity. Reay Brown, MD, in private practice in Atlanta and a prolific inventor of glaucoma-related devices, said, "I never thought I'd see the day that there was a glaucoma day at ASCRS."

Although cataract and refractive surgeons may not be well known for treating this disease, in fact a majority of them are involved in some aspect of glaucoma patient care. According to the American Academy of Ophthalmology (AAO; San Francisco) about 1,600 physicians, sometimes known as "glaucomatologists," specialize in managing the disease.

Glaucoma is a global vision care problem, with nearly 7 million people blinded directly as a result, and another 70 million affected by the disease. The World Health Organization (Geneva, Switzerland) recently stated that glaucoma is the second-leading cause of blindness in the world, exceeded only by cataracts. In the U.S., the Eye Diseases Prevalence Research Group has noted that open-angle glaucoma (OAG, by far the most dominant form of glaucoma) affects more than 2 million individuals. Owing to the rapid aging of the U.S. population, this number is predicted to increase to more than 3 million by 2020.

Glaucoma is a collective term used to describe a heterogeneous group of slowly progressive disorders characterized by an elevation of intraocular pressure (IOP) within the eye, optic nerve dysfunction and visual loss. Irreversible deterioration of the optic nerve eventually causes loss of peripheral and ultimately central vision.

A landmark development in the management of glaucoma, which is a "silent" disease, occurred in 2000, when the first glaucoma detection benefit under Medicare was approved. Culminating several years of intensive lobbying by the AAO, this provision included an exam for individuals at highest risk of developing the disease, including African-Americans and those with a family history.

Of all the diseases treated by ophthalmic medical professionals, glaucoma may be the most challenging one, for several reasons. For one, its exact origin and etiology are still controversial. Conventional wisdom is that glaucoma is precipitated by an elevated IOP and that this elevated pressure ultimately results in vision loss. This traditional explanation of the disease drives the management of glaucoma, with a wide range of pharmaceuticals whose overriding goal is to reduce IOP. The worldwide market for glaucoma drugs is currently estimated at about $2 billion, though many important agents are now off-patent and sell at a huge discount to patented compounds.

Contradicting this strategy to lower IOP is that only a portion of the estimated five million Americans who have an elevated IOP (so-called "ocular hypertensives") develop optic nerve damage and subsequent impairment or loss of vision.

There has been a proliferation of new anti-glaucoma drugs in recent years, complicating the prescribing patterns for physicians. According to a presentation made at the ASCRS symposium by Kuldev Singh, MD, associate professor of ophthalmology at Stanford University Medical Center (Menlo Park, California), "there have been more new glaucoma drugs released in the past 10 years than in the past 50 years."

Another frustration is that patient compliance with anti-glaucoma medications is abysmally low. According to a study cited by Stephen Obstbaum, MD, professor of ophthalmology at the New York University School of Medicine (New York), more than half of all glaucoma patients do not take their prescribed medications or even keep their scheduled office visit after a positive screening test. He cited a variety of reasons, including side effects, inconvenient and complex regimen, the symptomless nature of the early to mid stages of the disease and the financial burden.

Quoting Joyce Cramer, MD of Yale University (New Haven, Connecticut), who said that "drugs don't work for patients who don't take them," Obstbaum urged the audience to adopt a multi-disciplinary approach to improve patient compliance and thereby enhance patient care.

In a session devoted to "Surgical Innovations/Horizons," described by moderator Bradford Shingleton, MD, assistant clinical professor at Harvard Medical School (Boston) as "cutting edge and beyond," several innovative surgical approaches to the disease were discussed. This session included implants, laser therapy and new ultrasound imaging technology, which will be targeted to patients in whom medical management has failed or is inadequate to control their IOP.

This treatment patterns is in contrast to outside the U.S., where these technologies, supported by solid clinical trials that demonstrate efficacy and acceptable adverse events, play an important role in treating glaucoma patients. Most domestic patients are treated with medical management until there is a clear indication that more aggressive intervention is warranted.

In response to a question from BBI on why more aggressive surgical techniques are not used until later in the course of this progressive disease, one physician (who preferred to remain anonymous) said that the huge marketing clout of the pharmaceutical industry affected treatment patterns in the U.S.

While there is no doubt that the audience benefited tremendously from the day-long presentations, the ongoing frustration of glaucoma disease management was tersely summed up by one of the luminaries in the field, Robert Weinreb, MD, a professor of ophthalmology at University of California, San Diego. Responding to a question on how to manage a challenging glaucoma patient, he sarcastically quipped, "We are trying to add clarity here when there really is none." That comment, perhaps better than any statement made all day, perfectly sums up the state of confusion of the glaucoma market in 2005.