BBI Contributing Editor

SAN FRANCISCO, California This year's annual Symposium on Cataract, IOL and Refractive Surgery sponsored by the American Society of Cataract & Refractive Surgery (ASCRS; Reston, Virginia) was held here in mid-April, amidst uncharacteristically gloomy weather. However, inside the crowded Moscone Convention Center, there was an upbeat mood as several exciting technologies are having a positive impact on the cataract and refractive surgery market.

The ophthalmic surgical market, both for cataract and refractive procedures, has long been characterized by a seemingly insatiable quest to improve technology and patient outcomes. For example, the FDA approval of the first excimer laser in late-1995 was the initial impetus to the surge in the number of refractive surgery procedures being performed in the mid to late-1990s. This approval, for photo-refractive keratectomy (PRK) was soon superseded by laser in situ keratomileusis (LASIK), which virtually eliminated post-procedural discomfort and provided a "wow" phenomena for many patients. This new technology, coupled with a booming economy, fueled torrid growth of the laser vision correction (LVC) market in the 1998-2000 period. According to Marketscope (Manchester, Missouri), LVC procedures reached a peak of about 1.4 million procedures in 2000, compared to only 105,000 procedures in 1996. Table 4 on page 153 displays LVC procedures for the 1996-2003 (estimated) period.

While LASIK has been a significant improvement over other refractive surgical techniques, it is still fraught with patient risk and disappointing results. An article in the April issue of Ophthalmology authored by Peter Hersh, MD, of the Hackensack University Medical Center (Hackensack, New Jersey), revealed that in a study of 2,485 eyes of 1,306 patients who underwent LASIK, the one-year incidence of re-treatment was 10.5%. Since LASIK became accepted as the standard of care for LVC procedures, refractive surgeons have realized that the microkeratome, a mechanical device that creates the corneal flap prior to application of the laser's ablative beam, can be a major source of complications. These microkeratomes, which are sold by several ophthalmic surgical device companies, require considerable skill and training for proper use. If not used correctly, they can cause corneal irregularities, scarring and subsequent blurred vision.

An article in the February issue of EuroTimes, which is produced by the European Society of Cataract and Refractive Surgeons (Dublin, Ireland), quoted Jonathan Christenbury, MD, an ophthalmologist at Christenbury Eye Center (Charlotte, North Carolina). He said he believes that microkeratome-related complications account for 95% of vision-threatening LASIK complications.

These deficiencies have spawned a technology developed by IntraLase (Irvine, California), a private, venture capital-backed firm which markets a computer-controlled laser and proprietary software that brings a level of accuracy, precision and control to flap creation that is not possible with conventional microkeratomes. Trade-named the Intralase FS (femtosecond) Laser, this device can make corneal flaps that are very accurate and highly consistent in both thickness and diameter. The IntraLASIK software allows the surgeon to custom design precise corneal resections for individual patients. The key to this device's advantage over conventional microkeratomes is that its low energy pulse, which is in the femtosecond range (quadrillionth of a second) eliminates heat damage or shock to the surrounding tissue. Thus, it is less invasive than the mechanical microkeratomes and is well suited for delicate corneal surgery.

IntraLase procedures have grown rapidly in the past year and according to an article in the February issue of Ophthalmic Market Perspectives, which is produced by Marketscope, IntraLase has placed 40 units and has captured more than 8% of the market. Without doubt, refractive surgeons using this device are capitalizing on the mystique of a laser procedure but this device is also generating stellar clinical results.

At this year's ASCRS gathering, numerous presentations discussed these results. The basic theme of these presentations and the several physician talks given at the IntraLase booth is that IntraLase produces superior clinical results. Just prior to the ASCRS meeting, the company announced that Bob Palmisano, a seasoned veteran of the ophthalmic device industry, had become its new chief executive officer. In his most recent stint in the ophthalmic business, Palmisano had engineered an impressive turnaround of Summit Technology (Waltham, Massachusetts), which was acquired in 2000 for nearly $1 billion in cash by Alcon (Fort Worth, Texas).

In addition to excitement over the reduction in microkeratome-related complications, there was considerable buzz at ASCRS for wavefront-guided custom ablations. According to noted ophthalmologist Richard Lindstrom, MD, clinical professor of ophthalmology at the University of Minnesota (Minneapolis, Minnesota) and a managing partner of Minnesota Eye Consultants (also Minneapolis), "the technology I believe that will be the most important to the future of myopic surgery is wavefront-guided custom ablation." Wavefront technology uses advanced diagnostic tools (a wavefront aberrometer or similar diagnostic tool) to precisely measure how light is distorted as it travels through the eye and how well it is focused on the retina. The multivariate data, which is generated from the wavefront analysis, is then used to drive a precise and customized pattern of corneal tissue removal performed by the excimer laser. This is intended to remove optical aberrations and perfectly focus light on the retina, aiming for 20/20 or even better visual outcomes.

In mid-October 2002, Alcon became the first excimer laser company to obtain FDA approval. Its diagnostic and therapeutic combination is called LADARVision CustomCornea. LVC industry leader VISX (Santa Clara, California) is poised to enter the therapeutic market shortly. In April, VISX reported that it had paid nearly $6 million to acquire the technology, including patents and other assets associated with its WaveScan product line from 20/10 Perfect Vision (Heidelberg, Germany). This WaveScan technology, according to CEO Liz Davila, "is the foundation for CustomVue, a product that uniquely analyzes and corrects vision more precisely than ever before."

The 20/10 Perfect Vision device measures the standard refractive parameters (sphere, cylinder, axis) as well as higher order aberrations of the eye with several hundred data points over the diameter of the pupil within fractions of a second. Using this device, which is currently approved only for diagnostic purposes, VISX expects that LVC procedures can be performed much more accurately, leading to better visual outcomes. Its procedure, trade-named CustomLASIK, is expected to win FDA approval soon.

A plethora of clinical studies, including several at this year's ASCRS meeting, have demonstrated that CustomLASIK provides slightly improved rates of distance visual acuity over standard LASIK (rates of 20/20 or 20/16 vision), improved quality of vision (i.e. better contrast sensitivity), and lower rates of unwanted side effects (i.e., night glare and halos).

Vision care giant Bausch & Lomb (B&L; Rochester, New York) expects to enter the wavefront market in the second half of this year with its Zyoptix system, which it developed with the Center for Visual Sciences at the University of Rochester (also Rochester). According to Stephen Slade, MD, a noted cataract and refractive surgeon from The Laser Center (Houston, Texas), about 92% of the eyes treated in a Zyoptix clinical trial ended up with 20/20 vision or better without glasses. This compares with about 86% with traditional LASIK. Moreover, about a third of the eyes treated ended up with 20/12 vision. Only half of the patients saw an increase in so-called higher-order aberrations that can cause effects like halos. In traditional LASIK, by contrast, such aberrations almost always increase.

Nidek (Fremont, California) also intends to enter this market with its NAVEX (Nidek Advanced Vision Excimer Laser) platform, which consists of its new EC-5000 CX II laser system, its NAVFocus eye tracker, its NAVWave OPD-Scan that combines wavefront analysis with corneal topography to map aberrations of the entire optical system, and its microkeratome. This system has been approved in Europe with a CE mark since early 2002 and clinical trials in the U.S. are just beginning. FDA approval could come in 2H04.

The addition of wavefront-guided LASIK is increasing the cost of LVC procedures. Alcon has boosted the per-eye procedure fee it charges doctors from $100 to $200, and VISX and Bausch & Lomb are expected to follow suit after they receive FDA approval. Thus, the manufacturers are essentially doubling the per-procedure LASIK fee.

While laser refractive surgery was a key focus of this year's meeting, there also was considerable interest in non-laser refractive surgery. In particular, numerous papers were presented on phakic intraocular lenses (IOL), notably the STAAR Surgical (Monrovia, California) Implantable Contact Lens (ICL) and the Ophtec USA (Boca Raton, Florida) Artisan lens.

The ICL is a collagen co-polymer implant that is targeted to treat common refractive disorders such as myopia, hyperopia and astigmatism. It is folded and implanted in the posterior chamber behind the iris and in front of the natural crystalline lens, requiring only topical anesthesia on an outpatient setting. It is now approved for sale in several countries, including the entire European Union (via a CE mark), Korea, Canada, certain South American countries and South Africa. It also is close to approval in Taiwan and Australia.

In the U.S., STAAR recently reported that it had submitted the third module (containing relevant clinical data) of its premarket approval application, implying the possibility of an invitation to an FDA Ophthalmic Devices Panel meeting later this year. The current panel schedule suggests that this could occur as early as the Sep. 11-12 proposed meeting but more conservatively, the Nov. 6-7 meeting. Final FDA approval could come in early 2004.

During the ASCRS meeting, STAAR released the results of its pivotal ICL clinical trial, which encompassed the first three-year follow-up interim results in 369 eyes. According to Slade, an ICL investigator, STAAR's results were "exceptional." The mean level of myopia for the 369 eyes was minus 10.1 diopters. He reported that 95% of the patients with good pre-operative visual acuity targeted for emmetropia (zero postoperative correction) had uncorrected visual acuities (UCVA) of 20/40 or better and that 57% had uncorrected visual acuities better than their best corrected visual acuity (BSCVA) preoperatively. In addition, 38% gained one line of BSCVA and 10.8% gained two or more lines of BSCVA.

Stability and safety of the procedure was well demonstrated. In particular, the complication rates were extremely low, with a 0.6% rate of three cataract extractions and a 0.4% rate of clinically significant anterior subcapsular opacities. According to Slade, one of the most exciting findings was that 99.4% of the patients were satisfied with their ICLs three years after implantation.

The May issue of Cornea, the Journal of Cornea and External Disease, contained an article titled "Comparison of the Implantable Contact Lens with Laser Assisted In Situ Keratomileusis for Moderate to High Myopia," authored by John Vukich, MD, the company's medical monitor, who is based at Dean Medical Center (Madison, Wisconsin) and Don Sanders, MD, a professor at the University of Illinois College of Medicine (Chicago, Illinois) and a regulatory consultant to STAAR. This study compared the treatment of 210 ICL eyes to 559 LASIK eyes with moderate-to-high myopia. Every index of BSCVA, UCVA, predictability of refraction, and stability of refraction studied favored the ICL over the LASIK procedure. The authors concluded that the ICL was safer and more effective than LASIK and appears to be a viable alternative to corneal refractive surgery in the treatment of moderate to high myopia.

As with any new medical device, estimating the market penetration of the ICL is challenging. Nevertheless, at a STAAR-sponsored analyst meeting during ASCRS, CEO David Bailey provided a framework for potential North American ICL sales. His assumptions and projections are shown in Table 5 below.

STAAR also is moving forward with its plans to commercialize a toric (astigmatic) ICL. It initiated its U.S. trial in 4Q02 and thus far has enrolled 54 of the requisite 125 patients. Based on its current status, Bailey predicted that the toric ICL could receive final FDA approval 12 months after the ICL for myopia is cleared for sale. The toric ICL received the CE mark in December 2002. The company also has the CE mark and approval in Canada for its hyperopic ICL. In the U.S., its clinical trial is well into Phase III, with just a few patients left to complete enrollment.

Ophtec USA is likely to be the second entrant in the domestic phakic IOL market. According to its CEO, Rick McCarley, Opthec is completing its three-year follow-up and expects to submit its PMA to the FDA shortly. Papers presented at ASCRS indicate that this anterior chamber, hard non-foldable plastic lens is both safe and effective in treating high myopia and astigmatism. Advanced Medical Optics (Irvine, California) has secured exclusive distribution rights in North America and co-exclusive rights with Ophtec in the rest of the world. When cleared for U.S. marketing, its brand name will be Verisyse.

Medennium (Irvine, California) also is in the midst of its pivotal U.S. trial with its posterior chamber Phakic Refractive Lens (PRL). Once again, its clinical results, as reported at ASCRS, appear solid but the PRL is unlikely to receive final FDA approval until 2006. In March, Medennium reported that the Ciba Vision (Duluth, Georgia) division of Novartis (Basel, Switzerland) had purchased all intellectual property rights, product registrations and certain tangible assets related to the PRL. Previously, Novartis had obtained a worldwide distribution license for the PRL. The product already has garnered the CE mark and other offshore approvals.