at press time

Was Lucentis Trial Data "Leaked?"
The Seattle Times Report Omits Relevant Facts.

In its Sunday edition of Aug. 7, The Seattle Times created national news with an investigative report that appeared under the headline "Drug Researchers Leak Secrets to Wall Street." In the report, written by staff reporters Luke Timmerman and David Heath, the newspaper details numerous instances of investigators involved in clinical trials who engaged in paid consultations with Wall Street investment firms. According to the newspaper, a primary reason the investment firms held these consultations was to gain early insights into the safety and efficacy of investigational drugs.

Clearly, if investigators crossed the line and provided still-secret information about as-yet-unreleased clinical data, they would be violating their confidentiality agreements and also providing the Wall Street firms with insights that could be used by investors to profit in the stock market.

	The Seattle Times focused on a Citigroup Smith Barney investment report on competing AMD treatments.

The Seattle Times charged that this is exactly what happened. The newspaper buttressed its contention by naming the names of investigators who it said provided information to Wall Street while involved in clinical trials for specific drugs that were being studied for a variety of serious illnesses.

The Seattle Times report hit like a bombshell. It was carried in news reports across the country and triggered an immediate call from Sen. Charles Grassley (R-Iowa), chairman of the Senate Finance Committee, for the Securities and Exchange Commission (SEC) to open an investigation. Indeed, the SEC investigation has now begun.

Lucentis Trial Data

One of the examples cited by the newspaper involves a pivotal phase 3 study of Lucentis (Genentech) for wet AMD. The Seattle Times report describes consultations that the investment firm Citigroup Smith Barney held earlier this year with 26 ophthalmologists, during which Smith Barney securities analysts asked questions about the safety and efficacy of Lucentis, particularly in comparison to the recently approved wet AMD treatment Macugen (Eyetech Pharmaceuticals/Pfizer).

The Seattle Times reported:

"Based on its survey [of these ophthalmologists], Smith Barney predicted remarkable results: 97 percent of patients on Lucentis would have stable or improved vision, as measured by how many lines on the eye chart they could read. Smith Barney summarized those findings in a report to select customers May 5.

"As it turned out," the article continues, "the numbers were almost exactly on the money. On May 23, not long after Smith Barney's report, Genentech announced results from its Lucentis study: 95 percent of patients had stable or improved vision — just as predicted by the doctors Smith Barney talked to."

The implication that can easily be drawn from the paragraphs above is that there was no prior public information available on the efficacy and safety of Lucentis and that the doctors were bound by their confidentialty agreements not to comment at all on the effectiveness of Lucentis.

But that is not the case. Twelve-month results of a smaller phase 1 and 2 Lucentis study were publicly released in 2002 and were reported on widely. Additional 6-month extension data was released in 2003. The ophthalmologists surveyed by Smith Barney were free to comment on that data, which turned out to be almost identical to the phase 3 results in terms of efficacy.

In the December 2003 issue of this magazine, the following comparison of Lucentis and Macugen data was reported:

"In a phase 1b and 2 clinical trial, 97.5% of 40 patients with various forms of wet AMD who received monthly injections of Lucentis had stable or improved vision after 210 days, with 45% of those improving by 3 lines or more on an EDTRS chart.

"In a large phase 3 study of Macugen, which has been fast-tracked by the FDA for possible early approval, 33% of the patients with various forms of wet AMD who were injected with Macugen every 6 weeks showed stabilized or improved vision after 54 weeks."

The Times Responds

Ophthalmology Management asked The Seattle Times why it chose to omit any mention of prior, publicly available Lucentis data in its Aug. 7 report. An e-mailed response came from the newspaper's investigations editor, James Neff.

"With all due respect to your expertise, we strongly disagree with your interpretation that the story was unfair to doctors on the phase III Lucentis trial because we didn't mention that promising results of a tiny (40-patient) phase 2 trial had been made public two years earlier," Neff wrote. "The superiority of Lucentis was not a foregone conclusion in 2003. As you know, some promising phase 2 trials result in a dead end, which is why Lucentis was tested in a 700-patient phase 3 trial."

However, many ophthalmologists and industry analysts took the phase 1 and 2 data for Lucentis quite seriously and looked upon it as an indication of the drug's strong potential. For example, Joshua Schimmer, M.D., a securities analyst at SG Cowen & Co., wrote in a Jan. 21, 2005 report that "the robust nature of early Lucentis data" was a key reason why the drug would be likely to show superior efficacy over Macugen and Visudyne when the phase 3 data were released.

Tracking Eyetech Shares

The Seattle Times article also makes much of the fact that investors with access to the May 5 Smith Barney report predicting positive Lucentis data could have used it to make money by selling short Eyetech, the developer of Macugen. (Selling short enables an investor to profit if a stock goes down.)

While it is true that a tidy profit could have been made by selling short Eyetech on May 5, The Seattle Times article omits mentioning the fact the stock had been dropping precipitously months before Smith Barney released its May 5 report.

Eyetech stock was falling for months before the Smith Barney report of May 5 was released.

Eyetech (traded on NASDAQ under the symbol EYET) had reached its all-time high of $47.92 a share on Dec. 20, 2004. This peak coincided with the news of FDA approval of Macugen. However, in early May, even before the Smith Barney report was published, Eyetech shares were trading around $23. They had lost more than half of their value from the December high.

In addition, Eyetech officers and directors were heavy sellers of the stock in late 2004 and early 2005, with several sales reported on Dec. 20, the day Eyetech hit its all-time high. (Records of these sales can be accessed online in Yahoo Finance by typing in the stock symbol EYET and clicking on "Insider Transactions.")

Taken in this overall context, it appears that the looming threat of Lucentis superiority was well-recognized and being factored into the Eyetech share price months before the May 5 Smith Barney report ever saw the light of day. Investors who sold Eyetech short after reading the SG Cowen report of Jan. 21 (when EYET was trading at $39) would have made a much larger profit than those who acted upon the May 5 Smith Barney report.

The Ethics Question

Despite the omissions cited above, the heart of The Seattle Times report is the charge that investigators provided secret information to investment firms in violation of their confidentiality agreements.

In an e-mail to Ophthalmology Management, Seattle Times investigations editor James Neff made his newspaper's position clear. Neff wrote:

"Based [on] documents and on-the-record interviews, the [Seattle Times] reporters showed that Wall Street analysts clearly sought details about the ongoing 2005 trial from medical researchers who had a duty to keep those details confidential. It also is clear that what mattered to the analysts was this new 2005 information, not 2-year old data that the analysts, many of them doctors themselves, needed no help in understanding. Even more telling, the Smith Barney report itself said its analysts had obtained precise answers about confidential phase 3 results from the researchers."

In response to a question from Ophthalmology Management, Citigroup Smith Barney issued the following brief statement:

"Our analysts rely on a broad range of information sources in formulating their investment recommendations on a given company. We neither want nor seek access to information that is not legally in the public domain. Our research is openly sourced, disclosed and disseminated broadly to the investing public."

Colleagues Speak Out

Given these directly opposing views, Ophthalmology Management sent the May 5 Smith Barney report to several top retinal specialists with knowledge of the Lucentis clinical trial process and asked them to make a judgment as to whether doctors who had spoken to Smith Barney violated their confidentiality agreements. Because Ophthalmology Management asked these physicians to comment on the ethics of colleagues, they are being quoted anonymously.

The following are the comments of one leading retinal specialist:

"I read the report and, in general, it is NOT insider information. However, there is one exception to this statement. This is where the story clearly indicates that a majority of the docs surveyed were in the Lucentis trial. It does not matter if they were in the Macugen trial, the data is already out. And it doesn't matter if they speculate on how a positive outcome from Lucentis trial would affect Macugen. What is NOT allowed and is, in fact, a violation of the investigator agreement, is a comment on the clinical, angiographic and OCT findings in the Lucentis study population, even if 'just anecdotal.' This is the crux of the problem here and is a potential point of exposure for these docs.

"I was contacted by Smith Barney and may well be one of the docs used to get data," this retinal specialist continues. "When asked about my experience with Macugen and Visudyne, I gave personal opinion based on my practice's patients. However, when asked about Lucentis, I made it clear I could not speculate on the responses seen in the study. All I would speculate about had to do with how high a bar I would put on results of trial to make me 'impressed.' In other words, I gave then a range of 'ifs.' If it was in this range then I would feel this way, and if in that range I would feel that way.

"I am very concerned that some of my colleagues gave more than that — gave impressions of how their patients in the trial were doing. That would be a problem. If you take out the 'anecdotal comments' on how study patients were doing, there is nothing else in there that would be suspect. It was all out there from phase 1 and 2 and we all know how the other choices were doing. We were already performing the other treatments."

And from another respected retinal specialist:

"I see nothing confidential in this report. Much of this information is in the ASRS (American Society of Retinal Specialists) PAT (Preferences and Trends) survey. If this is all The Seattle Times has to base the allegations, they must be graduates of the Dan Rather School of investigative reporting."

And one more opinion:

"Doctors (who were blinded) were simply giving impressions (albeit some pretty pointed ones and some that may cross some ethical boundaries)."

A Wake-Up Call

Clearly, The Seattle Times report — and an earlier, similar article in the June 2005 issue of the Journal of the American Medical Association (JAMA) that was not mentioned in The Seattle Times report of Aug. 7 — have served as wake-up calls to physicians.

It is expected that drug companies and organizations such as the American Society of Retinal Specialists and the American Academy of Ophthalmology will be issuing guidelines detailing the recommended limits of interactions between clinical investigators and Wall Street firms.

One simple rule of thumb came from a retinal specialist interviewed for this article by Ophthalmology Management.

"Ophthalmologists are used to teaching and informing people. They should continue to share information with a wide variety of constituencies, including their patients, the press and even at times securities analysts. But they need to be aware of potential traps. I would suggest that if you are involved in a clinical trial, just don't talk about it with anyone outside of the trial."

Readers who would like to read the original Seattle Times investigative report of Aug. 7 will be able to access it at www.seattletimes.com/drugsecrets.

REFRACTIVE SURGERY UPDATE

New indications for IntraLase. IntraLase Corp. said it has received a new 510K clearance from the FDA for use of the IntraLase FS30 femtosecond laser in creating the corneal resections performed in lamellar keratoplasty and penetrating keratoplasty procedures. The IntraLase FS30 laser is the first laser to receive clearance for use in penetrating keratoplasty.

Surgeons can now use the precision of the laser to complete resections in a wide variety of corneal therapeutic applications. The new clearance allows use of the IntraLase FS30 laser to create deep corneal incisions and the full-thickness resections required for penetrating keratoplasty.

"This really opens up the door for additional uses of this extremely versatile device," said Roger Steinert, M.D., professor and vice chairman of the department of ophthalmology at the University of California, Irvine. "In our initial clinical work, we found that the laser has the ability to create shaped, full-thickness corneal transplants that are much stronger than traditional penetrating keratoplasty transplants with less induction of astigmatism. In addition, transplants created with the laser may require less suturing and faster visual rehabilitation."

Corneal sensitivity study. In a recent study conducted by Maria I. Kalyvianaki, M.D., and Vikentia J. Katsanevaki, M.D., Ph.D., a total of 90 patients with mild-to-moderate myopia had either epi-LASIK or LASIK. The 52 patients (79 eyes) who underwent epi-LASIK demonstrated reduced corneal sensitivity at 1-month postop, which recovered to preoperative levels at 3-months postop. The 38 patients (74 eyes) who had LASIK continued to display reduced corneal sensitivity at 1-, 3- and 6-months postop.

IN THE NEWS

Lucentis filing. Genentech plans to file a complete Biologics License Application (BLA) for the investigational wet AMD drug Lucentis in December. In addition, the company announced that it is in discussion with the FDA regarding plans to initiate a phase 3b clinical study of Lucentis for patients with wet AMD. The study is anticipated to begin before the end of 2005. One-year phase 3 data from the MARINA study presented in July showed Lucentis improved vision in most patients with wet AMD.

	Clinical trial results for Lucentis, developed by Genentech, have been impressive.

The phase 3b SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) study is being designed to evaluate the safety of two different doses (0.3 mg and 0.5 mg) of Lucentis in a broad wet AMD population. Patients will receive Lucentis once a month for 3 months with criteria-based retreatment options. Genentech anticipates that patients with wet AMD who have not received prior treatment for their disease or who continue to have active disease despite treatment with FDA-approved therapies may be eligible to enroll in SAILOR. The study will be conducted at more than 100 sites in the United States and enroll approximately 5,000 patients.

Vitrase clinical trials. ISTA Pharmaceuticals, Inc. announced the publication of the pooled safety and efficacy findings of the company's two randomized, double-masked, placebo-controlled phase 3 studies of Vitrase for the management of vitreous hemorrhage (VH), for which there is currently no drug treatment. Analysis demonstrated a statistically significant reduction in VH density as early as 1 month that persisted through 3 months following a single intravitreous injection of Vitrase when compared to a single injection of saline solution.

This reduction in VH density allowed the investigator to see into the back of the eye to diagnose the underlying cause of the hemorrhage and treat with laser therapy when appropriate. ISTA said the results also demonstrated that Vitrase has a favorable safety profile.

Contamination alert. Custom RX Compounding Pharmacy and the FDA have notified ophthalmologists and consumers about a nationwide recall of Trypan Blue 0.06% Ophthalmic Solution, intended for use in the eyes during cataract surgery, because it may be contaminated with Pseudomonas aeruginosa, a bacteria that, if applied to the eyes, might lead to serious injury, including possible blindness.

Custom Rx Pharmacy is asking that all unexpired syringes be collected and returned to the pharmacy. The product was distributed to hospitals and clinics in Maryland, Minnesota, Illinois, Nebraska, North Dakota, Michigan, the District of Columbia and Pennsylvania.

The recall includes, but may not be limited to the following lot numbers: 05042005:86@17, 05252005:36@13, 06282005:91@27, 08012005:63@24 and 08182005:43@17.

Lily to file NDA. Eli Lilly and Company said it has completed a Phase III clinical trial in which its investigational drug, ruboxistaurin mesylate (proposed brand name Arxxant) reduced the occurrence of vision loss in patients with diabetic retinopathy (DR). As a result, Lilly believes it is appropriate to submit a new drug application (NDA) to the FDA at the end of 2005 for the treatment of DR, the initial indication for Arxxant. If approved, Arxxant will be the first treatment for DR that can be taken orally.

Lily said Ruboxistaurin is a specific protein kinase C beta (PKC beta) inhibitor, the first of a new class of compounds being investigated for the treatment of diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN).

Inspire receives subpoenas. Inspire Pharmaceuticals, Inc. said the Securities and Exchange Commission is conducting a formal, nonpublic investigation, which the company believes relates to trading in the company's securities surrounding its Feb. 9, 2005 announcement of the results of its phase 3 clinical trial of diquafosol tetrasodium for treatment of dry eye, as well as the company's disclosures regarding this phase 3 clinical trial. The company and one of its directors have each received a subpoena in connection with this investigation.

AMD partnership. Pharmacopeia, an innovator in the discovery and development of novel small therapeutics announced that it has entered into an agreement with

Allergan, Inc. of Irvine, Calif., to evaluate proprietary active lead compounds, discovered at Pharmacopeia, in models of ocular disease.

The agreement resulted in an upfront cash payment from Allergan to Pharmacopeia, and may result in pre-clinical and clinical payments, plus milestone payments and royalties on ophthalmic drugs developed by Allergan.

Pharmacopeia has retained rights to other therapeutic areas.

Pharmacopeia's novel compounds target angiogenesis and the treatment of wet form of AMD. Pharmacopeia says the compounds may represent a new means of treating wet AMD, and could represent an important new treatment option for this disease.

"We are working with Allergan to investigate alternate mechanistic approaches that could complement or potentially improve upon existing therapies," said David M. Floyd, M.D., chief scientific officer of Pharmacopeia.

Pharmacopeia creates and delivers novel therapeutics to address significant medical needs. Using proprietary technologies and processes, Pharmacopeia discovers and develops novel drug candidates to advance internally as well as with strategic partners.

STAAR ships improved lens. STAAR Surgical Company said it has begun shipping its newly redesigned three-piece collamer lens, model CQ2015 along with the ONYX, a new injection system.

The redesigned lens includes polyimide loops, allowing the lens to self-center, and incorporates a continuous contact edge, reducing the potential for posterior capsule opacification. The lens is made of STAAR's patented collamer, a highly biocompatible material with properties that the company says greatly reduce glare and other optical aberrations. The lens is paired with the ONYX injector and cartridge, making the system predictable and easier to use, features which the company expects to increase surgeons' acceptance of the redesigned lens.

OMISSIONS

Two Visual Pathways Inc. instruments were missing from the Retinal Cameras section of the Diagnostic Instrument Buying Guide, which was distributed with the July issues of Ophthalmology Management and Optometric Management. Here are the listings as they should have appeared:

Manufacturer:
Visual Pathways Inc.
334 White Spar Road
Prescott, AZ 86330-4238
(928) 778-5002
(928) 778-5004 (fax)
sales@vispath.com
www.visualpathways.com

Model: Aris 70
Price: $38,350
Warranty: 2 years
Type: Digital; high-res; nonmyd (4 mm); constant base stereo
Field of View: 30�; up to 11 targets covering >70� on retina
Angiography: no
Number/Type of Ports: 4 USB; ethernet; RS232: DIN; analog video out; digital video out; sound; telemedicine ready
Flash stimulus: n/a
Video Capacity: no
Additional Features: Little operator training required; automation of virtually all steps in imaging process including pupil alignment, tracking, fundus alignment, focus, exposure, illumination; auto-wavelength selection for IR, red1, red2, red-free; ConstantBaseStereo; BiochromaticImageNavigation; color adjustments; image comparisons; internal computer; automatic paralleled image file backup system.

Model: Aris 110
Price: $45,350
Warranty: 2 years
Type: Same as Aris 70
Field of view: 30�; up to 26 targets covering >110� on retina
Angiography: no
Number/Type of Ports: same as Aris 70
Flash Stimulus: n/a
Video Capacity: no
Additional Features: Same as Aris 70.

Portions of the listing for Micro Medical Devices PalmScan P-200 FastPach were missing from the Pachymeters section of the Diagnostic Instrument Buying Guide, which was distributed with the July issue of Ophthalmology Management. Here is the listing as it should have appeared:

Company: Micro Medical Devices
Model: PalmScan P-200 FastPach
Price: $2,295
Warranty: 1 year
Type: Handheld
Weight: 10 oz.
Range: 12μm to 1200μm
Calculator: Yes
Portability: Yes
Source: Dual rechargeable batteries
Additional Features: More than 200 scans per charge; corneal waveform display; Wi-Fi/IR printing; high-res color touch-screen controls.

CORRECTION

In the August issue of Ophthalmology Management, the article, "Posterior Corneal Transplants" by Mark Gorovoy, M.D., did not contain the author's correct e-mail address. His e-mail address is bbarr@gorovoyeye.com.

FDA Approves Alcon's New NSAID.
Nevanac is Described as First NSAID "Prodrug."

Alcon, Inc. said the FDA has approved its new drug application (NDA) for nepafenac ophthalmic suspension 0.1% (Nevanac) for the treatment of pain and inflammation associated with cataract surgery. The recent approval came after a priority 6-month review.

Alcon says Nevanac suspension contains a novel prodrug that rapidly penetrates ocular tissues. It is the first ophthalmic nonsteroidal anti-inflammatory prodrug to receive FDA approval. Alcon said Nevanac will be commercially available this fall.

"The prodrug structure of Nevanac suspension offers significant advantages to ophthalmic surgeons. It provides unique, target-specific activity that promotes penetration into the ocular tissues of most concern to ophthalmologists. This maximizes efficacy at the target sites of pain and inflammation following cataract surgery," said Richard L. Lindstrom, M.D., adjunct professor emeritus, Department of Ophthalmology, University of Minnesota, and founder of Minnesota Eye Consultants.

The approval is based on results of two multicenter, placebo-controlled studies involving more than 680 patients. In these clinical trials, Nevanac suspension was dosed three times per day, beginning 1 day prior to cataract surgery and continuing on the day of surgery and for 14 days postoperatively. Patients were evaluated at baseline and at 1, 3, 7 and 14 days after surgery. Patients treated with Nevanac suspension were found to have significantly less ocular pain and inflammation in the early postoperative period through the end of treatment.

In these studies, more than 80% of patients treated with Nevanac suspension were pain free the day after surgery, compared to less than 50% in the placebo group. Following 2 weeks of treatment with Nevanac suspension, approximately 95% of patients were pain free, compared to 45% of patients in the placebo group. Additionally, 91% of patients treated with Nevanac suspension had no clinically significant inflammation at day 14, compared to approximately 47% of patients in the placebo group. In the studies, Nevanac suspension was shown to be safe and well tolerated with no unexpected adverse events reported.

In controlled clinical studies, the most frequently reported ocular adverse events following cataract surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased IOP and sticky sensation. These events occurred in approximately 5% to 10% of patients. They were similar to those reported with placebo and may be the consequence of the cataract surgery procedure.

WORTH NOTING

Dr. Lane honored. Stephen S. Lane, M.D., of St. Paul, Minn., will receive the Cornelius D. Binkhorst Medal of Honor and deliver the Binkhorst Lecture at the Symposium of the American Society of Cataract and Refractive Surgery (ASCRS) scheduled for San Francisco in March.

Dr. Lane's lecture, "The Convergence of Cataract and Refractive Surgery," will describe the important procedures and technology that have been developed leading up to where much of what ophthalmologists are now doing in removing the crystalline lens is in fact refractive surgery. Because of the advances in lens removal techniques, improved safety, IOL design and function, an increasing number of patients are opting for refractive lens exchange rather than more traditional refractive surgical procedures such as LASIK or PRK. All these advances will be discussed as well as implications for the future.

New leader for Iridex. Iridex Corporation has announced that its board of directors has appointed Barry G. Caldwell, 54, as its new president and CEO, succeeding Theodore A. Boutacoff, 58, who has served in the role since 1989. As planned and announced earlier this year, Boutacoff has been elected chairman of the board of Iridex. Caldwell will also serve on the board.

Iridex is a leading worldwide provider of semiconductor-based laser systems for the ophthalmology and dermatology markets.

Optos in partnership. Optos, Inc., a leader in ophthalmic retinal imaging, has formed a strategic alliance with Eyemaginations, Inc., an interactive design and multimedia firm. The goal of the partnership is to combine the strengths of the two companies to deliver superior patient education materials for use in eyecare settings.

The first project undertaken by the partners is an animated video explaining the Optomap Retinal Exam.