Article Date: 3/1/2006

SUBSPECIALTY NEWS
OSI's New Macugen Strategy
Lucentis and Macugen Now Seen as "1-2 Punch."

K In a confident presentation at a Merrill Lynch forum in February,
OSI Pharmaceuticals CEO Colin Goddard, PhD, outlined a bold plan designed to enable the company's recently acquired Macugen treatment for wet AMD to hold its own despite the increasing use of off-label Avastin and the anticipated approval of Lucentis sometime this year.

Dr. Goddard described a multifaceted strategy for Macugen, including a new proposal that Macugen be used in concert with Avastin or Lucentis. He suggested that 1 of the early-acting Genentech drugs could be used to treat the acute phase of wet AMD, with Macugen then being used for longer-term maintenance therapy. (Research abstracts that became available in late February indicate that 2 studies involving the use of Avastin and Macugen in combination will be presented at the upcoming ARVO meeting this spring.)

Emphasizing his contention that Macugen has a statistically better safety profile than the Genentech drugs, Dr. Goddard said a second opportunity for Macugen is with patients who are at risk for cardiovascular problems. The third opportunity, he noted, is with recently diagnosed patients who still have good vision.
A recent study has shown that patients treated after early diagnosis appear to do well on Macugen.

Dr. Goddard did not minimize the threat to Macugen of Avastin and Lucentis. In fact, he said OSI had "underestimated" the amount of Avastin usage for wet AMD that has suddenly appeared in recent months. He did note what he called "isolated" reports of strokes and coronary events in patients who had been given intravitreal injections of Avastin for wet AMD. He did not directly link those reports to use of Avastin, but repeatedly mentioned what he characterized as the better safety profile of Macugen, alluding to 2-year follow-up of patients in the pivotal Macugen VISION study. The follow-up study, led by Marcos Avila, MD, of Brazil, showed no evidence of an increase in mean blood pressure, or changes in electrocardiograms, kidney, or liver function. There was also no evidence in year 2 that Macugen was associated with thromboembolic or other serious hemorrhagic events.

Despite the admittedly controversial nature of the Eyetech acquisition that brought Macugen into the OSI drug portfolio, Dr. Goddard said he would not hesitate to do the deal again.

He said Macugen was turning out to be a better drug than originally perceived and that what he termed Genentech's "pan-VEGF" therapies would have to overcome issues of systemic safety. (Genentech says Lucentis targets VEGF-A and should not be characterized as "pan-VEGF").

"I believe we got the science right," Dr. Goddard concluded.

IN BRIEF

Positive Avastin study. A retrospective, short-term study of 81 eyes of 79 patients with subfoveal neovascular AMD indicates that intravitreal Avastin could be a safe, effective treatment for the wet form of AMD. Results in a significant number of these patients included resolution of retinal edema, resolution of retinal thickening, and median vision improvement from 20/200 to 20/80 at 8 weeks post-injection. No significant ocular or systemic side effects were observed.

Robert L. Avery, MD, who led the study, says the short-term results indicate that intravitreal Avastin (1.25 mg) is well-tolerated and associated with improvement in visual acuity, decreased retinal thickness as measured by OCT, and reduction in angiographic leakage in most patients. The majority of the patients in the study had previous treatment with PDT, Macugen, or both.

The study concludes that further evaluation of Avastin for wet AMD is warranted.

The complete study appeared in the February issue of Ophthalmology.

Visudyne U.S. sales drop. Novartis Ophthalmics and QLT Inc. reported that worldwide sales of Visudyne for the treatment of wet AMD dropped 13% overall in the last 3 months of 2005 as compared to the comparable quarter in 2004. A steep drop in sales in the United States more than offset growth in the rest of the world.
The approval of Macugen and off-label competition in the United States accounted for much of the drop. Visudyne growth, however, was strong in other worldwide markets, including the U.K., Germany, and France, with sales outside the U.S. up 18% in local currencies.

Fee cut rolled back. A 4.4% across-the-board cut in fees paid to physicians by Medicare was rolled back in early February after the House passed a budget reconciliation measure. The House had failed to take action on reconciliation in late December. The reconciliation legislation was necessary to bring the House and Senate into agreement on provisions of the overall federal budget.

Physicians will be reimbursed at the same levels as provided for in the 2005 Physician Fee Schedule, with the rate freeze retroactive to Jan. 1, 2006. CMS will automatically reprocess all claims submitted for services provided in 2006, so practices will not have to file new claims.

EU approves Macugen. OSI Pharmaceuticals, Inc. said that the European Commission has granted its development and marketing partner, Pfizer, approval to market Macugen for the treatment of neovascular AMD.

OccuLogix trial fails. A pivotal phase 3 clinical trial for a controversial, dialysis-like treatment for dry AMD has ended with overall results showing no statistically significant benefit.

OccuLogix, Inc. announced it had completed a preliminary analysis of the data from MIRA-1, its recently completed pivotal clinical trial using its RHEO System. MIRA-1 did not demonstrate a statistically significant difference in the mean change of Best Spectacle-Corrected Visual Acuity applying the Early Treatment Diabetic Retinopathy Scale between the treated and placebo groups at 12-months post-baseline.

Occulogix said the treated group demonstrated a positive response, but that an anomalous response of the control group was the principal reason that the primary efficacy endpoint was not met.

The company said there were subgroups that did demonstrate statistical significance in their mean change of ETDRS BCVA vs control. Further analysis of the study data is being undertaken.

The publicly traded shares of both OccuLogix and TLC Vision, the majority owner of OccuLogix, suffered sharp drops when the study results were announced.

Escalon acquires MRP Group. Escalon Medical Corp. said its subsidiary, Escalon Digital Vision, Inc., has completed its previously announced acquisition of substantially all of the assets of MRP Group, Inc., an ophthalmic technology solutions provider.

MRP Group, based in Lawrence, Mass, was founded in 1997 and has a wide installation base in ophthalmology practices. MRP Group's product line includes retinal and slit lamp digital imaging systems, OphthaVision image management software, and fundus camera power supplies. The retinal imaging systems consist of a unique 2-camera configuration that Escalon says provides elevated sensitivity and exceptional resolution when performing diagnostic eye tests such as fluorescein angiography and color retinal photography.

Retisert copromotion. Bausch & Lomb and Novartis Ophthalmics, a business unit of Novartis Pharmaceutical Corp, will co-promote Bausch & Lomb's patented orphan drug Retisert in the United States. The Retisert sustained-release implant is indicated for the treatment of chronic noninfectious posterior segment uveitis.

Sustained-Release for AMD Drugs?
Macugen may Lend Itself to Implant Delivery.
BY JERRY HELZNER, SENIOR EDITOR

It is now widely anticipated that 3 antiangiogenic agents will be available for use by retina specialists to treat the wet form of AMD later this year. The 3 drugs include the already-approved Macugen, off-label Avastin, and the investigational drug Lucentis, which is expected to win FDA approval sometime in 2006.

What all 3 of these drugs have in common now is that they are all being administered by intravitreal injection. However, efforts are already under way to develop a more patient-friendly delivery system.

Because it is generally agreed that an eye drop would be unable to penetrate deeply enough to deliver medicine to the back of the eye, most current efforts at improving drug delivery involve developing a sustained-release implant.

To this end, OSI Pharmaceuticals, which purchased Macugen developer Eyetech Pharmaceuticals late last year, is already partnering with PRP Pharmaceuticals, Inc. to collaborate on the development of sustained-release delivery of Macugen using PRP's proprietary ProPhase encapsulation technology.

"This is a somewhat groundbreaking effort because Macugen is the first aptamer to be approved by the FDA," says Anthony P. Adamis, MD, chief scientific officer for (OSI) Eyetech. "However, we believe Macugen is well suited to be effective in a sustained-release format. PRP is our main avenue to achieve sustained-release delivery. They have expertise in this area and their encapsulation technology is currently being used in commercialized products."

Dr. Adamis, who collaborated with Judah Folkman, MD, in the original research on anti-VEGF drugs at Harvard, says an initial goal is to create a formulation that can deliver Macugen for 6 months via implant, sparing patients a number of intravitreal injections. Such an implant would have to go through clinical trials, which would entail a 3-to 4-year approval process.

Under the terms of the collaboration, PRP is responsible for developing the formulations and manufacturing the test article for nonclinical and clinical trials. (OSI) Eyetech is responsible for clinical development activities and has the right to manufacture and commercialize any resulting product.

While formulating a sustained-release delivery system for an aptamer such as Macugen presents challenges, leading retina specialists say that the obstacles in achieving sustained-release delivery for Lucentis, a protein-based drug, might be almost impossible to overcome.

"The problem with most proteins such as Lucentis is that after an extended period of time at body temperature, there is a tendency for them to break down and loose their efficacy — especially if they are not encapsulated in some fashion," says Robert Avery, MD, of Santa Barbara, Calif, a leading researcher into investigational drugs for wet AMD.

Philip Rosenfeld, MD, of Bascom Palmer Eye Institute in Miami, who pioneered the use of off-label Avastin in wet AMD, is more blunt.

"There has never been a protein-based drug delivered by sustained-release implant," he says. "I believe Lucentis will be delivered by intravitreal injection for at least the foreseeable future."

Henry Hudson, MD, of Tucson, Ariz, says that alternative drug-delivery systems, such as liposomes, could be tried for Lucentis, but that these would probably only extend the efficacious life of the drug for a relatively short time.

Despite these hurdles, Abdhish Bashvar, MD, of Minneapolis, says he believes there are other ways to effectively deliver drugs into the eye. He is currently working on an alternative delivery system but is not ready to release details as yet.

In the January/February issue of Retinal Physician, the article The Pros of 23-g Vitrectomy was authored by Howard Fine, MD and Richard Spaide, MD.

Lucentis Prevails Against PDT
At 1-Year Mark of Head-to-Head Study.

Genentech, Inc. has announced positive 1-year results from its second pivotal phase 3 study of the investigational drug Lucentis in patients with wet AMD. Data from the ANCHOR study comparing Lucentis to Visudyne photodynamic therapy (PDT) showed a difference in mean change in visual acuity of 18 letters for patients treated with 0.3 mg of Lucentis and 21 letters for patients treated with 0.5 mg of Lucentis from study entry compared to those treated with PDT at 12 months.

In the first year of this 2-year study, patients treated with Lucentis gained an average of 8.5 letters in the 0.3 mg dose group and 11 letters in the 0.5 mg dose group compared to patients treated with PDT, who lost an average of 9.5 letters. In November, Genentech announced that the ANCHOR study met its primary efficacy endpoint of maintaining vision (defined as a loss of less than 15 letters in visual acuity) in patients with wet AMD. One-year data from the ANCHOR study were presented during the Macula 2006 meeting held in New York City early in the year.

"Lucentis is the first investigational therapy that has shown improved vision, not just a slowing of vision loss, in patients with all types of wet AMD," said Peter K. Kaiser, MD, director, Clinical Research Center, The Cleveland Clinic Cole Eye Institute, who presented the data.

An analysis of the 1-year data showed that adverse events were
similar to those seen in earlier trials of Lucentis. Common ocular adverse side effects that occurred more frequently in the Lucentis arms than in the control group were mild-to-moderate. They included conjunctival hemorrhage, increased IOP, eye pain, and vitreous floaters.

Link to AMD Progression Found
Specific Types of Drusen Seen as Predictors.

University of Kentucky researchers may have found a marker that identifies those cases of dry AMD that are most likely to progress to the wet form of the disease.

A team led by Jayakrishna Ambati, MD, associate professor and vice chair of the department of Ophthalmology and Visual Sciences at the University of Kentucky, found that certain types of drusen are present in patients whose disease will progress from dry to wet.

Although the presence of drusen is a risk factor for the development of late-stage AMD, it has been unclear whether, or how, drusen can provoke the development of the wet form of AMD.

Researchers say drusen in patients with AMD contain components known as complement C3 and C5. Dr. Ambati's team has identified that bioactive fragments of these components, known as C3a and C5a, are present in patients whose AMD progresses beyond the early dry stage and into the later wet stage.

Dr. Ambati's research concludes that the presence of the C3a and C5a components in drusen are not only markers of AMD cases that will develop into the late-stage form of the disease, but that they are a cause of this progression.

One potential use for this finding is that patients with early-stage AMD may be screened to determine if the C3a and C5a components exist in their drusen. Patients who have these components could then be considered at high risk for progression.

The next step is to develop a substance that can block the effectors, halting the progression of AMD from the dry to wet stages. Dr. Ambati's lab is already testing substances that could potentially be used in patients with "high-risk" drusen.

IN MEMORIAM
Pat Herron, Executive Publisher

On February 13, 2006, my business partner and dear friend Bob Boucher, 59, passed away after battling a serious illness for the past few months. Bob was a wonderful role model for all who knew him. His business savvy, knowledge and experience impacted the lives of so many in both vision care and business publishing over many years.

A 1968 graduate of Bucknell University, Bob started his business publishing career at The Chilton Company in 1969. During the next 23 years, Bob worked for The U.S. Business Press, Gordon Publications and served as President and CEO of Gralla Publications in New York. In 1992, Bob was recruited by the equity firm Brentwood and Associates to form Cardinal Business Media as President and CEO. Over the next 5 years, Cardinal grew to be a dominant player in business
publishing, serving numerous specialty areas including the optical and vision care markets. In 1997, I had the privilege
of acquiring the vision care titles and a number of technology publications with Bob, and Boucher Communications, Inc. was formed. The business grew steadily and by 2005, we were the publishers of 5 leading eyecare-related publications, Ophthalmology Management, Optometric Management, Eyecare Business, Contact Lens Spectrum and our newest publication, Retinal Physician, which we launched in 2004. Along with his tireless work in the office, Bob was also active on several boards, as well as the American Business Media.

In September 2005, we sold our company to Wolters Kluwer, a leading provider of healthcare communications around the world. As I look back over our years together in business, I realize how fortunate I was to know such a great man. Speaking for our employees, colleagues and many industry friends, Bob will be missed by everyone he touched in his life.

Bob is survived by his wife, Mary Lou, his sons, Michael and Brian, his parents, Robert N. Boucher, Sr., and Charlotte K. Boucher, 5 grandchildren, and his brother, David M. Boucher.

The family is requesting donations in Bob's memory be made to the American Brain Tumor Association. 1-800-886-2282 or hope.abta.org.

Pat Herron, Executive Publisher, LWW VisionCare



Retinal Physician, Issue: March 2006