Article Date: 9/1/2006

SUBSPECIALTY NEWS
Researchers See Promise in VEGF Trap

AMD Treatment Attracts Potential Partners.

JERRY HELZNER, SENIOR EDITOR

The recent approval of Genentech's Lucentis appeared to settle the issue of which drug would serve as the primary therapy for the treatment of wet AMD, at least for the foreseeable future. But in recent weeks a potential rival has stirred excitement based on highly promising results from a small phase 1 trial.

Interestingly, the drug that has created this new interest is a familiar name — VEGF Trap.

Regeneron Pharmaceuticals has spent a decade developing VEGF Trap. However, the progress of this therapy through clinical trials was interrupted when Regeneron changed the method of delivery from intravenous to intravitreal injection. The change was made to negate the possibility of systemic side effects that antiangiogenic agents are known to cause when delivered intravenously. In addition, a partnership with Aventis on VEGF Trap for AMD was sidetracked when Aventis was taken over by Sanofi and the entire Sanofi-Aventis drug development portfolio was re-evaluated.

"We are currently developing VEGF Trap for AMD on our own," says George Yancopolous, MD, Regeneron's chief scientific officer. "However, we have recently been approached by several companies that are showing an interest in partnering with us on VEGF Trap."

Regeneron recently completed a 6-week phase 1 trial on VEGF Trap in which patients demonstrated a mean improvement in BCVA of 13.5 letters, with some patients gaining 15 or more letters. These results are comparable to data from Lucentis trials. Regeneron has now initiated a 150-patient, 12-week phase 2 trial. Dr. Yancopolous anticipates that if all goes well in phase 2, a phase 3 trial could start early next year.

Though VEGF Trap is still at least 3 years away from possible approval as a treatment for wet AMD, its mechanism of action is intriguing. The drug creates a decoy receptor that "fools" VEGF into binding with the decoy and then converts into a harmless soluble complex. Hence, the name VEGF Trap.

"VEGF Trap has potential advantages in that it binds VEGF at a far higher rate than Lucentis, it probably can be safely given in much higher doses than Lucentis, and its effects may be longer-lasting than Lucentis," says Dr. Yancopolous. "Of course, these theories will have to be proven in the upcoming clinical trials but we have already safely given a 4 mg dose of VEGF Trap to patients, which is 8 times higher than the approved Lucentis dose."

Peter Campochiaro, MD, a retina specialist at the Wilmer Eye Institute of Johns Hopkins University, served as an investigator in the VEGF Trap phase 1 trial and is also participating in the phase 2. He calls VEGF Trap "a very good VEGF antagonist, just as Lucentis is a very good VEGF antagonist."

Dr. Campochiaro says the ability of VEGF Trap to bind to VEGF A, B and C and placental growth factor with high affinity (Lucentis binds only VEGF A) gives the drug "theoretical advantages" that will have to be proven through the clinical trials process.

"Being able to bind to VEGF with higher affinity can be an advantage if it prolongs the duration of the effect," says Dr. Campochiaro. "And being able to bind with placental growth factor could also be an advantage because placental growth factor may play a significant role in ocular diseases. The ability to give a higher dose is another theoretical advantage that will have to be tested in the trials."

Jeffrey S. Heier, MD, vitreoretinal specialist at Ophthalmic Consultants of Boston, recently became a member of the Regeneron Scientific Advisory Board. He finds VEGF Trap to be "one of the more interesting compounds currently under investigation." He is essentially in agreement with Dr. Campochiaro in pointing out the specific "theoretical advantages" of VEGF Trap but also notes that "there remains a great deal of work to appropriately gauge this compound's role in the treatment of AMD."

Regeneron has followed a path similar to Genentech in that the company has been developing antiangiogenic agents for both solid tumors and wet AMD. Regeneron also has another major drug development program that involves a treatment called IL-1 for inflammatory diseases. All of Regeneron's key drug candidates are currently in clinical trials.

IN BRIEF

Alcon partners with Eli Lilly. Eli Lilly and Company and Alcon, Inc. said they have signed a long-term agreement to co-promote ruboxistaurin mesylate (Arxxant) in the United States and Puerto Rico. Arxxant is an investigational oral drug for the treatment of moderate to severe nonproliferative diabetic retinopathy. The FDA recently gave Arxxant an "approvable letter" requiring that Lilly furnish additional clinical data, which could come from an ongoing study or from a new trial. The co-promotion agreement is dependent on FDA approval of the drug.

"We believe combining the respective expertise of Lilly and Alcon will allow us to maximize the value of this potential new therapy for patients, physicians and our shareholders," says Khoso Baluch, vice president, U.S. diabetes business unit, Lilly. "Alcon will lead the promotional efforts to the eyecare community, increasing awareness of the benefits that Arxxant could provide if approved as the first oral medication to reduce the risk of vision loss associated with diabetic retinopathy."

New Lucentis study planned. Retina specialists from Wills Eye Hospital in Philadelphia plan to begin a study to determine whether wet AMD patients who failed Avastin or Macugen can benefit by being switched to Lucentis. Richard S. Kaiser, MD, is serving as principal investigator for this Genentech-sponsored study.

Panel rejects IMT. An FDA advisory panel voted 10 to 3 not to approve the Implantable Miniature Telescope (IMT), a device designed to improve the sight of end-stage AMD patients. Though the IMT produced significant average gains in visual acuity in a large phase 2/3 clinical trial, panel members cited safety issues as the reason for not approving the device. The FDA can accept or reject the panel's recommendation. The IMT was developed by Vision Care Ophthalmic Technologies, located in Saratoga, Calif.

Visudyne sales drop. QLT Inc. reported global sales of its Visudyne therapy for wet AMD of $95.3 million for the quarter ended June 30. This represents a decrease of 26.1% compared to sales in the second quarter of 2005 and a 10.7% decline compared to the first quarter of 2006. Visudyne sales in the United States for the June quarter were approximately $18.9 million, representing 20% of total worldwide sales for the quarter.

The drop is largely attributable to the use of Avastin off-label and Macugen to treat wet AMD.

B&L licenses retinal patents. SurModics, Inc., a provider of surface modification and drug-delivery technologies, said it has granted Bausch & Lomb an exclusive license to patents relating to the use of Genistein in the treatment and prevention of retinal diseases. Technology relating to the use of Genistein was among the technologies acquired by SurModics in connection with the acquisition of InnoRx in 2005. InnoRx had licensed patents covering inventions made by InnoRx founder and retinal surgeon Eugene de Juan, Jr., MD.  

SurModics says Genistein is a soy isoflavone with strong anti-oxidant and anti-VEGF activity that has been shown to reduce retinal vascular leakage in diabetic animals. It is seen as a potential treatment for diabetic macular edema.

Medicare physician fees. CMS has proposed a cut of 5.1% across-the-board in payments for physician services provided by doctors under Medicare. The cut will take effect on Jan. 1, 2007 unless Congress takes action to roll it back. In recent years, Congress has rolled back proposed cuts in physicians' fees on 2 occasions.

CMS said the cut was required because spending on doctors' services was increasing faster than expected, and faster than the annual goals set by a statutory formula.

New laser treatment. Lumenis Ltd., a global developer, manufacturer, and seller of laser and light-based devices for a variety of applications, said it has received exclusive worldwide licensing rights for SRT, a new laser therapy for selectively treating retinal diseases.

Lumenis notes that while conventional laser treatments can be effective in slowing down the progression of disease, they seldom restore or improve visual acuity in the area treated due to the non-discriminating nature of the laser burn. In contrast, Lumenis says SRT is a novel technology that selectively targets and confines the treatment to specific cells at the back of the retina. Because there is little heat generated, the surrounding photoreceptors are left undamaged.

Allergan grant program. Allergan, Inc. has created the Allergan Horizon Grant Program, through which Allergan plans to contribute $1 million over 2 years. The program was established to provide awards to academic medical institutions to support fellows seeking to develop careers in academic medicine. These awards will fund fellowship programs that conduct clinical research in the diagnosis or pharmacological treatment of glaucoma, corneal, and retinal diseases. Grant applications should be submitted by the department chair, division chief or fellowship director of the academic institution and must be received by Allergan Medical Affairs, 2525 Dupont Drive, Irvine, Calif 92612, no later than Sept. 30, 2006.

Preserved Kenalog warning. A recent alarming increase in reported cases of sterile endophthalmitis associated with the intravitreal injection of preserved Kenalog is causing concern to retinal specialists.

Some doctors who have experienced almost no endophthalmitis from intravitreal preserved Kenalog injections in past years are now reporting rates as high as 15%. Bristol-Myers Squibb, the maker of the drug, says that there have been no changes in its manufacturing procedures. The company is conducting tests and has requested additional information from doctors

For now, doctors are advised to use preservative-free triamcinolone from a compounding pharmacy.

OSI Cuts Back Eyecare Research
Company Cites Declining Macugen Sales.

JERRY HELZNER, SENIOR EDITOR

With sales of its wet AMD drug Macugen expected to continue to fall in the face of strong competition from off-label use of Genentech's Avastin and recently approved Lucentis, OSI Pharmaceuticals has responded to the realities of the marketplace and suspended or curtailed some of its eyecare research. The company said there is no guarantee that suspended research efforts will resume.

However, the company will go forward with its recently announced phase 4 LEVEL study to determine Macugen's effectiveness as a maintenance therapy for wet AMD after initial treatment with one of the Genentech drugs. OSI will also continue to fund research for Macugen in diabetic retinopathy and central retinal vein occlusion.

In connection with the suspension/curtailment of research, the company has taken a $319 million goodwill impairment charge, which amounts to more than $5 for each outstanding share of OSI. The charge represents the value OSI had placed on the future stream of eyecare products arising from the research capabilities of Macugen developer Eyetech, which OSI acquired in 2005. OSI said that it believes the long-term value of the Macugen franchise itself had not been impaired and would not be written down.

OSI CEO Colin Goddard, PhD, had hinted in recent months that a continuing decline in Macugen sales would cause the company to re-evaluate its financial commitment to eye care. In the 3 months ending June 30, U.S. sales of Macugen amounted to $36.7 million, compared to $50.5 million in the first 3 months of the year, a quarter-over-quarter decline of more than 25%. Analysts have been persistent in questioning Dr. Goddard about the company's plans for continuing to fund its slumping eyecare business, as OSI has promising franchises in both oncology and diabetes.

OSI shocked Wall Street last year when it paid more than $650 million in cash and stock to acquire Eyetech. OSI shares dropped sharply when news of the planned acquisition was first announced as investors recognized that Lucentis, then in late-stage clinical trials, had already demonstrated a major efficacy advantage over Macugen.

Dr. Goddard had recently put forward several strategies designed to revive Macugen sales. He has advocated the drug as part of a "1-2 punch" in treating AMD, with Macugen serving as a maintenance therapy after initial treatment with Avastin or Lucentis. He also emphasized Macugen's excellent safety profile and its effectiveness when used in the early stages of wet AMD.

Some studies have confirmed that these approaches are valid. However, OSI's promotion of these strategies has not thus far been enough to overcome the greater efficacy offered by Avastin and Lucentis.

The key LEVEL trial using Macugen for maintenance will continue.

"Next-Generation" Wet AMD Drug?
Lpath Developing Drug with Multiple Mechanisms.

JOHN PARKINSON, ASSOCIATE EDITOR

In the 6 years since the start of the 21st century, major advances have been made in the treatment of wet AMD. Now, a startup company, Lpath Inc., is developing a drug that it says is potentially part of a platform of "next-generation" antiangiogenesis drugs.

This small, publicly traded San Diego-based company has developed Sphingomab — a drug indicated for the treatment of wet AMD. Specifically, the drug targets sphingosine-1-phosphate (S1P), a bioactive lipid, which has been found to contribute to tumor angiogenesis. Sphingomab is the first monoclonal antibody to be synthesized against a lipid target.

Ophthalmologist Glenn L. Stoller, MD, heads Lpath's ocular division and says the drug not only targets angiogenesis, but also inhibits scar formation and combats inflammation. Dr. Stoller adds that these multiple mechanisms — if proven efficacious in humans — would differentiate Sphingomab from any existing wet AMD drugs on the market or in development, including Lucentis.

However, Dr. Stoller notes that any comparison between these 2 drugs would be premature at this point.

Dr. Stoller joined the company earlier this year because he was excited about the science behind Sphingomab. "Bioactive lipids are unexplored targets in ophthalmology and S1P appears to play an important role in many of the processes that lead to AMD-related vision loss," he says. "Inhibiting S1P via Sphingomab appears to be a promising novel approach toward treating exudative AMD."

While Lpath is in early development with its drug for wet AMD — the company hopes to begin a phase 1 clinical trial in the middle part of 2007 — enthusiasm and expectations are high. "There's room for other players in the field. I don't think innovation for treating AMD ends with the introduction of Lucentis," says Dr. Stoller. "My
personal goal is to bring another valuable therapeutic drug to our patients."

Sphingomab was developed by Roger Sabbadini, PhD, chief scientific officer and founder of Lpath. Initially, Dr. Sabbadini was targeting cardiovascular disease with this monoclonal antibody, but later found that it may be efficacious for certain cancers and ocular diseases. The company has given this biotech platform a brand name called ImmuneY2, which can be defined as a series of technologies that, when combined, create antibodies against bioactive lipids.

Also, in the company pipeline is another ImmuneY2-based drug referred to as Lpathomab. This drug will target cancer and does not have any ocular indications, according to the company.

Overall, the company's goal is to get through the clinical trials with its ImmuneY2 platform drugs and bring them to market for multiple indications.

"We hope to develop a series of compounds that will demonstrate both safety and efficacy in humans in a wide range of indications," explains Scott Pancoast, president and chief executive officer. "With Sphingomab, this certainly seems the case because it has shown in animals and preclinical studies efficacy in different types of cancer, in AMD, and in post-myocardial infarction." Sphingomab may also someday be indicated for other ocular indications, including diabetic retinopathy, PVR, and modulation of post trabeculectomy scarring.

Looking to the longer term and assuming the company does get drugs to market, Pancoast would be open to options, including creating a separate subsidiary for the ocular division or a buyout.

Venture capital for the company was initially provided by Western States Investment Group and additional financing has come from Johnson & Johnson and Biogen Idec, as well as approximately 100 private investors. Lpath is also attempting to secure Small Business Innovation Research (SBIR) grants from the federal government.



Retinal Physician, Issue: September 2006