Agents in development for AMD, vitreolysis show promise

New pharmaceutical agents may allow surgeons to treat retinal disorders without invasive surgery.

Issue: March 1, 2002

NEW ORLEANS — A number of new pharmacological agents for retinal disorders such as age-related macular degeneration (AMD) and diabetic retinopathy are in development. Results to date with these agents were discussed here at the American Academy of Ophthalmology meeting.

“Numerous agents have been proposed to treat retinal disorders. Unfortunately, the track record has been poor” for most of these agents, David R. Guyer, MD, said.

“Currently there are a number of potential future drugs that are in the laboratory or under observation which hold great promise,” he added.

Drugs performing multiple actions for a variety of conditions are under observation for treatment of vitreous hemorrhage and for performing pharmacologic vitreolysis in diabetic retinopathy, macular edema and abnormal vascular endothelial growth.

Vitreous hemorrhage

Vitrase (hyaluronidase, Ista Pharmaceuticals Inc.) is a drug currently under clinical investigation for the clearance of vitreous hemorrhage. Successful application may prevent vitrectomy.

“This drug is an enzyme capable of liquefying the vitreous via hydrolysis of hyaluronic acid,” Baruch D. Kuppermann, MD, PhD, explained. The hydrolysis causes a temporary decrease in the viscosity of the cellular cement and modifies the permeability of connective tissue, he said.

“There are two key features to this process for hemorrhage,” Dr. Kuppermann said, “No. 1 is liquefaction, and No. 2 is the mild inflammatory cellular response.”

According to Dr. Kuppermann, liquefaction promotes the diffusion of molecules and migration of cells within the vitreous. The inflammatory cellular response facilitates the removal of vitreous and clot debris.

Ista Pharmaceuticals has completed phase 3 of trials with Vitrase for vitreous hemorrhage. “There were two large pivotal trials with almost 1,200 patients enrolled. Both the preclinical and clinical preliminary evidence shows hemorrhage clearance in over 1,200 patients subjected to the drug, with no serious safety concerns to date,” Dr. Kuppermann said.

As of late January 2002, data for phase 3 remained to be reviewed by the company, as well as the Food and Drug Administration.

Pharmacologic vitreolysis

Vitreous from a 9-month-old child. The sclera, choroid and retina were dissected off the vitreous body, which remains attached to the anterior segment. A band of gray tissue can be seen posterior to the ora serrata. This is neural retina that was firmly adherent to the vitreous base and could not be dissected. The vitreous body is solid. Although it is situated on a surgical towel exposed to room air it maintains its shape; owing to the young age of the donor, the vitreous is almost entirely gel.
(PHOTO REPRINTED WITH PERMISSION FROM J. SEBAG, MD.)

Early investigations into the clinical use of Vitrase for inducing posterior vitreous detachment (PVD) in patients with diabetic retinopathy have also been under way.

Inducing PVD involves pharmacologic vitreolysis, the manipulation of the vitreous used to eliminate its role in a number of vitreoretinal pathologies.

“The hope is that hyaluronidase may be able to facilitate a complete PVD or alter the course of development of proliferate diabetic retinopathy,” Dr. Kuppermann said.

Results from a recent study showed that hyaluronidase, SF6 gas and combination therapy were capable of inducing PVD in a preponderance of patients, Dr. Kuppermann said. Saline was unable to induce detachment.

However, there is skepticism regarding the efficacy of Vitrase for use in PVD.

“Vitrase was not found to cause PVD in some animal models,” said Jerry Sebag, MD, FACS, FRCOphth. “I believe there is also little theoretical basis for the use of pure hyaluronidase in detaching the vitreous.”

According to Dr. Sebag, a drug that does hold great theoretical merit for detachment is chondroitinase ABC. Chondroitinase ABC is a substrate-specific agent.

“The reason that it is theoretically sound is that it specifically cleaves chondroitin sulfate, and this is one of the few molecules that plays a role both in the maintenance of the gel state of vitreous and adhesion of the vitreous to the retina,” Dr. Sebag said.

Studies in cynomolgus monkeys with chondroitinase “showed successful liquefaction of the vitreous with separation from the retina up to and including the vitreous base,” Dr. Sebag said.

A phase 1 clinical trial found no toxicity. While there are no official results released on this study, Dr. Sebag believes chondroitinase ABC is an “extremely” useful agent in performing pharmacologic vitreolysis.

Pharmacological liquefaction

Additionally, according to Dr. Sebag, there are enzymatic and nonenzymatic approaches in development that have demonstrated efficacy in liquefaction for pharmacologic vitreolysis.

“Plasmin, a non-specific protease from the enzymatic group, has had the most extensive development to date,” he said.

Plasmin is an agent that manipulates the vitreous through biochemical components, achieving liquefaction, said Michael T. Trese, MD. It focuses on the vitreoretinal juncture, an area composed of plasmin substrates, and the vitreous core, where collagen is the primary component.

“Our research has found that autologous plasmin gives us an ideal biologic manipulator of the vitreous cavity,” Dr. Trese said.

In a study of eight human eyes treated with 0.8 IU of autologous plasmin enzyme, all eyes showed liquefaction of the vitreous.

Dr. Trese and colleageus developed a technique using an affinity cartridge and gel cartridge that allowed them to produce enzyme in various doses over a 30-minute period. This technique, together with a small-gauge cutting system, allowed surgeons to do sutureless procedures, which reduced operating time and increased safety, Dr. Trese said.

“We’ve come to a point in our careers where we need to look for other types of therapies that combine biology with technology,” Dr. Trese said, “With this in mind, our use of plasmin represents just the beginning of this type of manipulation. New applications will come in the future for treating diabetic retinopathy.”

Single agents for multiple actions

Also on the horizon are a number of treatments for diabetic retinopathy. Doctors are searching for safe, alternate methods of treatment with very clear objectives in mind.

“We want to slow the progression of retinopathy, decrease macular edema, and treat retinal neovascularization (NV) all at once,” Peter A. Campochiaro, MD, said.

Two agents are currently being investigated that fit this profile: a PKC-B inhibitor and Sandostatin showed no clinical significance in the most recent trial with long acting release (LAR) (octreotide acetate, Novartis Pharmaceuticals).

“The rationale for the PKC beta-inhibitor, which is an oral drug, suggests that this form of PKC is selectively up-regulated in diabetes and contributes to the vascular disease,” Dr. Campochiaro said.

Sandostatin LAR, which is delivered by injection, antagonizes growth hormones that have been suggested as stimulators for retinopathy, he added.

Both of these agents are being investigated in long-term trials with a similar strategy, Dr. Campochiaro said. They will be graded on the progression of retinopathy, and results will be analyzed once trials conclude.

VEGF inhibitors

Additionally, PKC 412, another drug from Novartis Ophthalmics, was not only found to slow retinal NV, but to completely halt the production of abnormal blood vessels in research conducted in 1999. Doctors found that the agent inhibited vascular endothelial growth factor (VEGF).

Now, in 2002, researchers are taking this data one step further, to determine if PKC 412 is effective in macular edema, by preventing retinal swelling and cyst formation.

Other anti-VEGF agents currently in clinical trials for anti-VEGF activity are EYE001, aptamers from Eyetech Pharmaceuticals, and PKC-B inhibitors from Eli Lilly and Co., Dr. Guyer said.

“This therapy presents a potential two-hit attack on choroidal neovascularization by both potentially blocking neovascularization and allowing resorption of fluid,” he said.

In recent laboratory findings, the antipermeability effects of anti-VEGF therapy showed that the diabetes-induced blood retinal barrier breakdown could be inhibited by the application of the therapy, Dr. Guyer said. “Thus, there seems to be strong scientific rationale for the use of these drugs in many retinal disorders,” he added.

For Your Information:

David R. Guyer, MD, can be reached at Vitreous-Retina-Macula Consultants of New York, 519 E. 72nd St., Suite 203, New York, NY 10021; (212) 861-9797; fax: (212) 628-0698. Dr. Guyer is in a management position with financial interest at Eyetech. He is not a paid consultant for the company.

Jerry Sebag, MD, is on the clinical faculty at Doheny Eye Institute, University of Southern California. He can be reached at Vitreous-Macula-Retina Institute, 18821 Delaware St., Suite 202, Huntington Beach, CA 95648; (714) 841-5002; fax: (714) 843-5620. Dr. Sebag is a paid consultant for Ista Pharmaceuticals.

Baruch Kuppermann, MD, can be reached at University of California Irvine Department of Ophthalmology, 118 MedSurge, Irvine, CA 92697; (949) 824-6256; fax: (949) 824-4015. Dr. Kuppermann has no direct financial interest in the products mentioned in this article. He is a paid consultant for Ista Pharmaceuticals.

Michael T. Trese, MD, can be reached at Associated Retinal Consultants, 632 William Beaumont Hospital, 3535 W. 13 Mile Road, Royal Oak, MI 48073; (248) 288-2280; fax: (248) 288-5644. Dr. Trese has a non-paid management position with NuVue Technologies.

Peter A. Campochiaro, MD, can be reached at Johns Hopkins Hospital, 600 N. Wolfe St., Maumenee Building, Suite 710, Baltimore, MD 21287; (410) 955-5106; fax: (410) 614-7083. Dr. Campochiaro is a paid consultant for Novartis Ophthalmics.

Ista Pharmaceuticals, developer of Vitrase, can be reached at 15279 Alton Parkway, Suite 100, Irvine, California 92618; (949) 788-6000; fax: (949) 788-6010.

NuVue Technolgies, developers of the kit for plasmin construction, can be reached at 168 Emerald St., Keene, NH 03431; (603) 352-4545; fax: (603) 352-4612.

Novartis Ophthalmics, developer of Sandostatin LAR and PKC 412, can be reached at 11695 Johns Creek Parkway, Duluth, GA 30097; (800) 656-5660; fax: (770) 905-1883.

Eli Lilly and Company, developer of kinase agents, can be reached at Lilly Corporate Center, Indianapolis, IN 46285; (317) 276-2000; fax: (317) 433-4340.

Eyetech Pharmaceuticals Inc., developer of EYE001, can be reached at 666 Fifth Ave., 35th Floor, New York, NY 10103; (212) 582-8376; fax: (212) 582-2645.