Biotech Values

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Squalamine mentioned pretty prominently

I hadn't seen this

Antiangiogenic Drugs May Stop Neovascularization in Wet Macular Degeneration
by Dan Roberts
Updated November, 2003

Research is currently underway to study the injection of antiangiogenic drugs as a means of stopping new blood vessel leakage (neovascularization). This is a report on nine of the drugs: rhufab V2 (aka lucentis), EYE001, tryptophanyl-tRNA synthetase (TrpRS), squalamine, Retaane 15 mg, Combretastatin A4 Prodrug (CA4P), VEGF-TRAP, and Macugen.

Rhufab V2 and EYE001

Two companies are conducting clinical trials on two separate drugs which evidence shows can prevent the growth of new vessels in the retina. The names of the drugs are rhufab V2 (also known as lucentis) and EYE001. Genentech, a pharmaceutical company, is conducting a phase I-II multi-center clinical trial to examine the safety and efficacy of rhufab V2, and Eyetech Pharmaceuticals is now in Phase III of a multi-center, randomized clinical trial. As of the date of this article, participating doctors estimate that from one-quarter to one-third of people with newly diagnosed wet macular degeneration have had significant improvement in their eyesight. In the remaining group, loss of sight has been stopped, at least temporarily.

A substance in the body called Vascular Endothelial Growth Factor (VEGF) is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues. Evidence shows that when the retinal pigment epithelial (RPE) cells begin to wither from lack of nutrition (a condition called "ischemia"), the VEGF goes into action to create new vessels. This process is called "neovascularization," and it acts as a restorative function in other parts of the body. In the retina, however, the vessels do not form properly, and leaking results. This leakage causes scarring in the macula and eventual loss of central vision.

Rhufab V2 and EYE001 both prevent the VEGF from binding with the receptors on the surface of the endothelial cells. The drugs are injected into the vitreous of the eyeball, then pass into the subretinal space, where the vessels proliferate. Researchers are hoping that neovascularization will then be blocked, preventing bleeding into the retina.

In a presentation to the 2002 ARVO convention ("Anti-VEGF Therapy for Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration: Phase IB Results"), researchers reported that VEGF therapy is showing promise in the treatment of wet macular degeneration. To determine if multiple injections might be harmful to the patient, a Phase IB study was set up using 21 patients with subfoveal chroidal neovascularization (CNV) secondary to AMD. Conclusions were that multiple injections were "well tolerated, and visual results were very encouraging. Further clinical trials are required, and a Phase III study to evaluate the efficacy and long-term safety of this treatment is currently underway at 115 centers in the USA and abroad."

For more detailed information on the methods and results of this study, see the ARVO web site at http://www.arvo.org/index.htm.

Tryptophanyl-tRNA synthetase (TrpRS)

Another potentially potent inhibitor of angiogenesis has been found by two scientists from The Scripps Research Institute (TSRI). As reported by Paul Schimmel, Ph.D., Ernest and Jean Hahnin, and Martin Friedlander, M.D., Ph.D. in the January 2002 issue of the journal Proceedings of the National Academy of Sciences, the antiangiogenesis activity of a fragment of the human protein tryptophanyl-tRNA synthetase (TrpRS) has many potential applications ranging from macular degeneration to cancer. In pre-clinical trials, the researchers have found that angiogenesis is completely stopped in 70% of cases. Also, since TrpRS is a naturally-occurring protein in the body, it may be more effective, because it would not bring toxicity and immune system problems into the treatment. Once the cells have been "taught" how to make the substance, the molecules could be delivered directly to the eye through gene- and cell-based vectors.

For more information and further updates about the TrpRS research, go to the Scripps Research Institute web site at www.scripps.edu.

Squalamine

In August, 2002, Genaera Corporation announced commencement of a Phase 1-2 clinical trial designed to test squalamine, an angiogenesis inhibitor that has shown good results in primate models of ocular angiogenesis, including abnormal vessel regression. The study is now being performed with leading ophthalmologists in Mexico, in consultation with Dr. Charles Garcia, Professor of Ophthalmology, University of Texas, and Dr. Gholam Peyman, Professor of Ophthalmology, Tulane University. Genaera currently anticipates completing this study in the first half of 2003.

In the company's press release, Roy C. Levitt, President and Chief Executive Officer of Genaera, was quoted as saying, "squalamine has a striking ability to treat abnormal ocular angiogenesis in numerous animal models. Successful treatment of AMD with squalamine (which is injected systemically, rather than into or around the eye) also provides an excellent opportunity to demonstrate single agent action for this potent anti-angiogenic drug. These results could support not only our efforts to develop this drug for the enormous additional potential clinical indication of AMD, but successful data will also support our ongoing oncology development efforts."

In May 2003, Genaera Corporation announced that early results in the trials were promising, with patients showing either stabilization or shrinkage of the size of the choroidal neovascularization lesions, and improvement in acuity of up to 3 lines on the chart.

As of August 2003, researchers reported that 97% of patients treated with squalamine had preserved or improved vision two months after initiation of therapy. 33% had three lines or greater improvement in visual acuity, and 64% had preserved vision. The greatest degree of improvement was eight lines, from 20/125 to 20/20 vision. In addition, multiple lesions were notably smaller, and blood vessel leakage was significantly less.

Retaane 15 mg (anecortave acetate for depot suspension)

On Sep 28, 2002, Alcon, Inc. announced that Retaane 15 mg (anecortave acetate for depot suspension) continues to "demonstrate effectiveness in reducing vision loss in patients with the wet form of age-related macular degeneration."

According to Dr. Jason Slakter (retinal specialist at Vitreous-Retina-Macula Consultants of New York and Clinical Professor of Ophthalmology at the New York University School of Medicine), the 12-month data from Alcon's ongoing study demonstrated that Retaane 15 mg (anecortave acetate for depot suspension) was significantly better at preserving vision, preventing severe vision loss and inhibiting lesion growth in the retina than a placebo. Statistics showed that, after one year, 79% of experimental subjects lost fewer than three lines of vision from baseline, compared to 53% of people in the placebo group. In the sub-group of subjects with predominantly classic lesions, 84% of treated patients maintained vision within three lines compared to 50% of the placebo group.

After 24 months (reported in September 2003), 73% of the patients treated with Retaane 15 mg showed stable or improved vision. This compared significantly to only 47% of patients in the placebo group. Treated patients also showed no increase in choroidal neovascularization.

The drug is different (and less invasive) than the others described in this article, in that it is injected around and behind the eye, rather than into the vitreous. To date, there have been no clinically relevent safety issues.

Alcon has enrolled approximately 500 subjects for Phase III of the clinical trials at more than 50 sites in the United States, Europe, Australia and Canada. This phase of the study will compare the effectiveness of Retaane 15 mg (anecortave acetate for depot suspension) with photodynamic therapy (PDT) using Visudyne. For more information, go to the company's web site at www.alconinc.com. Click on "USA," then "clinical studies."

Combretastatin A4 Prodrug (CA4P)

OXiGENE, Inc., a biopharmaceutical company based in Watertown, Massachusetts, has been conducting a clinical trial of its lead vascular targeting compound, Combretastatin A4 Prodrug (CA4P), in patients with advanced anaplastic carcinoma of the thyroid. The trial is being conducted at the Ireland Cancer Center at University Hospitals of Cleveland. Recently, the Foundation Fighting Blindness (FFB) chose to make CA4P the focus of its first-ever physician-sponsored human clinical trial. The organization agreed to fund a Phase I/II study to assess the safety and effectiveness of CA4P as a treatment for wet age-related macular degeneration (ARMD).

The studies are being conducted at the Wilmer Eye Institute of the Johns Hopkins University School of Medicine with a research team led by Peter A. Campochiaro, M.D., and Quan Dong Nguyen, M.D. The human trials are based upon successful results in recent animal studies, which showed the ability of CA4P to suppress the development of chroidal neovascularization leading to retinal degenerative diseases such as AMD. These results were published in the July 2003 issue of Investigative Ophthalmology and Visual Science,

VEGF-TRAP

An injectable protein that blocks growth of abnormal blood vessels associated with diabetic retinopathy may also be useful as a treatment for age-related macular degeneration.

VEGF-TRAP is a molecule which has been shown to block choroidal neovascularization in the retinas of mice. It was developed by researchers at the Johns Hopkins Wilmer Eye Institute and reported on in the June 2003 issue of the Journal of Cellular Physiology.

Macugen

Macugen, made by EyeTech Pharmaceuticals, is one of the newest anti-angiogenic drugs to be tested. It is a chemically synthesized strand of genetic material that bonds with VEGF cells to block replication. Early tests on the drug were promising, with significant percentages of patients either stabilizing or showing improvement in vision. A large trial of Macugen on 1,196 patients at 117 centers around the world was recently completed, and results should be published soon.

For more information on clinical studies related to macular degeneration, see Clinical Trial Watch

For further explanation of the terms used in this article, see the MD Support Glossary and Eye Anatomy