Caution on Overuse of Anti-VEGF
New research cites possible negatives.
■ Increasingly aggressive therapies that block VEGF could cause damage even when used to treat retinal diseases. Scientists reporting recently in the journal Investigative Ophthalmology & Visual Sciences (IOVS) discovered that inhibiting VEGF might have a harmful effect on the ciliary body.
This is the second cautionary note about the aggressive use of anti-VEGF drugs to treat retinal disease. Several noted retinal specialists, most notably Philip Rosenfeld, MD, PhD, of Bascom Palmer, have cited growing evidence that heavy dosing of anti-VEGF drugs can trigger geographicatrophy.
“Very little is known about the factors that regulate the integrity and function of [the ciliary body] in the adult,” said author Patricia A. D’Amore, PhD, of Schepens Eye Institute. “Our finding indicates that VEGF-A is at least one of the molecules that play a role in keeping the ciliary body healthy and functioning properly.”
In the study, investigators simulated the VEGF-A activity in adult mice and found that blocking the protein decreased intraocular pressure, an unexpected side effect that impaired the ciliary body.
Several anti-VEGF-A therapies have been used for the treatment of wet AMD, diabetic macular edema, retinopathy of prematurity, and other eye diseases. Dr. D’Amore agrees that thus far no evidence has indicated that the manner in which these drugs are being administered interferes with the ciliary body.
“However, there is a move toward developing methods to continuously deliver anti-VEGF to the eye and to have drugs that are more potent inhibitors of VEGF,” she said. “I would be concerned that more aggressive VEGF inhibition in the eye would have deleterious effects on the ciliary body.”
The investigation of anti-VEGF-A on the ciliary body was the result of prior studies that found blocking VEGF can lead to the degeneration of capillary beds, particularly those populated with fenestrated capillaries. Whole-body VEGF blockade in anticancer therapies has been found to damage the capillaries of the kidney, and anti-VEGF used for localized treatment of brain tumors can affect thyroid function.
The results of the IOVS study suggest the need for further research, including clinical trials. “I am hoping that revealing the possible negative side effects of VEGF inhibition in the eye will motivate research into new ways to block edema and blood vessel growth in the eye that does not require continuous inhibition of intraocular VEGF,” said Dr. D’Amore.
Ford K, Magali S, Walshe T, D’Amore P. Expression and role of VEGF-A in the ciliary body. Invest Ophthalmol Vis Sci. 2012;53:7520-27
■ First patients treated with Jetrea. Allen C. Ho, MD, Pravin Dugel, MD, and David Boyer, MD, treated the first patients with recently approved Jetrea (ocriplasmin, ThromboGenics) in mid-January. Jetrea is the first and only pharmacologic option approved for the treatment of symptomatic vitreomacular adhesion (VMA).
Dr. Ho is a professor at Wills Eye Hospital, Philadelphia. Dr. Dugel is in private practice with Retinal Consultants of Arizona, and Dr. Boyer is in private practice with Retina-Vitreous Associates in Los Angeles.
Jetrea intravitreal injection, 2.5 mg/mL, is now available and can be ordered immediately for authorized shipment. Only a single injection is required for each patient.
■ Sanofi to buy more Regeneron stock. Sanofi, which is partnering with Regeneron on several promising non-ophthalmic drugs, has filed notice that it intends to purchase a larger stake in Regeneron than the 16% stake it already holds. The move was seen as a signal that Sanofi sees strong potential in the cancer and cholesterol-lowering drugs that are included in the partnership.
Regeneron’s treatment for wet AMD, Eylea, has had a wildly successful launch following FDA approval in late 2011, but Sanofi has no stake in it. The international partner for Eylea is Baxter HealthCare. In its first full year of sales, Eylea recorded revenue of $838 million in the United States alone. Regeneron is predicting Eylea sales growth of approximately 50% in 2013, to the $1.2-$1.3 billion range.
Device and App for Image Capture, Transfer
The iExaminer can facilitate telemedicine.
■ Welch Allyn has received FDA 510(k) clearance for its iExaminer, a combined image-capture device and iPhone app that can facilitate the transfer of retinal images to patients and remote sites. The iExaminer consists of a hardware adapter and associated software that allows eye-care professionals to capture, store, send and retrieve images from the Welch Allyn PanOptic ophthalmoscope using the iPhone 4 or 4S.
The company noted the PanOptic features patented optical technology that creates a viewing area of the fundus and retinal nerve in an undilated pupil five times larger than that of a traditional ophthalmoscope and increases magnification by 26% to more easily see retinal details. The iExaminer is designed to rapidly capture and transmit retinal images the PanOptic creates for documentation.
The iExaminer adapter aligns the optical access of the PanOptic to the visual axis of the iPhone 4 or 4S camera to capture high-resolution pictures of the fundus and retinal nerve. The iExaminer software application, available from the Apple App Store, then allows physicians to save images to a patient file, as well as e-mail and print the images. “The iExaminer allows health-care providers to easily capture and share the images of a fundus at a moment’s notice, helping to improve the quality of care provided — especially for remote users who may not have easy access to specialists,” said Rick Farchione, senior manager, physical assessment at Welch Allyn.
Mr. Farchione added that the iExaminer will increase work-flow efficiency by allowing providers to capture and share images from any clinical environment.
“It is a low-cost way to digitally capture eye imaging and will also make it easier for providers to share images with their patients, helping to improve patient knowledge and compliance,” he concluded.
Regeneron reported earnings of $4.66 a share for all of 2012.
■ Gene mutation predictive of uveal melanoma outcomes. Scientists at the Washington University School of Medicine in Saint Louis have identified a gene mutation that is predictive of more favorable outcomes in often-fatal uveal melanomas. The research was recently published in the online edition of Nature Genetics.
“We found mutations in a gene called SF3B1,” said senior author Anne Bowcock, PhD, professor of genetics. “The good news is that these mutations develop in a distinct subtype of melanomas in the eye that are unlikely to spread and become deadly. This is the first time mutations in this gene have been found in uveal melanoma.”
As part of the study, the researchers also looked for SF3B1 mutations in uveal melanoma tumors from 102 patients, finding it in nearly 20% of them. Mutations in the gene were linked to favorable features, including a younger age at diagnosis and a far lower metastasis rate.
■ Argus II approved for RP. The FDA has approved the Argus II retinal prosthesis developed by Second Sight Medical as effective in bringing some limited functional vision to patients afflicted with retinitis pigmentosa. The approval follows the unanimous endorsement of the device by an FDA advisory committee and is the result of two decades of research and more than $200 million in funding from the federal government and private investors.
Genes Don’t Predict Response to AMD Treatments
Variants do help identify disease risk.
■ Newly released data from the landmark NIH CATT trial show that although certain gene variants may predict whether a person is more likely to develop AMD, these genes do not predict how patients will respond to the wet AMD treatments Lucentis (ranibizumab, Genentech) and Avastin (bevacizumab, Genentech).
The data, published online in the journal Ophthalmology, found no significant association between four gene variants and outcomes that measured the patients’ responses to treatment.
The genetics study cohort comprised 73% of the 1,149 CATT participants. These patients were evaluated for four gene variants linked to AMD risk: CFH, ARMS2, HTRA1, and C3. The patients’ genotypes were then compared to their responses to treatment with Lucentis or Avastin.
The researchers found no significant associations among the four gene variants and the outcomes that measured the patients’ responses to treatment, which were improvement or loss of visual acuity, the status of the retinal anatomy and the number of medication injections given.
The findings of the CATT genetic study appear to lend further weight to the 2012 recommendation of the AAO on the use of genetic testing. The Academy advises against routine genetic testing for AMD and other complex eye disorders until specific treatment or monitoring strategies have been shown in clinical trials to be of benefit to people with specific, risk-linked genotypes.
“Our genetic research team remains hopeful that gene variants that predict patient response to AMD treatments will be identified soon,” said team leader Stephanie Hagstrom, PhD, of the Cole Eye Center at the Cleveland Clinic. “This would enable a significant leap forward in ophthalmologists’ ability to individualize treatment and care plans for their patients.”
■ Trial approved for oral DME drug. Ampio Pharmaceuticals said the FDA has accepted its IND application for Optina, an investigational oral treatment for DME. Ampio plans to begin enrollment in a 12-week clinical trial in the near future. The FDA granted Optina 505(b)(2) status in July 2012. Drugs designated under this pathway can be approved on a single trial.
Optina is a drug based on a low dose of the weak-androgen, low-molecular-weight, very lipophilic steroid danazol. Oral administration of low-dose danazol to patients with DME has been shown to be safe with no serious adverse events. Ampio’s in vitro data suggest that danazol has a biphasic effect on endothelial cells: At low doses, danazol decreases vascular leakage, while at higher concentrations it increases vascular permeability.
■ Santen and Clearside in research partnership. Santen, Ltd, has made a financial investment in Clearside Biomedical, Inc, and also entered into a research partnership with Clearside for the treatment of retinal disease.
“Clearside Biomedical’s proprietary microinjection platform provides a novel access to the retina and choroid and may provide improvements in delivering drugs to the site of retinal diseases via the suprachoroidal space through an in-office injection procedure,” said Quan Dong Nguyen, MD, chairman of the Department of Ophthalmology and Visual Sciences at the University of Nebraska Medical Center. “Through joint research with Santen, one of the leading companies in ophthalmic technologies, it is hopeful that such collaboration will result in new approaches for the treatment of various back-of-the-eye diseases.”
The Clearside microinjection process is designed to allow eye-care professionals to treat patients in the office without complicated surgical techniques. The FDA has allowed Clearside to pursue testing of the investigational drug CLS1001 (triamcinolone acetonide) suprachoroidal injectable suspension. This drug would treat sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Clinical testing is scheduled to begin this month. RP