SUBSPECIALTY NEWS

Does Anti-VEGF Trigger Macular Atrophy?

A large study finds hints but no definitive answers.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ One of the ongoing mysteries in the treatment of neovascular AMD is whether repeated injections of anti-VEGF drugs can trigger macular atrophy, which is one of the leading causes of long-term vision loss.

“We know from large studies, such as CATT and IVAN, that after two or three years of anti-VEGF treatment approximately a third of patients develop atrophy or fibrosis,” says Pravin Dugel, MD, of Retinal Consultants of Arizona. “We have three possible explanations for this: either the drug is causing the atrophy; or perhaps this is the natural course of the disease; or possibly the atrophy has been there all time and the drug has cleared the fluid and enabled us to better image the atrophy.”

In an effort to obtain more definitive answers to the relationship between anti-VEGF therapy and macular atrophy, Dr. Dugel led a study of more than 1,000 patients who had participated in the HARBOR trial for Lucentis. He presented the results this summer at the annual meeting of the ASRS.

“HARBOR was a highly relevant clinical trial in terms of the study design and the imaging available for our research,” says Dr. Dugel. “What we found was that patients who received monthly injections of Lucentis showed more atrophy than patients who received as-needed injections. This finding may suggest the drug as a possible trigger. However, the answer is not that simple. We also found that patients who got the most as-needed injections had a lower incidence of atrophy than patients who got fewer as-needed injections. This contradicts a drug-related association.”

One unusual finding from the study was that subretinal fluid appears to be protective of the development of macular atrophy. Dr. Dugel believes this aspect of the research deserves further study as well.

Though Dr. Dugel’s study was not definitive as to the relationship between anti-VEGF drug and macular atrophy, he cautions that the biggest danger is to undertreat patients with neovascular AMD.

“More patients will lose vision from undertreatment than from any effects of the macular atrophy,” he asserts. “Macular atrophy needs to be further studied. However, given the current data, we should not change our treatment strategy. That should be the take-away message from the studies we have done so far.”

AGTC and Biogen in Development Pact

Gene-based therapies for blinding diseases

■ AGTC (Alachua, FL), a developer of gene-based therapies for serious retinal diseases, has entered into a major partnership with Biogen (Cambridge, MA) to develop treatments for a range of serious ophthalmic diseases.

The collaboration will focus on the development of a portfolio of AGTC’s therapeutic programs, including both a clinical-stage candidate and a preclinical candidate for orphan diseases of the retina that can lead to blindness in children and adults. The agreement also includes options for early-stage discovery programs in two ophthalmic diseases and one nonophthalmic condition, as well as an equity investment in AGTC by Biogen, and a license agreement for certain manufacturing rights to AGTC’s proprietary gene-vector technology.

“With this collaboration, we hope to advance gene therapies to open possibilities for patients who suffer from diseases that are well understood, but have no adequate treatment,” said Olivier Danos, PhD, senior vice president, cell and gene therapy, at Biogen. “AGTC is an exceptional partner to help us advance our gene therapy capabilities by targeting diseases of the eye — an organ that provides an ideal setting for the localized, selective delivery of gene-based therapies.”

“We expect this collaboration will further validate our novel adeno-associated virus (AAV) gene therapy platform and support the development of new therapies that may allow for transformative treatments for these rare inherited eye diseases and other clinical indications,” added Sue Washer, president and CEO of AGTC. “Biogen’s significant commitment to advancing gene therapies and demonstrated success in developing innovative therapies to treat complex diseases, combined with our proprietary manufacturing technology and extensive gene therapy experience, makes this an ideal partnership.”

The lead development programs in the collaboration include a clinical candidate for X-linked retinoschisis (XLRS) and a preclinical candidate for the treatment of X-linked retinitis pigmentosa (XLRP). XLRS, a disease affecting young males beginning during the teenage years, can lead to serious complications, such as vitreous hemorrhage or retinal detachment during adulthood. XLRP usually causes night blindness by the age of 10 and progresses to legal blindness by an individual’s early forties. Both conditions represent significant unmet needs that may be addressed by replacing the single, faulty gene causing each disease.

Regarding the financial terms of the agreement, the collaboration encompasses a $124 million upfront payment to AGTC, a $30 million equity investment by Biogen in AGTC, and potential milestone and royalty payments to AGTC that could amount to as much as $1 billion based on the progression of these initiatives toward approval and commercialization.

Argus II Improves Quality of Life in RP Patients

First implantation performed for dry AMD.

■ Second Sight Medical Products (Sylmar, CA), a developer, manufacturer, and marketer of implantable visual prosthetics to provide some useful vision to blind patients, announced positive three-year results post-implant of its Argus II Retinal Prosthesis System from a multicenter clinical trial.

The study highlighted 30 subjects with retinitis pigmentosa (RP) implanted with the Argus II at 10 centers throughout the United States and Europe. Three types of visual function tests were performed using computer-run assessments: object detection, motion detection, and visual acuity. Two types of real-world orientation and mobility (O&M) tests were also performed: a test where subjects were asked to locate and touch a door, as well as a test where subjects were asked to follow a white line on the floor.

In the absence of existing validated quality-of-life tools for this population, a Functional Low-vision Observer Rated Assessment (FLORA) was also performed by independent visual rehabilitation experts at the request of the FDA to assess the impact of the Argus II system on the subjects’ everyday lives, including extensive interviews and tasks performed around the home.

Of the 30 subjects tested, 29 remained implanted with functioning Argus II systems at three years post-implant. Results showed that with the Argus II System, improvements in visual function and O&M were maintained out to three years. Up to 89% of subjects performed statistically better with the Argus II system implanted compared with native residual vision in visual function tasks at year three. During the trial, the FLORA also demonstrated that up to 80% of the subjects received benefit from the system when considering both functional vision and patient-reported quality of life, and no subjects were affected negatively.

“The data from this study is quite remarkable for these patients who, previously, had little to no light perception, living in a world that we could consider complete darkness,” said Allen C. Ho, MD, FACS, director of Retina Research, Wills Eye Hospital, and professor of ophthalmology, Thomas Jefferson University, both in Philadelphia. “The fact that these individuals have increased independence, being able to navigate through their home, walk through doorways, and cross streets, is truly life changing.”

ARGUS II NOW IMPLANTED FOR DRY AMD

In related news, Second Sight said it had begun a feasibility study to determine if the Argus II could be effective in providing some vision to patients with dry AMD. The first of five dry AMD patients was recently implanted with the device in a procedure performed in the United Kingdom and has shown visual improvement. The main difference between RP and dry AMD is that RP primarily affects peripheral vision and dry AMD primarily causes loss of central vision. The potential marketplace for use of the Argus II could be as many as two million people, compared to 375,000 for RP.

Second Sight Chairman Robert Greenberg, MD, PhD, said: “We are very excited to begin such an important study for this patient population and to have the opportunity to help a great deal more people living with blindness. Though it is obviously still early in this clinical trial, we are very encouraged by these initial results.”

Allegro VMT Therapy Shows Promise

Release achieved by 65% of highest-dose patients.

■ Allegro Ophthalmics, LLC (San Juan Capistrano, CA), said its phase 2 clinical trial of Luminate (formerly ALG-1001) in patients with vitreomacular traction (VMT) or vitreomacular adhesion (VMA) met its primary endpoint. In this prospective, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of intravitreal injections of Luminate in 106 study subjects, 65% of eyes treated with the 3.2-mg dose of Luminate achieved release of VMT or VMA by day 90 (end of study), compared to 9.7% of those in the placebo control group.

The study, which included three Luminate groups (2.0 mg, 2.5 mg, or 3.2 mg) and a balanced salt solution placebo group, also found that Luminate was well tolerated with no drug toxicity or intraocular inflammation noted with repeated intravitreal injections. Allegro says these safety results are consistent with previously conducted Luminate studies on human subjects where there were no rod or cone photoreceptor dysfunction on full-field electroretinogram testing, no afferent pupillary defects, and no evidence of retinal tears or detachments.

“These findings appear to be very promising,” says Michael Tolentino, MD, associate professor of ophthalmology at the University of Central Florida, director of research for the Center for Retina and Macular Disease, and clinical investigator of this phase 2 VMT study. “It is a very positive outcome to have 65% of eyes treated with the 3.2-mg dose of Luminate achieve VMT/VMA release by day 90. These statistically significant findings, as assessed by the Duke Reading Center, coupled with the fact that Luminate has been shown to be well tolerated, makes me optimistic that Luminate will provide meaningful clinical benefit to patients with VMT or VMA.”

“These positive results continue to affirm the safety and efficacy of Luminate,” says Vicken Karageozian, MD, chief technical officer, Allegro Ophthalmics. “The vitreolytic properties confirmed in this study and the antiangiogenic properties demonstrated in earlier DME and neovascular AMD studies continue to validate our clinical development approach of advancing Luminate across multiple vitreoretinal indications.”

Luminate, a first-in-class integrin peptide therapy, treats vitreoretinal diseases by targeting integrin receptors involved in cell signaling and regulation and in the construction of new and aberrant blood vessels. By utilizing two mechanisms of action (vitreolysis and antiangiogenesis), Allegro says Luminate has been shown in clinical studies to date to effectively regress and inhibit new blood vessel formation, as well as reduce vascular leakage to maintain and restore vision. Currently Luminate is also in phase 2 clinical trials for DME and nonproliferative diabetic retinopathy.

First Eye Cancer “Working Day” Is a Success

Paris meeting draws 158 specialists.

■ In the first meeting of its kind ever held, eye cancer specialists from every continent convened recently to initiate worldwide collaboration within their specialty. Held at the Curie Institute in Paris, the first eye cancer “Working Day” exceeded organizers’ expectations, attracting 158 participants.

Divided into several sections, the Working Day addressed critical issues related to eye cancer research and treatment. Sections began with an overview presentation from moderators, followed by an interactive group session to brainstorm ideas.

“The Working Day demonstrated that eye cancer specialists want to work to improve our specialty and to help each other and unserved patients around the world” said Paul T. Finger, MD, an eye cancer specialist from New York City and organizer of the Working Day.

The Working Day encouraged international, multicenter cooperation by providing a platform for doctors to discuss their existing progress. This was especially true on the subject of international patient registries. The first collaborative data on choroidal melanoma and ocular adnexal lymphoma were presented, followed by a call to participate and share in ongoing and new registries.

Another theme of the Working Day was reaching out to the developing world. Participants committed to address the 70% worldwide mortality for children with the eye cancer retinoblastoma. The Eye Cancer Foundation and Princess Margaret Hospital in Toronto, Canada, joined together to provide funding for cost-effective training of 33 retinoblastoma eye cancer specialists for unserved countries.

The Working Day encouraged eye cancer specialists to join together by signing up for committees on various topics of interest throughout the day. The most represented committee included 43 specialists who volunteered to develop a new system to grade eye-related radiation side effects.

The next Eye Cancer Working Meeting is scheduled to be held at Princess Margaret Hospital. The event was endorsed and hosted by the Eye Cancer Foundation and the Curie Institute. It was also endorsed by the International Society of Ophthalmic Oncology (ISOO), the American Joint Committee on Cancer (AJCC), the Commission on Cancer (COC), the American Brachytherapy Society (ABS), the European Ophthalmic Oncology Group (EOOG), the American College of Surgeons (ACS), and the International Council of Ophthalmology (ICO). RP