SUBSPECIALTY NEWS

High-dose Statins May Combat Dry AMD

Small study shows promising effects.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ Researchers at the Massachusetts Eye and Ear Infirmary (Harvard Medical School) and the University of Crete have conducted a phase 1/2 clinical trial investigating the efficacy of high-dose statins for the treatment of patients with the dry form of AMD. The researchers found evidence that treatment with high-dose atorvastatin (80 mg Lipitor) is associated with regression of lipid deposits and improvement in visual acuity, without progression to advanced disease, in high-risk AMD patients. Their findings were recently published in the new online journal EBioMedicine.

“We found that intensive doses of statins carry the potential for clearing up the lipid debris that can lead to vision impairment in a subset of patients with macular degeneration,” said Joan W. Miller, MD, chair of ophthalmology at Harvard Medical School and chief of ophthalmology at Massachusetts Eye and Ear and Massachusetts General Hospital. “We hope that this promising preliminary clinical trial will be the foundation for an effective treatment for millions of patients afflicted with AMD.”

Ophthalmologists and vision researchers have long suspected that there may be a connection between dry AMD and atherosclerosis. In dry AMD, physicians often see soft, lipid-rich drusen in the outer retina, similar to the build-up of lipid material in the inner walls of blood vessels in atherosclerosis. Statin use is widespread in middle-aged and older individuals, who also have an increased risk of AMD; however, previous studies have shown very little correlation between regular statin use and improvements in AMD. The authors of the EBioMedicine paper hypothesized that, due to the heterogeneous nature of the disease, patients with soft, lipid-rich drusen may respond better to statins prescribed at higher dosages.

“Not all cases of dry AMD are exactly the same, and our findings suggest that if statins are going to help, they will be most effective when prescribed at high dosages in patients with an accumulation of soft, lipid material,” said Demetrios Vavvas, MD, PhD, a clinician scientist at Massachusetts Eye and Ear and codirector of the Ocular Regenerative Medicine Institute at Harvard Medical School. “These data suggest that it may be possible to eventually have a treatment that not only arrests the disease but also reverses its damage and improves the visual acuity in some patients.”

Twenty-three patients with dry AMD marked by soft lipid deposits in the outer retina were prescribed a high dose of Lipitor. Of the 23 patients, 10 experienced an elimination of the deposits under the retina and mild improvement in visual acuity. Other techniques that have attempted to eliminate the deposits have mostly failed, with the disease continuing to progress to more advanced dry AMD or a conversion to the wet form of AMD.

As the next step for this line of research, the investigators plan to expand to a larger prospective multicenter trial to further investigate the efficacy of the treatment in a larger sample of patients with dry AMD.

“This is a very accessible, FDA-approved drug that we have tremendous experience with,” said Dr. Vavvas. “Millions of patients take it for high cholesterol and heart disease, and based on our early results, we believe it offers the potential to halt progression of this disease, but possibly even to restore function in some patients with dry AMD.”

Ophthotech Begins Dry AMD Trial

Zimura studied in combating geographic atrophy.

■ Ophthotech Corporation (New York), a leader in developing novel therapies for retinal diseases, said the first patient has been dosed in a phase 2/3 clinical study of Zimura (avacincaptad pegol sodium), an inhibitor of complement factor C5, in patients with geographic atrophy, an advanced form of dry AMD. Complement factor C5 is a central component of the complement cascade believed to be involved in the development of AMD.

The phase 2/3 randomized, double-masked, controlled trial is designed to evaluate the safety and efficacy of Zimura monotherapy in patients with geographic atrophy. The company has also recently announced the initiation of a phase 2 study of Zimura in combination with anti-VEGF therapy in wet AMD patients to potentially reduce the treatment burden.

“Dry age-related macular degeneration continues to be a significant unmet medical need globally with no approved treatment options available to patients,” said David R. Guyer, MD, CEO and chairman of Ophthotech. “Multiple published studies suggest that the complement pathway has a central role in dry AMD. We plan to explore the potential of Zimura as a treatment for geographic atrophy. In addition, the emerging strength of science from published independent genetic variation studies relating to the role of complement inhibition in wet AMD along with our earlier Zimura study results in wet AMD are encouraging.”

Lucentis to Mark 10 Years as Approved Therapy

One of most successful drug launches in history

■ On June 30, 2006, the FDA approved Lucentis (ranibizumab, Genentech) as a monoclonal antibody fragment that could actually reverse the vision-robbing effects of wet AMD if injected intraviterally on a regular basis. As approvals for Genentech’s international partner Novartis followed suit, Lucentis quickly topped $1 billion in worldwide sales, making it one of the most successful pharmaceutical launches in history.

Today, Lucentis has FDA-approved indications for wet AMD, DME, macula edema associated with RVO, and diabetic retinopathy. It shares the market for combating retinal diseases with Regeneron’s Eylea (aflibercept) and Genentech’s own cancer drug Avastin (bevacizumab), which was discovered by Bascom Palmer ophthalmologist Philip Rosenfeld, MD, PhD, to be similar to Lucentis and effective in treating wet AMD.

A key to the success of Lucentis was its ability to attack vascular endothelial growth factor (VEGF), which causes the proliferation of abnormal blood vessels in the macula that are the hallmark of wet AMD. VEGF had initially been identified by the brilliant Genentech scientist Napoleane Ferrara, PhD. However, the first anti-VEGF therapy for wet AMD to be approved by the FDA was not Lucentis. It was a drug called Macugen (pegaptanib sodium, Eyetech) that beat Lucentis to market by a matter of months.

The major difference between Macugen and Lucentis was that Macugen could halt the progression of wet AMD, but Lucentis could actually restore vision that had been lost to the disease. The result was that Macugen’s success was very short lived.

Though the past decade of fighting retinal disease has been dominated by anti-VEGF monotherapy (Lucentis, Eylea, and Avastin), most retinal disease researchers believe we are on the cusp of next-generation advances that could include combination therapies, sustained-release formats, gene therapy, and stem cell treatments, among others. Genentech itself recently began a new clinical trial for a sustained–release implant for Lucentis that would reduce the need for repeated injections at four- to eight-week intervals.

Whatever advances occur in the future — and there are sure to be many — the place of Lucentis as a pioneering therapy that has improved the quality of life for millions of individuals afflicted with retinal disease is secure.

Fellows Forum Mixes Learning and Socializing

Donald D’Amico gives distinguished guest lecture.

■ The 16th annual Retina Fellows’ Forum took place on January 22 and 23 at the Westin River North in Chicago. Seventy North American vitreoretinal fellows from 62 different programs participated in an educational and social program that has become a much-anticipated fixture of the final year of vitreoretinal training.

As in past years, the fellows spent considerable time in the lecture hall with a panel of faculty led by course director David Chow, MD, and co-directors Carl Awh, MD, and Tarek Hassan, MD. Drs. Dean Eliott, Mike Jumper, Tamer Mahmoud, Jon Prenner, and Amy Schefler completed the faculty.

The meeting began on Friday with a session covering controversies in the management of AMD, OCT angiography, intraocular tumors, management of endophthalmitis, retinal detachment surgery, and an expert “Surgical Rounds” panel that emphasized the many “correct” ways to attack a surgical problem.

The Friday evening reception and dinner provided the first opportunity for the “graduating class” of 2016 fellows to socialize with their peers, the faculty, and representatives from industry.

Saturday offered a full day of panel-driven discussions on diabetic retinopathy, retinal vein occlusion, trauma, macular surgery, dislocated IOLs, and surgical instrumentation. As always, a highlight of the meeting was the Distinguished Guest Lecture, this year delivered by Donald D’Amico, MD, entitled “You Can Observe a Lot Just by Watching,” an entertaining and inspiring reflection on his life and career, with sage advice for the captivated audience.

The afternoon concluded with a “real world” panel discussion devoted to career decisions, practice building, and balancing work and personal demands.

The prestigious and competitive Retina Fellows’ Forum Research award went to Devon Ghodasra, MD, of the University of Michigan for his paper, “Safety and feasibility of quantitative multiplexed cytokine analysis from office-based vitreous aspiration.” Dr. Ghodasra will present his paper at the 2016 Annual Meeting of the American Society of Retina Specialists in San Francisco as a specially recognized lecture.

The meeting concluded with dinner, an informal awards ceremony, and the 11th annual Retinal Fellows’ Forum Bowling Tournament. Fellows and corporate representatives were divided into teams captained by the faculty. The team of rookie faculty member Amy Schefler emerged with a decisive victory.

Genentech was the major corporate supporter of the Retina Fellows’ Forum. Other companies representing a cross-section of devices and services important to vitreoretinal practice provided financial support and presented updates to the group about their businesses. Generous corporate support was provided by Alcon, Alimera, Allergan, Bausch and Lomb, Dutch Ophthalmic, Insight Instruments, Iridex, Katalyst Surgical, Keeler Instruments, Mallinckrodt Pharmaceuticals, Oculus Surgical, Optos, Regeneron, Thrombo-Genics, Topcon Medical Laser, Vitreq, Volk Optical, and Zeiss.

2016 Retina Fellows’ Forum Faculty: (left to right) Don D’Amico, Tamer Mahmood, Dean Eliott, Carl Awh, Tarek Hassan, David Chow, Amy Schefler, Mike Jumper, and Jon Prenner.

Improving Image Quality of Retinal Implants

USC researchers see longer pulses as key.

■ Retinal implants that deliver longer pulses of electrical current may noticeably improve image sharpness for individuals who have lost their sight due to retinitis pigmentosa, according to a new study by researchers from the USC Eye Institute and USC Viterbi School of Engineering. The research was recently published in the peer-reviewed journal Science Translational Medicine.

Retinal implants, such as the FDA-approved Argus II from Second Sight Medical (Sylmar, CA), give people with RP the ability to perceive light, using a system that includes a video camera mounted on a pair of eyeglasses, a video processing unit that transforms images from the camera into wirelessly transmitted electronic signals, and an implanted array of electrodes to stimulate visual neurons.

These retinal implants have enabled blind individuals to detect motion and locate large objects. However, because the implants may unintentionally stimulate axons in the retina, patients sometimes see large oblong shapes of light that reduce the quality of their vision. In order for patients to see more clearly, the images created by the implant should be composed of focal spots of light. Current implant technology stimulates the retina with brief pulses of electrical current roughly 0.5 msec in duration. The researchers found that increasing the duration of the stimulus pulses allows visualization of distinct focal spots of light.

“This is a huge step forward in helping restore sight for people with retinitis pigmentosa,” said Andrew Weitz, PhD, assistant professor of research ophthalmology. “Being able to create focused spots of light is important. Think of each light spot as a pixel in an image. By arranging many light spots into the shape of an object, we can generate sharp images of that object. For those of us who wear glasses, imagine the difference between trying to read a distant neon sign with and without your glasses on. For people with retinal implants, being able to see more clearly should have a big impact on their ability to recognize objects and navigate their environments. These improvements in vision can really boost a person’s sense of independence and confidence.”

The researchers tested various stimulus pulse durations in an animal model and validated their findings in a patient with an early version of the Argus. The results indicated that longer pulse durations allowed the retina to be stimulated more precisely. In the animal model, all pulses 8 ms and shorter activated axons, obscuring the ability to generate a focal spot of light. Sixteen-millisecond pulses also stimulated axons but to a much lesser extent. Pulses 25 ms and longer produced no evidence of axonal stimulation, instead resulting in focal spots of light.

“Our findings further support that it is possible for patients with RP to see forms using artificial vision,” said James Weiland, PhD, professor of ophthalmology and biomedical engineering. “This makes a strong case for developing high-resolution retinal implants.” RP