Toward Personalized Treatment of Retinal Diseases

Stunning progress is being made in genetics.


■ When the White House invited researchers from Regeneron (Tarrytown, NY) and other leading drug companies to a conference on “precision medicine” on January 30, it constituted a ringing endorsement of the work being done in many areas of medicine to develop genetically based treatments better-suited to individual patients. Toward that end, President Obama has proposed genotyping one million Americans as a start to building a national database of gene-sequenced individuals.

The White House conference also brought home the fact that what may also be called “personalized” or “customized” treatments are much closer to being a reality than many might think. Indeed, ophthalmology is emerging as a leader in the area of developing more individualized therapies.

“If you look at the way we are now treating wet macular degeneration, most of us have gotten away from giving patients an injection every month and we now seek to tailor the injection schedule to a patient’s individual needs,” says Pravin U. Dugel, MD, of Retinal Consultants of Arizona. “Some patients can go months without an injection and a very few might require an injection every few weeks. So we are practicing individualized medicine in that regard.”

But Dr. Dugel sees the longer-term goals of more personalized medicine as being closely tied to genetics and the genotyping of individual patients. He notes that in Genentech’s recent MAHALO trial of lampalizumab for the treatment of dry AMD, patients in the trial were genotyped. The resulting study data showed that the drug was significantly more effective in patients who were positive for specific biomarkers.

In other words, genotyping allowed the MAHALO researchers to determine varying levels of efficacy for different subsets of patients, which may soon make genotyping of patients a standard for future clinical trials.

“Creating subsets is fine if it is done strategically,” asserts Dr. Dugel. “The subsets have to be relevant to truly determining a drug’s efficacy. Otherwise, you might find that people with brown hair have better outcomes than people with blonde hair — and that would be meaningless. However, in a disease such as diabetes, which varies differently in individual patients, determining meaningful subsets and designing personalized treatment regimens could be highly beneficial.”

In just a few years, a number of companies involved in developing treatments for retinal diseases have focused on genetics and gene therapy. Probably no company has made a more extensive commitment to this area of research than Regeneron, which in 2014 established the Regeneron Genetics Center to study both large-population and family-based approaches to drug development. Regeneron is collaborating in this effort with the Geisinger Health System in Pennsylvania and the National Human Genome Research Institute of the NIH. Regeneron also has a partnership with the gene therapy company Avalanche Biotechnologies (Menlo Park, CA) to specifically develop gene replacement treatments for serious retinal diseases.

“We have started to engage in collaborations that we believe will enable the kinds of genetics discoveries that will lead to better patient care, insights into which patients might best respond to investigational treatments, and leads for new disease targets to develop novel therapeutics,” said George D. Yancopoulos, chief scientific officer and president, Regeneron Laboratories.  “The relationship with Geisinger is a cornerstone of the effort we are building, which we believe can advance the goals of human genetics research and personalized medicine.”


Anti-VEGF drug enters phase 3. Alcon (Fort Worth, TX) has moved its single-chain antibody fragment RTH258 into a worldwide, phase 3 trial for wet AMD following a 90-patient phase 2 study in which the drug demonstrated a prolonged duration-of-action that could be indicative of a reduced treatment burden. In the phase 2 trial, patients were dosed with 6 mg of RTH258 every three months.

Alcon said the phase 2 study met its primary endpoint, demonstrating visual acuity gains that were noninferior to aflibercept (Eylea, Regeneron, Tarrytown, NY). The primary objective of this phase 3 study is to compare the efficacy of RTH258 3 mg and 6 mg vs aflibercept 2 mg, with the mean change in BCVA from baseline to week 48 as the primary endpoint.

Spark Therapeutics Moves Ahead in Gene Therapy

Company in phase 3 trial for inherited retinal dystrophies.

■ Two decades of research into blinding diseases at the Children’s Hospital of Philadelphia (CHOP) may be coming to fruition in the form of Spark Therapeutics (Philadelphia), a company formed by the hospital in 2013 with an initial goal of commercializing gene therapy cures for inherited retinal dystrophies (IRDs) caused by autosomal recessive mutations in the RPE65 gene. Subtypes of Leber congenital amaurosis and retinitis pigmentosa are included in this overall category.

The company’s single-injection SPK-RPE65 product, currently in a fully enrolled phase 3 trial, has already received both fast-track and orphan drug status from the FDA. The gene therapy vectors used by Spark are engineered using a benign adeno-associated virus, or AAV, designed to encapsulate a genetic sequence and demonstrated to be effective vehicles for delivering genetic material into targeted cells. Spark expects that clinical data from the phase 3 trial will be available in the second half of 2015.

Since Spark was formed in October 2013 with $50 million in seed money from majority owner CHOP, it has attracted $72.7 million in venture capital financing and raised an additional estimated $161 million through a public stock offering that was completed in late January. The company trades on NASDAQ under the symbol ONCE, which indicates that SPK-RPE65 is seen as a cure and not as just a treatment for a chronic disease. Two other gene therapy companies also targeting serious retinal diseases — Avalanche Biotechnologies (Menlo Park, CA) and Applied Genetic Technologies Corporation (Alachua, FL) — went public in 2014.

“The FDA’s breakthrough therapy designation for SPK-RPE65 underscores the serious unmet medical needs faced by patients faced with genetic blinding conditions,” said Jeffrey D. Marrazzo, cofounder and CEO of Spark Therapeutics. “We look forward to working closely with the FDA to facilitate the review of SPK-RPE65 as we work to bring this potentially transformative treatment to patients.”

In addition to targeting the mutated RPE65 gene for IRDs, Spark also has product candidates in development for the treatment of additional blinding conditions, hematologic disorders, and neurodegenerative diseases. The company currently has about 50 employees.


Eylea highly effective in severe DME. Recently released 52-week data from the NIH-sponsored 660-patient Protocol T study of DME treatments indicated that a subset of patients with worse than 20/40 vision at baseline demonstrated unprecedented vision gains after being treated with Eylea (aflibercept, Regeneron). The mean change in this subset of 305 patients at 52 weeks was +19 letters, which was five letters better than Lucentis (ranibizumab, Genentech) and exceeded the gains reported in any previous clinical trial for DME treatments.

In patients with less severe vision loss (20/40 or better), Eylea, Lucentis, and Avastin (bevacizumab, Genentech) all demonstrated an approximately eight-letter gain at 52 weeks. All three therapies were deemed safe and effective.

The median number of protocol-specified Eylea injections reported over the 52-week period was nine, while the other two anti-VEGF therapies had a median of 10 injections.

The Protocol T data was initially published in the New England Journal of Medicine.

Eylea hits $1.74 billion in 2014 US sales. Regeneron Pharmaceuticals (Tarrytown, NY) reported that US sales of its Eylea anti-VEGF drug for retinal diseases increased by 23% in 2014 to $1.74 billion, while overall global sales of Eylea were $2.78 billion. The company expects that US Eylea sales will increase by 25% to 30% in 2015.

In related news, Regeneron said Eylea has been recommended for approval by the European Committee for Medicinal Products for Human Use (CHMP) for the treatment of visual impairment due to macular edema secondary to CRVO or BRVO.

The European Union (EU) submission is based on the previously approved indication for macular edema secondary to CRVO and the positive data from the phase 3 VIBRANT study.

Eylea is approved in the United States for the treatment of wet AMD, macular edema following RVO, and DME. Eylea has also been approved in the EU and other markets for use in wet AMD and DME.

Fellows Forum Celebrates 15 Years

Dr. Mark S. Blumenkranz gives guest lecture.

■ The 15th annual Fellows Forum took place in Chicago on January 23 and 24. Seventy-seven North American vitreoretinal fellows participated in a lively educational and social program that has become a seminal event marking the final year of vitreoretinal training.

As in past years, the fellows spent considerable time in the lecture hall with a faculty led by David Chow, MD, course director, and codirectors Carl Awh, MD, and Tarek Hassan, MD. This year’s faculty also included Maria H. Berrocal, MD, Dean Eliott, MD, Tamer H. Mahmoud, MD, PhD, Jonathan L. Prenner, MD, and J. Michael Jumper, MD.

The meeting began with a session primarily devoted to AMD. Controversies in the management of AMD, including the issue of prognostic genetic testing for AMD and genetic testing to select AREDS-type supplements, made for stimulating discussion. Additional discussions about retinal detachment and submacular hemorrhage highlighted differences in how the faculty treats similar problems.

The Friday evening reception and dinner provided the first opportunity for the “graduating class” of 2015 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 vascular occlusion, trauma, macular surgery, complex diabetic vitrectomy, and instrumentation. The afternoon concluded with a “Real World” panel discussion on getting started in practice, career advice, and life decisions.

The special guest speaker was Mark. S. Blumenkranz, MD, chairman of the Department of Ophthalmology at Stanford University and noted ophthalmic innovator and entrepreneur. Dr. Blumenkranz has been associated with a number of major ophthalmic innovations and has played a leading role in the development of such companies as Oculex, Peak Surgical, Optimedica Corporation, MacuSight, and Avalanche Biotechnologies.

The prestigious and competitive Fellows’ Forum Research Award went to Dr. Ashkan Abbey of Associated Retinal Consultants/William Beaumont Hospital for his paper, “Screening for Retinopathy of Prematurity: Evaluating Use of the ROP Tool in a Computerized Telemedicine System.” Dr. Abbey will present his paper at the 2015 Annual Meeting of the American Society of Retina Specialists in Vienna as a specially recognized lecture.

The meeting concluded Saturday evening with dinner, an informal awards ceremony, and the annual Retinal Fellows’ Forum Bowling Tournament. Fellows and corporate representatives were divided into teams captained by the faculty. The team of rookie faculty member Tamer Mahmoud, MD, emerged with a close victory.

2015 Retina Fellows’ Forum Faculty: Front: Jon Prenner, Maria Berrocal, Tarek Hassan. Back: Tamer Mahmoud, Carl Awh, Dean Eliott, Mike Jumper, David Chow, Mark Blumenkranz.

Genentech was the major corporate supporter of 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. These included Alcon, Alimera Sciences, Allergan, Bausch + Lomb, Carl Zeiss Meditech, Dutch Ophthalmic, Insight Instruments, Iridex, Keeler Instruments, MedOne Surgical, Oculus Surgical, Optos, Quantel Medical, Regeneron, Synergetics, ThromboGenics, Topcon Medical Laser, and Volk Optical.


Corrections & Clarifications

■ In the Jan./Feb. 2015 issue, the article “Steroids in Diabetic Macular Edema,” page 28, the wrong fluocinolone implant that was used in the FAME study was cited. The correct implant is the Iluvien implant (Alimera Sciences, Alpharetta, GA).

■ In the Nov./Dec. 2014 issue, “Subspecialty News,” page 14, the name of a company producing a retinal implant was misreported. The correct name of the company is Retina Implant AG (Reutlingen, Germany).

We apologize for the errors.


Allegro Has Asian Partner for Integrin Peptide Therapy

Hanmi will also make $20 million investment in Allegro.

■ Allegro Ophthalmics, LLC (San Juan Capistrano, CA), and Hanmi Pharmaceutical Co., Ltd. (Seoul, South Korea) have entered into a license agreement for Luminate (formerly known as ALG-1001), Allegro’s integrin peptide therapy currently in multiple phase 2 studies in the United States for the treatment of several vitreoretinal conditions. The license applies to the development and commercialization of Luminate in the Republic of Korea and the People’s Republic of China. Hanmi Pharmaceutical will also be making a strategic investment in Allegro that will advance and accelerate the global development program for Luminate.

Under the terms of the agreement, Hanmi is obtaining a license from Allegro for Luminate as an intraocular injection for vitreoretinal diseases, including DME, wet AMD, and vitreomacular traction (VMT). Hanmi Pharmaceutical has agreed to pay Allegro upfront license fees, sales milestone payments, and running royalties as a percentage of net sales. In addition to license rights for Korea and China, Hanmi Pharmaceutical will be making a $20 million strategic investment in Allegro.

“Luminate has shown great promise in clinical studies, and we anticipate that it soon will help the millions of patients with DME, AMD, and VMT in China and Korea regain and maintain functional vision, significantly improving their quality of life,” said Dr. Lee Gwan Sun, Hanmi president and CEO.

“Allegro is delighted to collaborate with Hanmi Pharmaceutical, an innovative and leading pharmaceutical company with a strong presence across Asia and a dedication to ophthalmology,” said Marc Kirshbaum, Allegro COO. “This strategic partnership is a validation of the clinical results to date and the potential of Luminate to be a valuable treatment option to millions of people who are at risk of vision loss and blindness, while providing Allegro with the capital required to significantly advance Luminate’s global clinical program across multiple indications and phases.”

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 (antiangiogenesis and vitreolysis), 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.

In 2013, Allegro licensed the Japanese rights to codevelop and market Luminate to Senju for what was termed “an eight-digit” upfront fee, additional milestone payments, and royalty fees.

In other Allegro news, the company was awarded a $2 million grant from the Helmsley Charitable Trust to support Allegro’s recently commenced phase 2 clinical trial using Luminate for the treatment of DME. This is the second grant to Allegro from the Helmsley Charitable Trust. RP


Fovista plus anti-VEGF effective in small trial. Ophthotech provided a stunning preview of the possible potential of anti-PDGF/anti-VEGF combination therapy for the treatment of wet AMD when Pravin Dugel, MD, of Retinal Consultants of Arizona, reported three-month results of his investigator-sponsored study during an Ophthotech conference call. Results from Ophthotech’s own phase 3 studies of its anti-PDGF/anti-VEGF combination will not be available until early 2016.

In reporting on the small pilot study undertaken by his practice, Dr. Dugel said that, of the 30 patients enrolled, 27 are classified as anti-VEGF-resistant, demonstrating little or no vision improvement after an average of 25 anti-VEGF injections. After three doses of combination therapy, they showed an average vision improvement of seven letters at three months. A 10-patient subset received additional Fovista pretreatment prior to beginning the combination phase and gained an average of 11+ letters after three months.

The three treatment-naïve patients in the study gained an average of 17+ letters after three months of combination therapy. The anti-VEGF agents being used in the pilot study are Avastin (Genentech) and Eylea (Regeneron).

Dr. Dugel cautioned that a much larger study is needed to confirm the results of his pilot study.