In determining who is at risk for such serious, vision-robbing inherited retinal diseases as retinitis pigmentosa (RP) and Leber’s congenital amaurosis (LCA), genetic factors and family history always top the list. However, until recent years, the risk factors for more common retinal diseases, such as macular degeneration, were more closely associated with age, smoking, diet, high blood pressure, diabetes, cardiovascular disease, and exposure to the sun. Though genetics made the list, it was one of many risks to be considered.

But that perception is changing as newer studies indicate a broader role for genetics in determining who is most at risk for the more common retinal diseases and in developing new therapies that can be most effective in treating patients with specific genetic profiles. To that end, companies are pursuing initiatives that advance the use of genetic information in the diagnostic and treatment process. And notably, at the recently concluded ARVO 2017 meeting, six of the nine featured lectures focused on various aspects of genetics and their relevance in ophthalmic research. Here are a few examples of how the area of genetics is influencing efforts to combat retinal disease:

Commercial genetic testing. Arctic DX, a genetics testing company, is teaming up with ophthalmologists to offer a relatively simple, low-cost test (a cheek swab taken in the doctor’s office) designed to evaluate the risk profile of individuals who have either been recently diagnosed with AMD or who have a family history of AMD. The test, Macula Risk PGx, is prognostic of the risk of progression to advanced AMD and aids in the selection of eye health supplement formulations appropriate for individual patients.

Genotyping clinical trial subjects. Genentech genetically profiled every patient in its phase 2 MAHALO clinical trial using the drug lampalizumab for dry AMD and geographic atrophy and found that specific genetic subsets of patients — those with complement factor I (CFI) — attained more therapeutic benefit from the drug than other subsets. Genentech believes this was the first ophthalmic clinical trial in which all patients were genetically profiled.

Lampalizumab is now in two major, pivotal phase 3 clinical trials, CHROMA and SPECTRI, encompassing a total of 1,872 patients.

“MAHALO contained some interesting findings regarding genetic factors and subsets of patients, but it was a smaller study, and the findings have to be confirmed in the large-scale phase 3 studies,” said Anthony P. Adamis, Genentech’s global head of ophthalmology, immunology, infectious disease and metabolism, clinical science.

An important new study is also genetically profiling all participants. The study, called Proxima A, is led by Brandon Busbee, MD, of Nashville, TN, and will eventually enroll approximately 360 individuals with geographic atrophy to follow the course of their disease over 48 months. Thus far, 173 participants have been genotyped, with about half presenting with the complement factor I biomarker.

Building genetic databases for drug development. Three years ago, Regeneron began a collaboration with Geisinger Health System to genetically profile at least 150,000 individuals to develop a database for future drug development that encompasses genetic factors. During the initial 5-year collaboration term, Geisinger plans to collect samples from consenting patient volunteers, while Regeneron, through its subsidiary, Regeneron Genetics Center LLC, will perform sequencing and genotyping to generate de-identified genomic data. The size and scope of the study are meant to facilitate precision in identifying and validating the associations between genes and human disease.

More recently, Regeneron and GSK have embarked on an even more ambitious project to genetically profile 500,000 individuals in the United Kingdom over the next 3 to 5 years to identify promising paths for drug development.

Genotyping candidates for eye health supplements. Some members of the retina community are now advocating that at-risk patients who are considering taking eye health supplements for macular degeneration should first be genetically profiled to determine whether the supplements would be of any benefit. This position has sparked fierce debate in the retina community, with studies on the merits of supplements for specific patient cohorts being both cited and challenged (See “Debate Over Supplements and Genetic Tests”, page 10).

TOWARD MORE PERSONALIZED THERAPIES

Researchers are looking for genetics to provide the key to more personalized therapeutic options tailored to the needs of individual patients. Since the advent of anti-VEGF drugs for retinal disease about a decade ago, practitioners have been puzzled as to why a third of their macular degeneration patients receive very little or no benefit from these therapies. This despite the fact that almost all of their patients show the same manifestations of retinal disease — vision loss, increased macular thickness, and subretinal fluid.

Although macular degeneration patients clinically present similarly, 40% respond differently to the same drugs and dosages,¹ says Pravin Dugel, MD, of Retinal Consultants of Arizona and a lead investigator in many clinical trials for retina drugs.

In the future, personalized medicine specifically tailored to the individual may be the answer to containing costs, while also improving the quality of care.

“What we’re realizing is that we need to look at the genotype of the patient and personalize the diagnostics and therapeutics for that particular person,” Dr. Dugel says.

In that regard, the MAHALO trial may prove to be a true landmark study for more personalized therapies if the phase 2 findings are confirmed in the much larger phase 3 trials.

The phase 3 study program will evaluate the safety and efficacy of lampalizumab and its potential to slow the progression of geographic atrophy (GA). The studies will also further explore whether people with a specific genetic biomarker, a mutation in complement factor I, may benefit more from lampalizumab treatment. No approved treatment currently exists for GA.

The MAHALO phase 2 primary endpoint showed a 20% reduction in GA lesion progression in patients treated monthly with lampalizumab as compared with sham at month 18. Additionally, data from a subpopulation of GA patients receiving monthly lampalizumab who were positive for the CFI biomarker demonstrated a 44% decrease in the rate of disease progression at 18 months. This exploratory biomarker analysis will be further evaluated in the phase 3 study.

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

GENE THERAPY AND GENE EDITING

Some of the most ambitious initiatives aimed at curing retinal disease with a single procedure are in the relatively new fields of gene therapy (replacement of a defective mutated gene) and gene editing (replacing the part of the gene that has caused the disease). Most of the current efforts in gene therapy target the rarer “inherited retinal dystrophies,” such as RP, LCA, achromatopsia, and x-linked retinoschisis. Leading companies in gene therapy include Spark Therapeutics, AGTC, and Advernum (formerly Avalanche). Companies prominent in gene editing include Editas, Intellia, and CRISPR. Editas recently announced an extensive drug development partnership with Regeneron.

Spark Therapeutics is the furthest advanced company in gene therapy, having completed a successful phase 3 clinical trial for RPE365-mediated inherited retinal dystrophy that met the endpoint of improved visual function and mobility. The trial involved the delivery of restorative genetic material via an adeno-associated viral vector to 31 patients with Leber’s congenital amaurosis. Spark has already commenced an FDA filing for the RPE365 indication and is likely to have the first FDA-approved indication for the use of gene therapy. The company also started a free screening program called “ID Your IRD” to help individuals identify the genetic profile of their inherited retinal dystrophy.

STEM CELL THERAPY: MUCH TO BE LEARNED

Stem cell therapy represents another promising concept (See “The Truth About Stem Cells,” page 4) for the longer term but many of the basic aspects of stem cell therapy that directly affect safety and efficacy remain unproven. For example: Should existing cells be replaced or can they be stimulated to repair themselves? Should the cells be taken from the patient’s body or from an outside source? And what type of stem cells would be most safe and effective for a particular indication?

One of the most advanced stem cell trials is being conducted by the Janssen drug development division of Johnson & Johnson. For several years, Janssen has been pursuing an initiative using cell therapy to attempt to reverse the vision loss associated with geographic atrophy.

After an encouraging but preliminary and uncontrolled small phase 1/2 clinical trial, Janssen has moved its proprietary cell therapy CNTO 2476 into the major 255-patient phase 2b PRELUDE study. Following some instances of retinal detachment in the earlier trial, a new subretinal delivery system and some changes in the surgical procedure have been implemented for the PRELUDE trial, according to the company.

In the earlier 35-patient trial, the mean BCVA gain at 1 year was more than four letters, while 25% of the patients gained three lines of vision or more. The average vision loss at 1 year was two letters for untreated fellow eyes.

Patients in the PRELUDE study receive a single injection of 60,000 cells, 300,000 cells, or sham and will be evaluated at 6 months and 1 year. Cell therapy can have either a regenerative or trophic approach. In the regenerative approach, the transplanted cells are meant to take the form of the dead or damaged native photoreceptor cells. With the trophic approach, the new cells are intended to support, repair and rescue the native photoreceptor cells but remain differentiated from the native cells. The PRELUDE study uses a trophic approach.

Janssen selected human-derived umbilical cells for these studies because they were judged as having the best chance of being effective of the four cell types tested.

FUTURE IS BRIGHT FOR GENETIC RESEARCH

Almost all of the genetics-related initiatives described in this article are recent in nature, and not all will prove fruitful. However, more and more research efforts are now focused on the premise that retinal disease is highly individualized, and must be approached as such. This thesis is borne out by the widely varying range of efficacy of anti-VEGF therapies with specific patients. Thus, the broad spectrum of opportunities in genetic research offers many potential avenues to achieving a more personalized and rewarding approach to combating retinal disease. NRP

REFERENCE

1. Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537-2548.