BANGOR, Maine (WABI) Geographic Atrophy Now in Researchers' Sights
Healthy Living - June 12, 2018
Michael Johnson, MD - Eastern Maine Medical Center
With no FDA-approved therapies yet for the treatment of geographic atrophy (GA), some companies and institutions, eager to change that fact, are initiating or resurrecting past research approaches to discern effective methods of combating this advanced form of dry AMD. Aptly alphabetical, the multiple investigational therapies being studied range from A (APL-2, Apellis Pharmaceuticals, Crestwood, KY) to Z (Zimura, Ophthotech, New York).
The treatment types also cover a wide range. These include complement inhibitors, neuroprotectives, cell therapy, approved drugs for other disorders, and a peptide that blocks the FAS pathway to stop photoreceptor cell death.
Inhibiting Complement Factors
The most common targets for investigational GA therapies are the complement factors and complement factor pathways that have been shown to play a role in the development of retinal diseases. While part of the normal immune system, these factors and pathways can also get out of control in some individuals. The complement system can be subject to excessive and uncontrolled activation, generating mutant proteins that contribute to retinal disease.
The following investigational drugs - all delivered by intravitreal injection - target the complement system:
Lampalizumab (Genentech, South San Francisco), is an antigen-binding fragment of a humanized monoclonal antibody, and will be tested in two identical, 900-patient, phase 3 trials, CHROMA and SPECTRI. These will encompass a wide range of endpoints, including BCVA, low-luminance visual acuity, reading speed, and patient-reported outcomes.
Zimura is an aptamer that inhibits the complement C5 pathway. A phase 2/3, 300-patient clinical trial started last January. The primary endpoint will be BCVA at two years. Though Zimura is dosed as monotherapy in this trial, it is also being studied in combination with anti-VEGF agents in wet AMD with a goal of reducing the treatment burden.
CLG561 and LFG316 (Alcon, Fort Worth, TX) are also aimed at the complement pathway in GA, but with different targets. CLG561 inhibits a complement pathway protein called properdin, while LFG316 is a monoclonal antibody designed as a complement C5 inhibitor. In a proof-of-concept 114-patient study, Alcon is looking at CLG561 as both a monotherapy and in combination with LFG316.
APL-2 is a conjugate of a synthetic cyclic peptide that broadly targets the complement cascade at the C3 level, where three complement pathways converge. Apellis believes its approach can block all effects of the complement cascade regardless of which pathway excessively or uncontrollably activated the complement.
Almost a decade ago, Allergan (Dublin) began to study its glaucoma drug brimonidine (now known as Alphagan) as a potential treatment for Geographic Atrophy because it had demonstrated neuroprotective qualities in the company's animal studies. In addition, the specific receptor target of brimonidine is in the retina, which is important in achieving optic neuroprotection.
In a 119-patient study begun in 2008, the drug, an alpha-2 adrenergic receptor agonist, was delivered via an intravitreal implant at higher concentration than its usual use as a topical glaucoma treatment. At one year, results were equivocal and a second clinical trial was indicated to obtain stronger data.
Blocking the FAS Pathway
David N. Zacks, MD, PhD, of the Kellogg Eye Center, University of Michigan, has spent more than 15 years studying photoreceptor cell death and its impact on vision loss. His conclusion: Inhibiting the FAS-pathway through medical intervention is key to stopping unwanted photoreceptor cell death (apoptosis) in retinal detachment, wet and dry AMD, geographic atrophy, and diabetic retinopathy. Though blocking the FAS pathway is a specific therapeutic goal, it could well come under the broader category of neuroprotection.
The first human clinical trials of the neuroprotective ONL1204 peptide drug that Dr. Zacks' spin-off company ONL Therapeutics (Ann Arbor, MI) will be conducting are still at least one year away. The 25,000 annual US cases of "macula-off" retinal detachment are the initial targets. This is an area of treatment for which surgical results have been excellent, but visual outcomes almost uniformly poor, with average BCVA at one year after surgery at 20/70 - with many patients' visual outcomes much worse than that.
Dr. Zacks says ONL1204 should also be able to provide neuroprotection in geographic atrophy, treating the root cause of vision loss which is photoreceptor cell death.
The Janssen (Beerse, Belgium) drug development division of Johnson & Johnson has for several years been pursuing an initiative using cell therapy in an attempt to reverse the vision loss associated with geographic atrophy.
In the earlier 35-patient trial, the mean BCVA gain at one year was more than four letters, while 25% of the patients gained three lines of vision or more. The average vision loss at one year was two letters for untreated fellow eyes.
As to whether he expected these preliminary results to be replicated in the larger trial, Dr. Ho says he is hopeful.
Patients in the PRELUDE study will get a single injection of 60,000 cells, 300,000 cells, or sham. Cell therapy can have either a regenerative or trophic approach, says Dr. Ho.
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.
Previously Approved Oral Drugs Studied
Clinical trials for Geographic Atrophy are being conducted for three oral drugs that are FDA-approved for other indications.
The National Eye Institute is conducting a study in which 40 patients will be given 100 mg of the antibiotic Minocin (minocycline) twice daily for 36 months. Minocycline has demonstrated neuroprotective and anti-inflammatory properties in neurodegenerative diseases such as Parkinson's and Huntington's, and is being studied for potential use in Alzheimer's.
The primary endpoint for this study is the rate of change in the area of GA at 24 and 36 months. Secondary endpoints include number of adverse events, change in BCVA, and change in low-luminance BCVA.
Oracea (doxycycline) is an anti-inflammatory indicated for treatment of rosacea. Paul Yates, MD, PhD, of the University of Virginia, the University of Virginia Department of Ophthalmology, and the Medarva Foundation are conducting this ongoing, 206-person, 31-month study. The goal is to slow disease progression. Patients take one 40 mg Oracea capsule daily for 24 months. The primary endpoint is the rate of enlargement of the area of GA at 6 and 30 months. A secondary endpoint is change in BCVA at 6 and 30 months.
Metformin (Glucophage, EMD Serono, Inc., Rockland, MD) a widely used first-line treatment for type 2 diabetes, belongs to the biguanide class of antidiabetic, sugar-lowering drugs. The University of California, San Francisco, is sponsoring a 100-patient, 18-month phase 2 study to determine if oral metformin can decrease the rate of Geographic Atrophy progression in nondiabetic patients. Fifty patients will be given increasing doses of metformin and another 50 will be observed only. The metformin patients will start on a low dose to avoid gastrointestinal discomfort.
Drug researchers use the term "shots on goal" to discuss the number and variety of therapeutic approaches aimed at any specific disease. Their reasoning is that, with many varied concepts in play, it increases the chances of success in combating the disease. Given the myriad approaches described above, it's clear that researchers are serious about crashing the net. Only time will tell if any succeed with a breakaway.