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) to Z (Zimura, Ophthotech).
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.
This article will identify, describe, and categorize the specific therapies being studied for this an increasingly prevalent, often blinding disease.
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. This point was proven more than a decade ago by Gregory Hageman, PhD, now of the University of Utah Moran Eye Center, and since documented in numerous studies: 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), 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. This comprehensive approach is a nod to those researchers who have asked for more metrics to fully assess the level of overall visual impairment (not just central vision) and the rate of disease progression.
Lampalizumab targets complement factor D and the alternative complement pathway, which have both been implicated in AMD pathophysiology. In the phase 2 MAHALO study, in which all patients were genetically typed, lampalizumab demonstrated overall effectiveness but was particularly effective with a subset of patients who were found to have Complement Factor I. Genentech researchers say this finding may lead to the use of genetic typing in more clinical studies of retinal disease.
Zimura (Ophthotech) is an aptamer that inhibits the complement C5 pathway. A phase 2/3, 300-patient clinical trial started in 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) 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 Apellis) 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 began to study its glaucoma drug brimonidine (now known as Alphagan) as a potential treatment for GA 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.
This second study, called BEACON, has 311 patients. This study is ongoing, with each patient receiving 400 microns of brimonidine via intravitreal implant every three months for 21 months. Primary endpoint is change in the GA lesion area at two years. Secondary endpoints are change in BCVA and change in low-luminance BCVA.
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 will be conducting are still at least a 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.
"The photoreceptor cell death that takes place between the time the retinal detachment occurs and the reattachment surgery is significant," says Dr. Zacks. "That lost vision is not being regained. Our goal is to get our ONL1204 drug [an analog of the small-molecule peptide Met12] injected into the patient's eye as quickly as possible to shut off the FAS pathway and stop the cell death, which should allow much better visual outcomes in retinal detachment surgery."
Dr. Zacks says ONL1204 should also be able to provide neuroprotection in geographic atrophy, treating the root cause of vision loss in GA, which is photoreceptor cell death.
The Janssen drug development division of Johnson & Johnson has for several years 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. Because there was a 15% incidence of retinal detachment in the earlier trial in which the human-derived umbilical cells were inserted by micro-catheter, a new subretinal delivery kit and some changes in the surgical procedure have been implemented for the PRELUDE trial, says Allen Ho, MD, of Wills Eye Hospital, the lead investigator for both studies.
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.
Asked whether he expected these preliminary results to be replicated in the larger trial, Dr. Ho said he was 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 for Studied for GA
Clinical trials for GA 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 such neurodegenerative diseases as Parkinson's and Huntington's, and is currently 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 206-person, 31-month study, which is ongoing. 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 six and 30 months. A secondary endpoint is change in BCVA at six and 30 months.
Metformin (Glucophage, Merck) 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 GA progression in nondiabetic patients. Fifty patients will be given increasing doses of metformin and another 50 will be observation only. The metformin patients will start on a low dose to avoid gastrointestinal discomfort.
Then There Was One
One drug that was tried but failed is Emixustat Hydrochloride, a visual cycle modulator from Acucela. This oral drug did not meet its primary endpoint in a phase 2b/3, 508-patient clinical trial earlier this year. Acucela had partnered with Otsuka for development of this drug, but that partnership has been terminated. Acucela said it is continuing to review the data from the trial.
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. RP