Figure 1. This eye was exposed to a Q-switched double Nd:YAG laser (532 nm). The macular lesion, originally corresponding in size to the laser beam's diameter (50 to 100 µm), spread to become disc sized (1,500 µm).
The term neuroprotection refers to the use of any therapeutic modality—external or internal to the affected neurons—that prevents, retards, or reverses apoptosis-associated neuronal cell death resulting from primary neuronal lesions. It is achieved by favorably altering the balance between survival and death processes resulting in the salvage, recovery, or regeneration of neurons and thus the structure and function of the nervous system. Because neuroprotection does not refer to the treatment of the causes of the disease but only to the manipulation of events that occur after the original lesion was initiated, the term thus does not apply to safety helmets or ocular hypotensive drugs.1
It is of historical interest that the possibility of neuroprotection was first realized by a glaucomatologist. In 1972, Becker tried to use hydantoin for treating visual field loss in primary open-angle glaucoma.2 A few years later, Astrup conceptualized secondary degeneration, and clinical trials soon started for the treatment of stroke.3,4
The realization that it is theoretically possible to arrest and perhaps reverse neurological lesions and their functional aftermath engendered intensive research activity spanning the entire spectrum of medical investigations, from in vitro and animal experiments to phase 1 (healthy volunteers), phase 2 (a few patients), and phase 3 (hundreds of patients) clinical trials. These investigations seeking potential cures for many previously untreatable neural diseases (eg, Alzheimer's and glaucomatous neuropathy) continue unabated to the present. Establishing a neuroprotective agent for clinical use, however, has proven unsuccessful thus far for a variety of reasons.
NEUROPROTECTION IN CLINICAL PRACTICE
More than 30 years of neuroprotective research and development have yielded few, if any, clinical benefits to patients. This unfortunate truth is in spite of the facts that neuroprotection, in its various forms, has repeatedly proven effective in tissue culture experiments and that hundreds of compounds have been successfully tested on animal disease models. Nevertheless, more than 100 neuroprotective drug candidates have failed phase 2 and 3 clinical trials. Only two have thus far been approved by the FDA, and both have limited efficacy. Riluzole for amyotrophic lateral sclerosis prolongs patients' lives by 2 to 3 months.5 Memantine is prescribed for moderate-to-severe Alzheimer's disease. It slightly benefits the areas of cognition, global assessment, and behavior, but the effects are not consistently significant.6
The last failure of a costly phase 3 study was that of NXY-059 free radical scavenger (AstraZeneca LP, Wilmington, DE) in acute stroke. NXY-059 did not significantly improve neurological function and did not affect subjects' mortality compared with a placebo.7 The most recent disappointing news in this sorry saga is that the glutamate antagonist memantine failed to exhibit a statistically significant effect on the functional measure chosen as the primary endpoint in the 4-year phase 3 study of primary open-angle glaucoma by Allergan, Inc. (Irvine, CA), a clinical trial that involved around 1,000 patients. In a number of analyses using the secondary functional measure, however, the higher tested dose of memantine exhibited a statistically significant benefit compared with a placebo.8 Nonetheless, like scores of other neuroprotective drug candidates, memantine did not fulfill its investigators' expectations despite the fact that all of the trials preceding the lengthy, expensive phase 3 study were successful, including a primate study.9
There is still some hope that memantine will prove effective in lowering the rate of visual decline in glaucoma. A paradigm shift expected in glaucoma therapy will probably not occur, however, and, for many years to come, glaucoma treatment will probably be restricted to lowering IOP when attempting to preserve glaucoma patients' vision.
WHY CLINICAL TRIALS HAVE FAILED
There are many reasons for the continuous, consistent failures of neuroprotective drug candidates in phase 3 clinical trials after they have exhibited effectiveness in earlier phases of drug development.
Therapeutic Index
These compounds have a relatively low therapeutic index. The secondary degeneration-inducing molecules such as glutamate have essential physiological functions, and effectively blocking them necessarily causes undesirable side effects.
Multiple Pathways
The process of secondary degeneration has multiple pathways. Blocking the activity of only one of those pathways (eg, blocking glutamate by using memantine) is therefore unlikely to effectively prevent continuous degeneration.
Molecular Size
Although various growth factors have been shown to be effective in arresting and even reversing neural degeneration, they are large molecules that do not traverse the blood/brain and blood/retina barriers.
Window of Opportunity
For acute diseases, there is the obstacle of time. Neuroprotective modalities are ineffective when administered more than a few hours after the onset of an acute disease. It is generally impossible to diagnose and treat a large number of patients having acute neural diseases such as stroke and even head trauma within such time constraints.
Heterogeneity
In the early phases of a drug's clinical development, the patient population is rather homogeneous. In contrast, the elderly patients who constitute the trial population in the large phase 3 trial are inherently heterogeneous, with many intercurrent diseases making uniform grouping difficult. Furthermore, the subjects usually receive multiple medications, some of them neuroprotective in themselves such as diazepam and its derivatives. Moreover, most of the neuroprotective drug candidates have multiple effects and possibly unknown interactions with the drugs used chronically by patients. As a result, the inclusion criteria in most relevant trials were too wide, thus limiting the likelihood of positive results. This considerably hampers neuroprotection trials in acute and chronic neurological diseases. In glaucoma, the parallel problem is the concurrent use of hypotensive drugs and the variable degree of IOP control, which necessarily alters the progress of damage to the nerve fiber layer.
Endpoints
Most of the trials were carried out on neurological diseases with their inherently imprecise, mostly subjective endpoints. This factor might explain investigators' ability to demonstrate the effectiveness of memantine in Alzheimer's disease but not regarding the visual fields in glaucoma.
Risk
Prolonged phase 3 studies, which are necessary for assessing novel interventions for chronic diseases, are both exceedingly expensive and risky. Pharmaceutical firms typically conduct two studies to meet the US Kefauver-Harris requirement and select a statistical power of 80% or higher. The NEI usually conducts one study at 90% power or more. Even at 90% power, however, there is a 10% chance that a study will fail to find a treatment with an appreciable difference between the new treatment and the negative control (G. Novack, PhD, written communication, February 2007).
COMMERCIAL CONSIDERATIONS
In addition to the scientific obstacles to finding a successful neuroprotective agent, there is a commercial one—an almost insurmountable difficulty to choose which of the hundreds of drug candidates to develop. Thousands of articles describing the successful results of neuroprotective research have been published. For instance, in the week ending on February 11, 2007, 17 articles related to neuroprotection were published that mentioned no fewer than 13 compounds shown to be neuroprotective, from melatonin to the heat shock protein HSP90. The intense interest in this subject is well illustrated by the ARVO Annual Meeting during the last 5 years; neuroprotection-related presentations constituted 2% to 3% of all presentations, with more than 100 neuroprotective compounds and interventions described in 2005 alone.
The problem of selection is compounded by the fact that there is no generally agreed upon model for accurately comparing the efficacy of neuroprotective compounds. How can a drug company executive choose the right compound in which to invest the hundreds of millions of dollars for research and testing that are required to reach FDA approval?
THE FUTURE
There is still hope that neuroprotection can provide an entirely new approach to glaucoma treatment to complement the reduction of IOP and thus improve the currently less-than-satisfactory results in preventing glaucomatous optic neuropathy and blindness. Reading the literature on this subject raises the following suggestions.
First, standardizing the animal glaucoma model would allow the large number of available neuroprotective candidates to be screened accurately and compared. Second, only highly efficacious compounds should be selected for FDA clinical trials, or the chances of clinical proof of success will be low. Third, the randomized, controlled, phase 3 clinical trials should be of sufficient size to ensure clinically meaningful results, despite the inherent variability of the patient population.
In addition, trials should enroll patients with rapidly deteriorating visual fields, and investigators should rigidly adhere to the inclusion and exclusion criteria as well as to strictly and frequently monitored IOP control. Moreover, the use of surrogate imaging endpoints for clinical trials might not lead to a drug's FDA approval, but it might weed out ineffective compounds more quickly and cheaply than at present.
Radically new approaches to neuroprotection would include using a modality that simultaneously and continuously modifies more than one of the pathways of secondary degeneration with intrinsic control of activity, for example, via a neuroprotective vaccination.10 Alternatively, researchers might evaluate the use of growth factors such as brain-derived neurotrophic factor and ciliary neurotrophic factor. Despite some concerns in the past, intravitreal injections can deliver large molecules to the retina, either directly or by cells transfected with proper genes. Striking results were obtained when the latter method was tested on patients with retinitis pigmentosa.11 Finally, stem cells might replace damaged ganglion cells and perhaps restore patients' vision,12 as occurred in mouse models of retinitis pigmentosa13 and ischemic retinopathy.14
Michael Belkin, MA, MD, is Professor of Ophthalmology and Director, Ophthalmic Technologies Laboratory, Goldschleger Eye Research Institute, Tel Aviv University, Sheba Medical Center, Tel Hashomer, Israel. He acknowledged no financial interest in the products or companies mentioned in this article. Dr. Belkin may be reached at +972 3 530 2956; belkin@netvision.net.il.
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