184.108.40.206.1 Dry age-related macular degeneration
Perhaps the most significant hurdle for dry AMD clinical trials is that disease onset occurs late in life as a cumulative result of chronic damage to the RPE cells and their dependent photoreceptors. Most dry AMD patients are likely unaware of their disease until visual acuity begins to decline, at which point substantial morphological damage and dysfunction have occurred. It is thus unclear that intervening in a recognized AMD risk-increasing pathway (e.g., by administering an anti-inflammatory drug or by cessation of smoking) will work at this late stage. Since the RPE, photoreceptors, and Bruch's membrane target tissue are in the posterior segment of the eye, delivering an efficacious NCE concentration is usually ineffective using a topical eyedrop and instead requires locally invasive (e.g., intraocular injection) or systemic methods. On the positive side, since the most important disease risk factor is aging, a therapy that slows but does not arrest or reverse progression of dry AMD and its transition to wet AMD could still effectively prevent disease-induced blindness for many people due to life expectancy considerations (i.e., patients die of old age before they become blind). In addition, clinical determination of functional improvement using visual acuity testing is straightforward.
Although clinical trials for several different approaches to treat dry AMD could in theory be justified based on clinical observations and preclinical research (e.g., statins, apoptosis inhibitors, and anti-inflammatory drugs), there are only a few methods currently being investigated in clinical trials. One is the use of the carotenoid pigment, lutein (Figure 4) as an oral supplement. In theory the anti-oxidant and preferential retinal accumulation properties of lutein would be expected to have a salutary effect on dry AMD progression, but the unexpected negative effect of b-carotene consumption on lung cancer development in smokers counsels caution.
Another method being studied is the use of a blood filtration procedure called rheopheresis. In rheopheresis blood is removed from the patient, the platelets and plasma are separated, the plasma is filtered through a membrane designed to remove high molecular mass proteins, including low-density lipoprotein (LDL), and the platelets and plasma are reintroduced into the patient. The rationale behind this treatment can be summarized as follows: removal of high molecular mass proteins from blood leads to decreased blood viscosity and increased leaching of the same high molecular mass, permeability-decreasing proteins from Bruch's membrane. This in turn leads to improved diffusional exchange of oxygen/nutrients and waste products between the choroidal capillaries and the RPE through Bruch's membrane, and finally disease arrest. In a 43-patient study where eight rheopheresis filtrations were performed over 10 weeks, the treatment group demonstrated enhanced visual acuity compared with controls after 1 year.54 Note that the functional benefit of treatment versus placebo was evident even though the rheopheresis group received no treatment for more than four-fifths of the time (42/52 weeks). Although the procedure has several drawbacks (e.g., a several hour filtration and reinfusion timeframe, intravenous intervention, and contraindication in those patients without adequate venous access), if the clinical benefit is confirmed in larger phase III clinical trials this could represent a major advance in dry AMD treatment.
Due to the more rapidly progressing nature of wet than dry AMD, the most important clinical goal is to slow significantly CNVand the associated loss of visual acuity. As is the case for dry AMD, drug delivery remains a difficult issue, with intravenous and intraocular injection methods predominating in current clinical trials. An advantage for clinical trials for wet as opposed to dry AMD treatment is the more detailed knowledge of the immediate causes for the
Figure 4 The structure of the carotenoid pigment lutein.
Figure 4 The structure of the carotenoid pigment lutein.
former, largely due to research on cancer angiogenesis. Antiangiogenic agents to treat cancer also provide a pool of potential anti-wet-AMD therapeutics, e.g., squalamine, pegaptanib sodium, and ranibizumab.55
Table 1 summarizes ongoing and recently completed FDA-approved clinical trials for the treatment of wet AMD as of mid-2005 with structures shown in Figure 5.
Two important goals of potential anti-wet-AMD therapeutics in clinical trials are the ability to improve visual acuity and the use of a noninvasive, preferably local delivery method. With respect to the first objective, recently released phase III clinical data for the anti-VEGF antibody, ranibizumab55 demonstrated that patients had improved, while the untreated control group had worse, visual acuity scores after receiving therapy. This is the first anti-wet-AMD therapy to demonstrate functional improvement in patients instead of only slowing loss and may represent an important therapeutic advance.
With respect to the second aim, there are a variety of drug-delivery methods being investigated for wet AMD treatment, including: topical ocular application (none yet in humans, but see ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and nepafenac information below), noninvasive posterior segment delivery as in a juxtascleral depot (e.g., anecortave acetate), oral delivery (e.g., celecoxib), intravitreal injection (e.g., ranibizumab), intravenous infusion (e.g., squalamine), and the use of a drug-impregnated intravitreal insert device (e.g., fluocinolone). While each of these methods has associated benefits and risks, in general the ideal is topical ocular application for reasons of convenience and minimization of local and systemic side effects. Although this is widely perceived to be a daunting problem in the art, recent publications indicate that this is surmountable.56 Topical ocular application of recombinant CNTF provided almost complete functional and morphological retinal protection in streptozotocin-induced diabetic rats,57 and topical ocular application of NGF to adult rats efficiently delivered the protein to the retina and ONH.58 With respect to small molecules, topical ocular delivery of the nonsteroidal anti-inflammatory drug nepafenac,
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