Ageing has many biological consequences, ranging from the merely annoying through to conditions that profoundly affect everyday living. The eye is a complex organ and susceptible to a variety of age-related conditions, including cataract formation, glaucoma, dry eye syndrome and loss of retinal function.
Age-related macular degeneration (AMD) is a progressive loss of function of the macula, the central portion of the retina responsible for precise vision. The condition starts with the accumulation of fat and protein waste- "drusen" in the subretinal space, causing a loss of essential pigmentation in the retina. The majority of individuals with AMD experience a slow decline in visual acuity- "dry" AMD, but around 10-20% experience acute and catastrophic loss of vision through the formation of new, leaky blood vessels below the retina- neovascular or "wet" AMD.
New blood vessel formation in AMD (and in several types of solid tumours) is stimulated by vascular endothelial growth factor (VEGF). Anti-VEGF drugs have proved reasonably effective over the last decade in slowing the progress of wet AMD when injected into the eye . A variety of other agents targeting VEGF are in clinical development, including brolucizumab (Novartis); RG7716 (Genentech) and abicipar (Allergan).
Unfortunately, no single point of attack is established for dry AMD. Nutritional supplements can slow AMD progression, presumably through reducing oxidative stress (diet, smoking and cardiovascular disease are all implicated as risk factors for drusen formation), but, being an inflammatory condition, a variety of immune mechanisms are likely to contribute to macular damage.
The alternative complement pathway serves as a first line defence against infection and kicks in before the body mounts a specific immune response. On the back of a strong correlation between AMD and genetic changes in complement regulatory proteins, targeting various complement proteins provides a rational basis for AMD therapy development.
A clinical study with eculizumab, an antibody approved for another complement-mediated condition, failed to show benefit but some progress has been made with other complement-directed agents. Until last week, lampalizumab (Roche) was widely regarded as the first drug to be approved for late-stage dry AMD; unfortunately, treatment for 48 weeks did not show any improvement over placebo. A second Phase III study in ongoing but further development (and a marketing approval submission) will depend on establishing beneficial effects on visual acuity.
Lampalizumab acts by targeting complement factor D, while other investigational agents are specific for other complement proteins. Opthotech's Zimura (a non-antibody drug) binds to C5, as does tesidolumab (Novartis) while APL-2 (Apellis Pharmaceuticals) targets C3. These other complement directed therapies might yet prove to be effective in AMD, although the decline in Opthotech's share price suggests investor nervousness over the approach.
Discontinuation of lampalizumab development could effectively dry up the AMD clinical (and pre-clinical) pipeline should it take the other complement inhibitors with it. A few AMD studies with repurposed drugs are ongoing and stem cell implantation might eventually prove capable of restoring some degree of vision to a handful of fortunate individuals, but there is little in the late stage development pipeline that offers any cheer for the three million or so individuals in Europe and the US handicapped by late-stage AMD.
A new generation of AMD candidates awaits better understanding of the retinal microenvironment in disease, particularly an unravelling of the role of macrophages in the inflammatory process, alongside the contribution made by genetic and environmental factors.
Photo credit: National Eye Institute, National Institutes of Health