Geographic atrophy associated with age-related macular degeneration (GA) is a type of advanced age-related macular degeneration, or AMD. AMD is a disorder of the central portion of the retina in the eye, known as the macula, which is responsible for central vision and color perception. AMD affects vision in one or both eyes and results in progressive and chronic degeneration of the macula, often resulting in irreversible vision loss. AMD is a disease of aging, typically occurring after the age of 50. In the early stage of the disease, yellow deposits, or drusen, appear under the retina. Over time, the disease can progress to an intermediate stage where drusen deposits grow larger and other changes reflective of disease progression appear. Patients with intermediate AMD are at risk of progressing to GA or wet AMD. In contrast to intermediate AMD, these advanced forms are associated with progressive and often severe vision loss. GA is characterized by a degenerative process resulting in the progressive loss of retinal cells, which over the course of several years results in blindness. Wet AMD is characterized by the rapid abnormal growth of blood vessels beneath the retina. If left untreated, wet AMD rapidly progresses to severe vision loss. Wet AMD is typically treated with anti- VGEF therapies.
According to the American Society of Retina Specialists, approximately 15 million people in the United States have some form of AMD. Based on published studies, we believe that at least one million people in the United States have GA.
While the pathological mechanism of AMD is not fully understood, uncontrolled and excessive complement activation in AMD has been observed in a number of studies. Markers of complement activation have been found in drusen and multiple tissues of the retina of patients with AMD. In addition, multiple mutations in the genes associated with the complement pathway have been linked with the incidence of all forms of AMD. Related studies looking at the functional impact of these mutations on complement activation provide evidence for the role of uncontrolled and excessive complement activation in the disease process. Furthermore, antibodies against retina-specific phospholipids, which are indicative of immune dysfunction, have been found in patients with AMD and have been correlated with disease severity.
Current Therapies and Their Limitations
There are no therapies approved to treat GA. There are, however, a number of therapies in development for GA, the most advanced of which is lampalizumab, a complement factor D inhibitor being developed by Roche that is currently in Phase 3 trials. Although lampalizumab showed a treatment effect in its Phase 2 trial, it only had a treatment effect in patients with complement factor I (CFI), a component of the alternative pathway, and only when administered monthly, and it was not evaluated in patients with wet AMD in the fellow eye.
Benefits of Our Approach
We believe APL-2, with its inhibition of complement activation at the level of C3, may provide the following benefits:
- Prevention or Reduction of the rate of retinal cell death progression. We believe APL-2 may mitigate or prevent retinal cell death in GA. In our ongoing Phase 2 trial of APL-2 in patients with GA, treatment with APL-2 resulted in a significant reduction in the rate of GA lesion growth over 12 months.
- Potential application to all patients with GA independent of complement pathway causing disease progression. APL-2, by targeting C3, has been designed to inhibit all three principal complement activation pathways and may therefore be effective in a broad patient population. We plan to complete an analysis of the 12-month results of the trial, including genetic markers, in the fourth quarter of 2017 and expect that such analysis will be presented at an upcoming major medical meeting.
- Potential for every other month administration. In our Phase 2 clinical trial of APL-2 in GA, APL-2 met its primary endpoint in both the monthly and the every other month APL-2 administration treatment arms.