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Significant strides have been made in the understanding and treatment of neovascular age-related macular degeneration (AMD). Two anti-VEGF medications are approved for use by the US Food and Drug Administration for treatment of wet AMD: ranibizumab (Lucentis; Genentech) and aflibercept (Eylea; Regeneron). Strong data from well-controlled clinical trials indicate that, if treatment is initiated with anti-VEGF drugs early in the disease cycle, there is a high likelihood that disease progression can be stopped and patients can regain visual acuity.1
There are no similar options for patients with the dry form of AMD at this time. In about 90% of patients, dry AMD does not cause vision loss; in the absence of visual symptoms, patients can be observed and no treatment is necessary. However, for the 10% of so of patients with dry AMD who experience visual symptoms, there is no treatment that slows the disease or preserves or restores vision. Management strategies for dry AMD are akin to those available for wet AMD before the introduction of anti-VEGF drugs; laser is sometimes useful, but the best that can be hoped for is to slow progression.
Results from a phase 2 clinical trial of the drug lampalizumab (Genentech/Roche) now offer a sense of optimism for treatment of dry AMD. The MAHALO study demonstrated that lampalizumab was well tolerated and that it slowed progression of geographic atrophy (GA) in AMD.2 A phase 3 trial is enrolling patients, with enrollment expected to be completed by the second quarter of this year.
Dry AMD is characterized by the accumulation of drusen on the retinal surface. The exact etiology of drusen and their correlation to loss of visual potential is unknown. However, it is understood that drusen formation is not mediated by VEGF, and, therefore, anti-VEGF therapy is ineffective. Studies in which laser was used in an attempt to clear drusen have been largely unsuccessful; even in trials in which laser successfully removed drusen, no correlation with improving vision or stabilizing the disease was seen.
GA is an advanced stage of dry AMD. It is characterized by loss of neurosensory retina and damage to the retinal pigment epithelium (RPE). Patients with GA may develop a central scotoma and thereby lose central vision. Several pathways have been implicated in the development of GA, most notably the alternative complement pathway. It is believed that upregulation of inflammatory markers plays a significant role in the formation of GA and subsequent vision loss.3,4 Genetic factors also appear to play a role: individuals who are positive for the gene that codes for protein CFI or complement factor I appear to be at greater risk for activation of the alternative complement pathway.
Although the complement pathway plays a crucial role in regular immune function, overexpression of local inflammatory markers may trigger the cascade of events that leads to dry AMD and subsequent GA. Histopathology studies have identified elements of complement proteins in drusen; however, it is unclear what role, if any, complement plays in drusen formation.
Lampalizumab is an antigen-binding fragment. It is a humanized monoclonal antibody that is directed at complement factor D (CFD) to prevent it from binding with complement factor B (CFB). Activation of CFD would yield formation of the enzyme C3 covertase (Figure); in turn, C3 convertase helps to transform protein C3 into C3a, which is responsible for inflammation, or C3b, which is responsible for opsonization.
Once it is activated, C3 convertase can loop back to produce more inflammation and subsequently greater upregulation of C3 in a vicious cycle. This sequence likely plays a crucial role in the progression of GA. Therefore, inhibition of CFD in a rate-limiting fashion at an early point in the complement cascade (ie, the mechanism of action of lampalizumab) appears to be an advantageous therapeutic target to reduce inflammation related to C3a and C5 convertase, the latter of which is vital in formation and activation of membrane attack complex, or MAC. Another plus for lampalizumab is that it preserves the classical and lectin pathways, both of which are crucial for regular immune function.
CLINICAL TRIAL PROGRAM
In the phase 2 MAHALO study, no unexpected or unmanageable serious adverse events were associated with lampalizumab. Active treatment was associated with a 20.4% reduction in GA area at 18 months. Benefits were especially pronounced among individuals who were CFI-positive; they experienced a mean 44% reduction in GA progression by the end of the study. In a subset analysis of patients who were CFI-positive and who had baseline visual acuity of between 20/50 and 20/100, progression of GA area was reduced by a mean 54%.
Based on these results, the drug’s sponsor decided to move forward with a phase 3 study program, composed of four individual studies. The first two, CHROMA (NCT02247479) and SPECTRI (NCT02247531), are identical, parallel, interventional studies that will each enroll approximately 936 patients in four study arms (188 biomarker-positive patients and 124 biomarker-negative patients in each arm of each study). Patients will be randomly assigned 2:1:2:1 to lampalizumab 10 mg every 4 weeks, sham treatment every 4 weeks, lampalizumab 10 mg every 6 weeks, or sham every 6 weeks. The primary endpoint is mean change in GA lesion area from baseline to 1 year.
A second set of studies, Proxima A and Proxima B, will be observational studies that will add important information to the current understanding of dry AMD and GA. In these trials, for the first time, patients with GA will be studied in a prospective fashion using the most current diagnostic modalities. No previous study has followed patients with GA prospectively using autofluorescence, reading speed, and other measures to see how GA affects vision. Proxima A will enroll 360 individuals, 240 of whom are positive for the CFI gene and 120 of whom are negative; patients must have bilateral GA without choroidal neovascularization. Among other things, this trial will offer insights into the role of genetics in this disease. Proxima B will enroll 200 patients who have unilateral GA without choroidal neovascularization or who have GA with choroidal neovascularization in the fellow eye.
The overall lampalizumab phase 3 clinical trial program, including the four trials described herein, will help to answer several important questions regarding GA. With respect to treatment, GA remains a tremendous unmet need in retinal medicine. If data from the phase 3 trials of lampalizumab are positive, then a viable treatment strategy may soon be available for patients who now have few options for preserving vision. The interventional studies will show us whether this new treatment paradigm for dry AMD will be somewhat analogous to anti-VEGF therapy for wet AMD. These studies should also help establish whether the alternative complement pathway is, in fact, a viable therapeutic target.
The planned observational studies are an additional benefit of the clinical trial program. Proxima A and B promise to offer a wealth of understanding regarding the anatomic and visual function changes in a broad population of GA patients. n
1. Brown DM, Regillo CD. Anti-VEGF agents in the treatment of neovascular age-related macular degeneration: Applying clinical trial results to the treatment of everyday patients. Am J Ophthalmol. 2007;144(4):627-637.
2. Roche initiates phase III trials for lampalizumab, first potential treatment for geographic atrophy (GA) [press release]. September 15, 2014. Roche. Basel, Switzerland. http://www.roche.com/investors/updates/inv-update-2014-09-15.htm. Accessed March 2, 2016.
3. Owen J, Punt J, Stranford S, eds. Kuby Immunology, 7th ed. New York: W.H. Freeman and Co. Ltd.; 2013.
4. Walport MJ. Complement: first of two parts. N Engl J Med. 2001;344:1058-1066.
Brandon G. Busbee, MD
• Private practice at Tennessee Retina in Nashville
• Financial disclosure: consultant to Genentech