Meeting an Unmet Need: Geographic Atrophy
Could retina be on the verge of a treatment for GA?
Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that causes progressive, irreversible vision loss. It affects more than 5 million people worldwide.1
To clarify the impact of GA, it is worth noting that the number of patients with GA is essentially equal to the number of patients with neovascular, or wet, AMD.2 It surprises many retina specialists that the prevalence of GA is so high. In addition, the burden of GA is likely to increase over time as the population ages. It is projected that the numbers of patients with GA and with wet AMD are going to increase in parallel over time, with both numbers almost doubling during the next 25 years, culminating in approximately 8 million to 9 million people with each condition globally.3 Given these epidemiologic data, GA is likely one of the most significant unmet medical needs in any discipline.
WHEN VITAMINS WORK, AND WHEN THEY DO NOT
There is a variety of treatment options available for wet AMD. The combination of vitamins and nutrients commonly known as the AREDS formulation has been shown to reduce the rate of advance from intermediate dry AMD to wet AMD.4 It is important to note that the AREDS Research Group has also used its study database to analyze the impact of antioxidant micronutrients on progression to GA. There has been no evidence that the AREDS formulation protects against or accelerates progression from intermediate dry AMD to GA.5 It is fair to conclude that, to date, no effective therapy for GA is available.
The complement system is part of the innate human immune system. The complement system consists of three pathways: the classical pathway, the mannose-binding lectin pathway, and the alternative pathway. The alternative complement pathway, in particular, has been implicated in the pathogenesis of AMD.6 Complement byproducts are found in drusen, and genetic polymorphisms for certain complement factors have been shown on fundus autofluoresence (FAF) to contribute to the progression of GA.7 Tissue samples from human postmortem maculas with advanced AMD have also been shown to have elevated levels of complement proteins.8 The preponderance of data suggests that targeting complement may be a reasonable strategy in the treatment of GA.
Lampalizumab (Genentech) is an antigen-binding fragment of a humanized monoclonal antibody designed to bind to complement factor D. Complement factor D is required for the initiation and amplification of the alternative complement pathway.
GOING TO TRIAL
A phase 1a clinical investigation was performed to determine the safety and tolerability of administration of a single dose of intravitreal lampalizumab in patients with GA.9 Eighteen patients received escalating doses of intravitreal lampalizumab. All patients completed the study with no dose-limiting toxicities or ocular or systemic adverse effects. The maximum tolerated dose in the study was 10 mg, the highest dose tested. This then became the treating dose for future trials. Based on the elimination half-life of the drug, it is predicted that it takes approximately 2 months after administration of a 10-mg intravitreal dose for the vitreous concentration to fall below the estimated minimum concentration required for biologic activity. Therefore, it was concluded that it was therapeutically plausible to achieve a sustained biologic effect with intravitreal administration.
The observed safety and tolerability of single-dose administrations of intravitreal lampalizumab led to the initiation of a phase 2 multidose study, MAHALO, to investigate the biological activity of the drug in preventing progression of GA. The MAHALO trial compared monthly lampalizumab with placebo. Trial data showed a positive treatment effect at 18 months. On average, patients in the treatment arm had a 20% reduction in the rate of enlargement of the area of GA. In subpopulations identified by exploratory biomarkers, the GA progression rate on FAF decreased by as much as 54% (P < 0.05).10 Further details of this study will be presented in a forthcoming publication by the study investigators.
These promising results encouraged the development of the lampalizumab clinical trial program. The four studies comprising the lampalizumab clinical trial program will enroll more than 2,400 patients with GA at more than 275 sites in more than 20 countries. Proxima A and B are a pair of prospective natural history studies of visual function and genetics in a broad population of GA patients. Patients in Proxima A and Proxima B will be followed every 6 months. Researchers will gather anatomic and functional data to better understand the relationship between anatomic changes and visual function metrics.
The other two studies comprising the lampalizumab clinical trial program are the phase 3 trials Chroma and Spectri. These are two parallel trials each enrolling approximately 936 patients randomly assigned to receive 10 mg of intravitreal lampalizumab or sham injection every 4 weeks or every 6 weeks. The trial includes patients who are at least 50 years old and have well-demarcated GA in both eyes but do not have choroidal neovascularization in either eye. Patients must have baseline BCVA of 20/100 or greater. GA can be a single lesion from approximately 1 to 7 disc areas (DA) in size or multifocal with a least one lesion greater than or equal to 0.5 DA. Patients with significant comorbid retinal vascular disease are excluded.
The primary outcome is change in GA assessed by FAF imaging at 1 year. Secondary outcomes include BCVA and metrics to assess changes in visual function (eg, reading speed, low-luminance visual acuity, visual function questionnaire, microperimetry) that often precede changes in BCVA and also significantly affect quality of life.
The estimated study completion date for Chroma and Spectri is October 2018. The retina community and the patients with GA we treat will be eager to see whether lampalizumab will be the first safe and effective approved therapy for this sight-threatening condition. n
1. Rudnicka AR, Jarrar Z, Wormald R, et al. Age and gender variations in age-related macular degeneration prevalence in populations of European ancestry: a meta-analysis. Ophthalmology. 2012;119:571-580.
2. Rudnicka AR, Kapetanakis VV, Jarrar Z, et al. Incidence of late-stage age-related macular degeneration in American whites: systematic review and meta-analysis. Am J Ophthalmol. 2015;160(1):85-93.
3. Wong W, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-116.
4. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2012;11:CD000254.
5. Lindblad A, Lloyd P, Clemons T; Age-Related Eye Disease Study Research Group. Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26. Arch Ophthalmol. 2009;127(9):1168-1174.
6. Charbel Issa P, Chong NV, Scholl HP. The significance of the complement system for the pathogenesis of age-related macular degeneration - current evidence and translation into clinical application. Graefes Arch Clin Exp Ophthalmol. 2011;249(2):163-174.
7. Caire J, Recalde S, Velazquez-Villoria A; Spanish Multicenter Group on AMD. Growth of geographic atrophy on fundus autofluorescence and polymorphisms of CFH, CFB, C3, FHR1-3, and ARMS2 in age-related macular degeneration. JAMA Ophthalmol. 2014;132(5):528-534.
8. Loyet K, DeForge L, Katschke K, et al. Activation of the alternative complement pathway in vitreous is controlled by genetics in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2012;53(10):6628-6637.
9. Do DV, Pieramici DJ, van Lookeren Campagne M, et al.; Phase Ia Investigators. A phase Ia dose-escalation study of the anti-factor D monoclonal antibody fragment FCFD4514S in patients with geographic atrophy. Retina. 2014;34(2):313-320.
10. Roche’s lampalizumab phase II data shows benefit in patients with the advanced form of dry age-related macular degeneration [press release]. F. Hoffman-La Roche Ltd. August 27, 2013. www.roche.com/investors/updates/inv-update-2013-08-27.htm Accessed September 13, 2016.
Salman Yousuf, DO
• second-year retina fellow, University of South Florida, Tampa, Fla.
• financial disclosure: none
David Eichenbaum, MD
• partner, Retina Vitreous Associates of Florida, Tampa, Fla.; clinical assistant professor of ophthalmology, University of South Florida, Tampa, Fla.
• financial disclosure: Genentech, speaking honoraria, consulting, research funding
Studying the Studies
Design: strong> 18 patients received escalating doses of intravitreal lampalizumab.
Investigating: strong> safety and tolerability of single-dose administration of intravitreal lampalizumab in patients with GA
Findings:strong> No dose-limiting toxicities or ocular or systemic adverse effects were seen; patients tolerated the highest tested dose (10 mg).
Design: monthly intravitreal lampalizumab versus placebo for 18 months
Investigating: whether lampalizumab therapy curbs GA progression
Findings: Patients in the treatment arm had a 20% reduction in the rate of GA area enlargement. Data analysis of subpopulations identified by exploratory biomarkers showed that the GA progression rate on FAF decreased significantly in lampalizumab groups.
Name: Chroma and Spectri
Design: parallel trials, each enrolling more than 900 patients randomly assigned to receive one of the following: 10 mg lampalizumab every 4 weeks, 10 mg sham every 4 weeks, 10 mg lampalizumab every 6 weeks, or sham every 6 weeks
Investigating: primary outcome measurement: change in GA assessed by FAF imaging at 1 year; secondary outcomes: BCVA, reading speed, and low-luminance visual acuity
Findings: scheduled for completion October 2018
Name: Proxima A and Proxima B
Design: pair of prospective, natural history studies that will follow patients every 6 months for imaging and functional measurement
Investigating: the relationship between anatomy and function in patients with GA untreated with lampalizumab