Treating Geographic Atrophy in AMD Remains the Holy Grail
By Nancy M. Holekamp, MD
In the anti-VEGF era, legal blindness from exudative (commonly called wet) age-related macular degeneration (AMD) is often preventable. Having utilized various anti-VEGF agents over the past 13 years, retina specialists are realizing that, in many cases, we are preventing vision loss from wet AMD only to see our patients ultimately lose vision due to an advanced form of non-exudative (commonly called dry) AMD known as geographic atrophy (GA). In fact, many patients aging into their 80s and diagnosed with AMD, with or without a history of exudative disease requiring injections, find themselves losing the ability to drive or read due to GA. There is currently no proven effective treatment for GA; it remains an unmet medical need.
The lack of effective treatment for GA is not for lack of trying. In fact, Roche/Genentech has conducted both phase 2 and phase 3 clinical trials targeting the alternative complement pathway with intent to slow the progression of GA. The favorable phase 2 trial and the negative phase 3 trials will be discussed here.
MAHALO is the name given to the phase 2 clinical trial designed to evaluate the safety, tolerability and evidence of activity of lampalizumab, an anti-factor D antibody thought to be integral to the alternative complement pathway, in patients with GA.1 It was also designed to look at specific biomarkers, called SNPs or single nucleotide polymorphisms, for possible associations with GA disease characteristics and differential response to lampalizumab. In MAHALO, 129 patients were randomized to lampalizumab 10 mg monthly, sham injection monthly, lampalizumab 10 mg every other month, or sham injection every other month. All groups were followed for 18 months.1
Monthly 10 mg lampalizumab injections reduced the mean enlargement of the GA lesion area from baseline to 18 months by 20% compared with sham injections. Furthermore, in an exploratory subgroup analysis, patients with the complement factor I (CFI) biomarker showed a greater reduction of 44% compared to sham injection when treated monthly with 10 mg lampalizumab. No benefit was observed in the cohort of patients treated with 10 mg lampalizumab every other month.1
Encouraged by these phase 2 clinical trial results, Roche/Genentech embarked on two parallel, international, large-scale phase 3 clinical trials in which patients with bilateral GA due to AMD were treated with 10 mg lampalizumab every 4 to 6 weeks and compared to sham injections given every 4 to 6 weeks and followed for 2 years.2 The trials were called Chroma and Spectri, and the intent was to slow the rate of GA progression, analyzing the results with respect to the absence or presence of the CFI genetic biomarker.
CHROMA and SPECTRI were the largest studies of GA conducted to date; 906 patients were recruited from 275 sites in 23 countries. Unfortunately, this herculean effort produced negative results; 10 mg lampalizumab did not reduce GA enlargement compared with sham over 2 years of treatment. The results for the treated groups and the sham groups were identical. In addition, no benefit was demonstrated in the CFI profile biomarker subgroup. Essentially, CHROMA and SPECTRI became the largest natural history studies of GA in AMD. Of importance, these studies found that GA lesions enlarge at a substantial and consistent mean rate of approximately 2 mm2 per year.2
Why were the MAHALO results favorable, particularly in the CFI biomarker subgroup, while the CHROMA and SPECTRI results were not? The simple answer may be in the numbers. Studies with a small number of patients are prone to errors in which a beneficial treatment effect may appear to exist when, in reality, no such effect is present. (Hence, the FDA requires positive results from two large, concurrent, phase 3 clinical trials prior to drug approval.) What about MAHALO may have made it prone to falsely positive results? The answer may be, at least in part, the unusual control group. In MAHALO, the GA enlargement rate in control eyes was much faster than 2 mm2 per year. Eyes receiving study drug demonstrated the natural history of GA lesion enlargement of 2 mm2 per year. This apparently "slower rate" by comparison was attributed to a treatment effect of the study drug, not an anomalous control group.
The search for the holy grail in treating GA in AMD continues. The www.clinicaltrials.gov website currently lists 30 studies of GA in AMD, and at least 21 are looking at potential therapies.3 The scientific strategies include targeting the complement system, using stem cells, and injecting gene-carrying viral vectors. The modes of delivery of these potential therapies include intravitreal injections, subcutaneous injections, topical drops, and oral pills. Regardless of the approach, a word of warning is indicated: if studying bilateral GA in AMD, be sure your control group demonstrates a GA lesion growth rate of approximately 2 mm2 per year before drawing any conclusions.
Yaspan BL, Williams DF, Holz FG, et al. Mahalo Study Investigators. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. Sci Transl Med. 2017;9(395).
Holz FG, Sadda RS, Busbee B, et al. Efficacy and Safety of Lampalizumab for Geographic Atrophy due to Age-Related Macular Degeneration. Chroma and Spectri Phase 3 Randomized Clinical Trials. JAMA Ophthalmol. 2018 Jun 1;136(6):666-677.
Dr. Holekamp is a professor of Clinical Ophthalmology at the Washington University School of Medicine in St. Louis. She is also director of Retina Services at the Pepose Vision Institute in St. Louis. She has been actively involved in more than 28 national clinical trials dealing with age-related macular degeneration, retinal vascular occlusion, and diabetic retinopathy. Her efforts in research have resulted in 74 peer-reviewed publications, 21 book chapters, and more than 100 speaking invitations. She served on the AAO Ethics Committee for six years.