Emerging Treatment Strategies for Neovascular Age-Related Macular Degeneration
By: Sarina Amin, MD, and Pravin U. Dugel, MD
Anti-vascular endothelial growth factor-A (VEGF-A) therapy has revolutionized the treatment of neovascular age-related macular degeneration (nvAMD). However, there remains a subset of patients in whom anti-VEGF-A monotherapy is not an optimal treatment. Patients with resistant or persistent disease are the impetus for new treatment strategies, including next-generation anti-VEGF-A and new classes of drugs.
Brolucizumab (Alcon/Novartis) represents the smallest active unit of antibody that allows for concentrated molar dosing—22 times that of ranibizumab and more than 11 times that of aflibercept. Two phase 3 studies (HAWK and HARRIER) compared brolucizumab dosed every 12 weeks to aflibercept dosed every eight weeks in patients with nvAMD. Patients receiving brolucizumab could be adjusted to eight-week dosing based on disease activity.
In these two registration trials, brolucizumab was found to be noninferior to aflibercept with respect to mean change in visual acuity from baseline to week 48, and was found to be superior to aflibercept with respect to mean reduction in central subfield thickness (measured with optical coherence tomography [OCT]) from baseline to week 16 and from baseline to week 48. In addition, the majority of patients receiving brolucizumab were maintained on 12-week dosing intervals after the three-month loading period, suggesting longer efficacy and decreased treatment need compared with aflibercept.1,2,3
Abicipar pegol (Allergan) belongs to a new class of genetically engineered antibody mimetic proteins (designed ankyrin repeat proteins [DARPins]). Its small size and high potency, coupled with stability and solubility, makes this protein a viable potential treatment for both nvAMD and diabetic macular edema (DME).
Results from the phase 2b PALM trial showed that abicipar pegol injected every eight or 12 weeks for DME offered comparable functional and anatomical effects to ranibizumab injected monthly. In the phase 1/2 REACH trial of patients with nvAMD, similar outcomes were noted. Two phase 3 trials, Cedar and Sequoia, are currently underway.4
Conbercept (Khanghong Biotech) is a soluble trap molecule that blocks all isoforms of VEGF-A, VEGF-B, VEGF-C, and placental growth factor (PlGF). It has a high binding affinity for VEGF-A and a long half-life in vitreous. DME studies have been initiated, and the drug is approved for the treatment of nvAMD and pathologic myopia in China. In both the FRONTIER and SAILING studies, conbercept has been associated with an improvement in visual acuity and a corresponding decrease in central retinal thickness as measured by OCT.5
In times of health, angiopoietin-1 is secreted at a basal rate. This maintains a stable vasculature by activating the Tie2 receptor tyrosine kinase. In disease states, an angiogenic switch occurs and angiopoietin-2 (Ang2) is upregulated. Ang2 functions as an antagonist to Tie2 receptor tyrosine kinase and attracts pro-angiogenic and inflammatory cytokines. This is often coupled with up-regulation of VEGF-A, which causes increased permeability and angiogenesis.4,6
RG7716 (Genentech/Roche) is a bi-specific monoclonal antibody that simultaneously inhibits Ang2, as well as VEGF-A. This compound features two important genetic engineering feats: it increases systemic clearance and decreases inflammation. The phase 2 AVENUE study is evaluating the primary endpoint of visual acuity change from baseline to 36 weeks with ranibizumab as the direct comparator in patients with nvAMD.4 A similar phase 2 study, BOULEVARD, is evaluating two different doses of RG7716 with ranibizumab 0.3 mg for patients with DME.
Of note, a second Ang2 inhibitor compound called nesvacumab (Regeneron/Bayer) was also developed; however, this antibody failed to meet primary endpoints in two phase 2 trials (RUBY and ONYX) and will not progress to phase 3.7
Other combination agents
OPT-302 (Ophthea), which blocks both VEGF-C and VEGF-D, has already completed phase 1/2a trials for nvAMD with a phase 2b trial underway. Early results showed an additive benefit of combining OPT-302 with ranibizumab, particularly for patients who had previously received treatment with standard anti-VEGF therapy.8
Although anti-VEGF drugs have revolutionized the treatment of nvAMD, there remains a need for therapies with better outcomes. There is opportunity to change our treatment paradigm with the next generation of anti-VEGF-A drugs and combination drugs currently in development.
Dugel PU, Jaffe GJ, Sallstig P, et al. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: A randomized trial. Ophthalmology. 2017;124(9):1296-1304.
Alcon Research. Efficacy and Safety of RTH258 Versus Aflibercept. ClinicalTrials.gov. Identifier NCT02307682. Available at . Accessed Feb. 2018.
Schlottman PG, Alezzandrini AA, Zas M, Rodriguez FJ, Luna HJD, Wu L. New treatment modalities for neovascular age-related macular degeneration. Asia Pac J Ophthalmol. 2017;6:514-519.
Lu X, Sun X. Profile of conbercept in the treatment of neovascular age-related macular degeneration. Drug Des Devel Ther. 2015;9:2311-2320.
Chakravarthy U, Bailey C, Brown D, et al. Phase I Trial of Anti–Vascular Endothelial Growth Factor/Anti-angiopoietin 2 Bispecific Antibody RG7716 for Neovascular Age-Related Macular Degeneration. Ophthalmol Retina. 2017;1(6):476-485.
Sarina Amin, MD is a first-year vitreoretinal fellow at Retinal Consultants of Arizona in Phoenix. She plans to continue her second year of the combined private practice/academic fellowship at the University of Southern California (USC) Roski Eye Institute in Los Angeles.
Pravin U. Dugel, MD is managing partner at Retinal Consultants of Arizona in Phoenix and clinical professor of ophthalmology at the USC Roski Eye Institute, Keck School of Medicine in Los Angeles.