Weighing Therapy Options for AMD

Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in individuals aged 65 and older in the United States, with an economic burden of $9 billion per year.^1,2 Globally, AMD is projected to increase in the coming years with an estimated 196 million affected by 2020 and 288 million by 2040.^1,3 Although the pathogenesis of AMD is poorly understood, it is believed that metabolic and mitochondrial dysfunctions are the main triggering factors of the disease.⁴

AMD is classified into two main types: dry AMD, with a prevalence of 85% to 90% among affected individuals, and wet AMD affecting 10% to 15% of individuals.⁵ Risk factors for AMD include family history, older age, smoking, higher body mass index, hyperlipidemia, and unchecked cardiovascular disease or high blood pressure.⁶ Treatments for dry AMD are limited to nutritional supplements and lifestyles changes that may slow disease progression but do not provide vision improvement. In contrast, significant advancement has occurred over the last two decades in treatment of wet AMD.^2,4

Treatment of Wet AMD

Wet AMD involves choroidal neovascularization (CNV) and associated retinal edema; blood vessels under the macula start to leak or bleed, affecting central vision, and, in turn, activities of daily living.⁷ Early symptoms of wet AMD include distorted vision and difficulties seeing objects clearly. Early diagnosis and intervention are important. As the disease progresses, cell damage increases, further reducing vision quality. This progression can lead to complete loss of central vision.⁸

Treatment has evolved from laser therapy in the 1980s to photodynamic therapy in the 1990s to current antivascular endothelial growth factor (anti-VEGF) therapy, which has changed the paradigm of treatment for wet AMD. VEGF has been suggested to be the main driver of CNV and associated edema observed in patients with wet AMD. Anti-VEGF treatment via intravitreal injection limits the leaking or bleeding of submacular vessels.⁷

Anti-VEGF agents include brolucizumab (Beovu, Novartis), aflibercept (Eylea, Regeneron Pharmaceutic Inc), ranibizumab (Lucentis, Genentech), bevacizumab (off-label Avastin, Genentech), and pegaptanib (Macugen, Bausch & Lomb Inc). 

Brolucizumab the newest wet AMD treatment was FDA approved in October 2019 based on results from the randomized, double-blind, phase 3 HAWK and HARRIER clinical trials comparing the efficacy and safety of brolucizumab vs aflibercept.^8,9 

Brolucizumab was noninferior to aflibercept in mean change in best-corrected visual acuity from baseline to week 48 (primary end point). Approximately 30% of patients in both studies gained 15 or more letters at year 1. Patients in both studies experienced greater reductions in central subfield thickness with brolucizumab vs aflibercept as early as week 16 and at year 1, and fewer patients taking brolucizumab developed intra-retinal and/or subretinal fluid. At year 1, 56% of patients in HAWK and 51% of patients in HARRIER were maintained on the every 3-month dosing schedule and the remaining patients followed a 2-month dosing schedule. Brolucizumab was generally well tolerated, with adverse event rates similar to aflibercept. The most common adverse events (≥5% of patients) with brolucizumab were blurred vision, cataract, conjunctival hemorrhage, vitreous floaters, and eye pain.^8,9

From a payer perspective, cost and comparative-effectiveness are key factors used to determine inclusion of therapies onto a formulary. In a cost-effectiveness analysis using a Markov cohort model, Hernandez et al⁷ estimated the lifetime quality-adjusted life-years (QALYs) and costs of treating patients with aflibercept 2 mg every 8 weeks after 3 initial monthly doses vs ranibizumab 0.5 mg either monthly or as needed. Over a lifetime, aflibercept provided equal health benefits with ranibizumab monthly (5.44 QALYs) at a lower cost ($33,745 vs $48,031, respectively) as a result of fewer injections. Aflibercept also yielded slightly greater QALYs compared with ranibizumab as needed (5.44 vs 5.40, respectively) at a slightly increased cost ($33,745 vs $33,652, respectively), with an incremental cost per QALY gained of $2583.

In a separate study, Mulligan et al² looked at the economic value of anti-VEGF using data from published literature to simulate vision outcomes for a cohort of 168,820 patients with wet AMD aged 65 or older. Visual acuity improvement associated with anti-VEGF treatments generated $5.1 billion to $8.2 billion in patient benefits and $0.9 billion to $3 billion in societal value across 3 years.

Burden of Care

Although anti-VEGF therapies have been shown to prevent further vision loss and produce vision improvement, it is important for clinicians to consider treatment challenges associated with these therapies. An understanding of the factors that contribute to treatment burden may help clinicians develop strategies to lessen its impact and help patients to better manage the challenges of treatment.

Mulligan et al² reported that approximately 53% to 58% of Medicare patients discontinue treatment within the first year due to cost, fear or discomfort associated with injections to the eye, or lack of perceived need. In a separate study, Senra et al¹⁰ reported that patients with wet AMD receiving treatment with anti-VEGF often experience anxiety related to treatment regardless of how many injections received. The most common sources of anxiety were fear of going blind due to injections/needle, fear of treatment not working/symptoms worsening, anticipatory anxiety, and fear of unknown outcomes and AMD progression. The researchers suggested that clinicians speak to patients about their anxiety, communicate risks to mitigate unfounded patients fears, and be aware of the common sources of anxiety related to wet AMD treatment. ν

References :
1. Yannuzzi NA, Freund KB. Brolucizumab: evidence to date in the treatment of neovascular age-related macular degeneration. Clin Ophthalmol. 2019;13:1323-1329. doi:10.2147/OPTH.S184706
2. Mulligan K, Seabury SA, Dugel PU, et al. Economic value of anti-vascular endothelial growth factor treatment for patients with wet age-related macular degeneration in the United States [published online November 14, 2019]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2019.4557
3. Wong WL, 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. doi:10.1016/S2214-109X(13)70145-1
4. Supuran CT. Agents for the prevention and treatment of age-related macular degeneration and macular edema: a literature review. Expert Opin Ther Pat. 2019;29(10):761-767. doi:10.1080/13543776.2019.1671353
5. What is macular degeneration? AMDF website. https://www.macular.org/what-macular-degeneration. Accessed December 3, 2019.
6. Al-Zamil WM, Yassin SA. Recent developments in age-related macular degeneration: a review. Clin Interv Aging. 2017;12:1313-1330. doi: 10.2147/CIA.S143508
7. Hernandez L, Lanitis T, Cele C, Toro-Diaz H, Gibson A, Kuznik A. Intravitreal aflibercept versus ranibizumab for wet age-related macular degeneration: a cost-effectiveness analysis. J Manag Care Spec Pharm. 2018;24(7):608-616. doi:10.18553/jmcp.2018.24.7.608
8. Novartis receives FDA approval of Beovu®, offering wet AMD patients vision gains and greater fluid reduction vs aflibercept [news release]. Basel, Switzerland: Novartis; October 8, 2019. https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-beovu-offering-wet-amd-patients-vision-gains-and-greater-fluid-reductions-vs-aflibercept. Accessed December 3, 2019.
9. Dugel PU, Koh A, Ogwa Y, et al; HAWK and HARRIER Study Investigators. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration [published online April 12, 2019]. Ophthalmology. doi:10.1016/j.ophtha.2019.04.017
10. Senra H, Balaskas K, Mahmoodi N, Aslam T. Experience of anti-VEGF treatment and clinical levels of depression and anxiety in patients with wet age-related macular degeneration. Am J Ophthalmol. 2017;177:213-224. doi:10.1016/j.ajo.2017.03.005