Economic and Quality of Life Benefits of Anti-VEGF Therapy

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Communication

Economic and Quality of Life Benefits of Anti-VEGF Therapy Nickisa Hodgson, Frances Wu, Henry Ferreyra, Jie Zhu, Wenqui Wang, Kang Zhang, and Jiawei Wang Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.5b00775 • Publication Date (Web): 02 Feb 2016 Downloaded from http://pubs.acs.org on February 15, 2016

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Molecular Pharmaceutics

Economic and Quality of Life Benefits of Anti-VEGF Therapy Nickisa Hodgson, MD, MAS, Frances Wu, BS, Jie Zhu MD, PhD, Wianqui Wang, MD, PhD, Henry Ferreyra, MD, Kang Zhang, MD, PhD, Jiawei Wang, MD

Corresponding Author: Jiawei Wang, MD Zhongshan Ophthalmic Center Sun Yat-sen University Guangzhou, China

ACS Paragon Plus Environment


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Abstract: Vision impairment and blindness create a significant impact on quality of life and loss of productivity. Health care expenditures for vision problems, including direct medical costs and indirect costs for support services and loss of productivity, amount to $139 billion annually. It is projected that by 2020, 5 million people will have visual impairment due to age related macular degeneration and diabetic macular edema. VEGF inhibitor therapy has been shown to be a cost-effective treatment for age related macular degeneration and diabetic macular edema that has reduced the incidence of vision loss and can reduce the associated economic and societal cost.

Keywords: Cost-effectiveness, macular degeneration, diabetic macular edema, VEGF, QALY


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Communications Manuscript: Vision impairment and blindness are major disabilities that represent a significant and growing healthcare expenditure. A study by Prevent Blindness America estimated the economic burden of vision problems in the United States to be $139 billion annually with direct medical costs compromising $65.1 billion of the total cost.1 (Figure 1) In addition to direct medical costs, vision loss results in a significant loss of productivity and quality of life. 2-4 The visually impaired have a 44% labor force participation rate and the blind have a 33% labor participation rate compared with the national 85% labor participation rate, which results in an $1.7 billion productivity loss from decreased earnings.5 Furthermore vision impairment affects quality of life, and improvements in visual acuity have been shown to improve perceived quality of life as measured by the National Eye Institute Visual Function Questionnaire (NEI VFQ25).6 Visual impairment affects participation in activities of daily living thereby increasing the reliance on family members, support services, visual aids and federal assistance programs. It is expected that number of blind persons in the US will increase by a staggering 70% to an estimated 1.6 million people by 2020 creating major economic and social implications.7 A substantial and rising burden is associated with vision loss from diabetic macular edema (DME) and age related macular degeneration (ARMD). It is projected that by 2020, 3 million people with ARMD and 2 million with DME will be visually impaired in the United States.8 Currently, approximately 750,000 people with diabetes have DME9 and an estimated 28.7% of people with DME are visually impaired.10 Similarly, ARMD affects 8 million Americans and accounts for the leading cause of blindness in the white population in the United States.7



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The use of intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors has transformed the treatment for ARMD and DME following initial introduction as an anti-angiogenic growth factor for colon cancer. VEGF inhibitors including bevacizumab (Avastin, Genentech/Roche), ranibizumab (Lucentis, Genentech/Roche/Novartis), and aflibercept (Eylea, Regeneron) have been shown to prevent vision loss and even improve vision.11 Thus, VEGF inhibitors have shifted the paradigm of ARMD and DME from diseases of permanent vision loss to treatable chronic diseases with potential for vision preservation. A theoretical model from phase 3 trials for neovascular AMD revealed that monthly ranibizumab reduces the incidence of legal blindness by 72% and visual impairment by 37% over 2 years.12 Analysis and modeling of an Australian population revealed that monthly ranibizumab reduces blindness by 72% while as needed treatment reduces blindness by 68%. Visual impairment would be reduced by 37% with monthly treatment and 28% with as needed treatment.13 Additionally, anti-VEGF treatment has been shown to improve perceived quality of life in studies using the NEI-VFQ.14 Interestingly, in a seven year follow up of patients on ranibizumab in the MARINA and ANCHOR trials, 40% of a eyes had better or stable visual acuity while 34% of eyes did have a decline of 15 letters or more. The long-term results of anti-VEGF therapy will need further analysis and methods to optimize enduring results warrant future investigations. 15-17 Anti-VEGF therapy has undoubtedly revolutionized treatment for retinal disease and can reduce the economic burden associated with vision impairment. However, a review of medicare Part B expenditures in 2010 revealed that $1.6 billion or 10% of the drug budget was spent on ranibizumab for retinal disease.18 In addition to the


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pharmaceutical cost, monthly injections and frequent clinic appointments with fundus examination and optical coherence tomography are required to maintain therapeutic benefits. A recent time-and-motion study revealed that patients with neovascular AMD account for 20% of clinic staff time and that 49% of retina specialists believed the frequency of injections was an encumbrance on clinical office space. Patients reported visits for injections were an average of 12 hours long including time for travel, office time, treatment and recovery (9 hours) with 22% of patients requiring caregivers to take off time from work for transportation to visits.19 Further, patients report anxiety and pain with intravitreal injections despite local anesthesia. Intravitreal injections are fairly safe however have associated risks including a 0.049% risk of endophthalmitis in a metaanalysis review and a low potential risk for cardiovascular adverse events.20 Several studies have determined that patients are willing to accept a high treatment burden including monthly visits and more frequent injections when associated with an improvement in visual acuity.21-22 As healthcare costs rise, it is critical to determine the cost-effectiveness of anti-VEGF therapy and particularly the most cost-effective and time- saving dosing regimen to reduce the burden on patients and clinicians. The expected total lifetime cost per patient for VEGF inhibitor monotherapy for diabetic macular edema is $133,126. Analysis of costs and quality-adjusted life-year (QALY) estimate QALY cost for DME ranges from $824 to $25,566.23-24 Other analyses have determined the cost per line of acuity per year for treatment of DME range from $60-561.23 A cost effectiveness analysis of treatment for diabetic macular edema, with a primary outcome designated as incremental cost-effective ratio (ICER) per cost of QALY gained, found all VEGF inhibitors were cost-saving compared with no treatment.24



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Though all VEGF inhibitors are cost-effective, costs vary widely per injection with aflibercept costs reported as $1,950, ranibizumab $1,200 and avastin $50.25 A randomized controlled trial of all three anti-VEGF therapies found that all three agents were effective in patients with mild vision loss, however aflibercept was more effective in patients with worse visual acuity (20/50 or worse). 25 More studies are required to determine the optimum cost-effective drug and schedule to prevent vision loss. The efficacy of ranibizumab was demonstrated in the MARINA and ANCHOR trials for treatment of neovascular AMD demonstrating that ranibizumab was superior than sham treatment and superior to verteoporfin in classic CNV, respectively.15-16 AntiVEGF therapy has since become the standard of care, and the estimated two-year medical treatment costs range from $3,100-$5400 for VEGF inhibitor therapy.26 Costeffectiveness analyses have determined that cost per QALY for serial injections of ranibizumab in choroidal neovascularization is $43,594.27 Some authors suggest that therapies that are considered cost-effective cost less than $100,000 per QALY28 while very cost effective therapies are typically less than $50,000 per QALY.29-31 Using these cost per QALY criteria, anti-VEGF therapy can be considered cost-effective for choroidal neovascularization in ARMD. When comparing treatment with bevacizumab to ranibizumab, the CATT trial demonstrated there was no significant difference in visual acuity at two years, though ranibizumab outperforms bevacizumab in reduction of fluid. The CATT trial also compared monthly bevacizumab and ranibizumab to PRN dosing and found monthly dosing had slightly better visual acuity outcomes; however, the outcomes were equal if monthly dosing was switched to PRN dosing at one year.32 In the IVAN trial, bevacizumab was found to be non-inferior to ranibizumab with similar safety


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profiles, however continuous ranibizumab cost £3.5million per quality adjusted life year when compared with continuous bevacizumab. Additionally, continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab.33 Other studies have analyzed cost-effectiveness between different treatment schedules, and found monthly bevacizumab is less cost-effective than as needed bevacizumab.34 Additional studies will be needed to determine the optimal dose regimen for visual acuity, cost, and quality of life. In China, the prevalence of AMD in Shanghai was 15.5% in 2005 and has been increasing with an aging population.35 AMD is the leading cause of blindness in Shanghai, and anti-VEGF agents have been widely introduced for the treatment of patients with neovascular retinopathy after bevacizumab was proven effective in reducing macular edema in central retinal vein occlusions and inhibiting CNV in 2006. Li et al36 reported that ranibizumab for neovascular AMD patients gained similar QALY at significantly higher costs in comparison with bevacizumab in China. Patients on ranibizumab treatment obtained 0.007 QALY more than patients on bevacizumab treatment, while the average total cost was CNY 794,400 higher. The ICER reached CNY 109.23 million per QALY. Despite its high cost, ranibizumab became the first on-label anti-VEGF reagent approved for use in China, and ranibizumab sales grew rapidly reaching CNY 245 million sales in 2014 with a year-on-year growth of 26.29%. Conbercept (KH902, Chengdu Kanghong Pharmaceutical Group), was recently developed for the treatment of wet AMD and has received China Food and Drug Administration approval. Conbercept is similar to aflibercept, however has a higher binding affinity and lower VEGF dissociation rate which may allow for reduced dosing



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frequency. One-year total costs for conbercept were CNY 79,189.94 and for ranibizumab were CNY 141,291.23, while conbercept QALY was 0.725 and ranibizumab QALY was 0.715, indicating that conbercept for wet AMD had better efficacy and overall lower costs in China.37 Conflibercept is currently under investigation by the US Food and Drug Administration and the European Medicines Agency to bring this drug to other countries. Innovations in pharmaceutical delivery and home monitoring may assist with reducing the cost of anti-VEGF therapy and the overall medical costs associated with retinal disease and vision impairment. Advances in smart phone capabilities may allow for wide based screening by non-ophthalmologic personnel and thus earlier diagnosis and referral for treatment of retinal disease.38-39 In addition, home monitoring devices have been developed to monitor for CNV and may be used to reduce the cost associated with frequent clinic visits and imaging.40-42 Similar principles for home monitoring are applicable to monitoring diabetic macular edema and warrant investigation. Future improvements in pharmaceutical delivery of VEGF inhibitors include possibilities of topical treatments, depot formulations, encapsulated cell transplants that secrete VEGF, and nanotechnology.43 Other considerations include genotyping of VEGF to determine individualized patient response and vitreous sampling of VEGF levels to assess requirement for need of repeat intravitreal injection. A delivery system or dosing regimen that reduces frequency and maintains efficacy will be the gold standard to decrease the burden of physicians, clinical staff, and patients. Future efforts should be directed to enhancing anti-VEGF delivery to provide an optimized cost-effective treatment model for the leading causes of vision impairment.


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Conclusions: Vision loss and blindness comprise a large annual healthcare expenditure. AntiVEGF therapy is a cost effective treatment for the leading causes of vision loss and blindness, ARMD and DME, in the United States. Anti-VEGF therapy has the ability to not only preserve or improve vision but also to improve quality of life, reduce loss of productivity, and decrease the need for support programs and services. Efforts to improve drug delivery and monitoring will be critical to optimize cost-effectiveness by reducing direct costs associated with medical care and pharmaceutical administration, time for clinicians, and treatment burden for patients.

Figure 1:

Cost of Vision Impairment in the United States (Billions)

$65.10 $73.90

Direct Medical Costs Indirect Costs



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Figure 1: Total direct medical costs and indirect medical costs related to vision impairment.

References:

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Economic and Quality of Life Benefits of Anti-VEGF Therapy

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