The biologic anti-VEGF agents ranibizumab and aflibercept have transformed the management of neovascular (‘wet’) age-related macular degeneration (AMD), the world’s leading cause of severe visual loss. The high cost of biologics frequently puts them beyond the reach of many eligible patients worldwide but, once they approach patent expiry, other companies are able to begin developing less costly versions known as biosimilars. For regulatory approval, biosimilars need to undergo head-to-head clinical trials with the originator biologic to demonstrate a matching mechanism of action and highly similar efficacy, safety and immunogenicity.
Please note: For legal reasons, the use of off-label medications cannot be discussed here.
Age-related macular degeneration (AMD) is a degenerative disease of the retina that can cause significant loss of central vision, and sometimes, blindness. It has been described as the world’s leading cause of legal blindness, affecting 10–13% of adults over 65 years of age in North America, Europe, Australia, and recently, Asia.1 AMD has been described as epidemic in the developed world, because roughly one in three people will be affected to some degree by the age of 75.2 Since the predominant risk factor for AMD is old age, its prevalence is likely to increase still further as life expectancy improves with advances in medicine and public health.3 By 2020, the number of people with AMD is projected to be in the region of 196 million, increasing to 288 million by 2040.3
There are two types of AMD: ‘dry’ (non-exudative or atrophic) and ‘wet’ (neovascular or exudative). Wet AMD accounts for only 10% of cases, but is responsible for by far the greatest morbidity attributable to the disease.4
In the past, people with wet AMD were treated primarily with photodynamic therapy (PDT), together with the photosensitizer drug verteporfin, or with laser photocoagulation. These therapies often had only modest clinical benefit and their effectiveness could be compromised by disease recurrence.1 In addition, PDT sometimes left scarring.1 However, after vascular endothelial growth factor-A (VEGF-A) was identified as one of the key mediators in the pathogenesis of wet AMD, the development of anti-VEGF biologic medications provided the first opportunity to dramatically improve visual outcomes in patients with this rapidly progressive form of the disease. If administered within a window of ‘treatability,’ anti-VEGF biologics given by intraocular (intravitreal) injection can effectively prevent further visual loss and sometimes even restore lost sight.5 Wet AMD was previously responsible for 90% of AMD-related blindness, but anti-VEGF treatment now prevents vision loss in over 90% of patients, with about one-third experiencing significant improvements in visual acuity.4
As of May 2016, there are three anti-VEGF biologics licensed for the management of wet AMD. The first, pegaptanib, has now been superceded by the other two, ranibizumab and aflibercept, which have shown superior efficacy.1 Ranibizumab is a monoclonal antibody that inhibits all the biologically active forms of VEGF-A.6 In addition to its small size (relative to other biologics), ranibizumab is genetically engineered to have very high affinity for VEGF-A and is formulated specifically for intraocular use so that drug penetration into the retina is optimized.6 Moreover, any drug that leaks out of the eye into the circulation has a short half-life, which may help to limit systemic toxicity.6 Aflibercept is a newer anti-VEGF agent that has provided an alternative method of VEGF suppression. It is a recombinant fusion protein that binds both VEGF-A (essentially acting as a VEGF ‘trap’) and the placental growth factor PlGF, which is also thought to be involved in angiogenesis and neovascularization.7 Aflibercept has been shown to have similar efficacy to ranibizumab when administered every 2 months rather than monthly.4
“Intraocular inhibition of VEGF is one of the most efficient therapies in medicine. It has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD.” 1
“Anti-VEGF agents represent a huge leap forward in treatment for macular degeneration. Ten years ago, wet AMD was a one-way ticket to blindness, but I now have patients who are able to read and drive; and some even maintain 20/20 vision.” 8
However, the reality is that many patients with wet AMD are not able to reap the considerable benefits of anti-VEGF biologics. The reason, of course, is the high cost of these medicines. Ranibizumab costs approximately USD $2,000 per monthly injection. In the US, ranibizumab treatment is covered under Medicare Part B but patients are responsible for a 20% co-payment for each injection.6 The manufacturer does offer patient access programs to help subsidize costs but, despite this, out-of-pocket costs can ultimately add up to thousands of dollars.8 In the UK, where clinicians may submit an Individual Funding Request (IFR) for a named patient when a local NHS body will not fund a certain treatment, it was found that 10% of all IFRs submitted in 2012 related to biologic treatments for AMD.9 In Brazil – where biologic treatments for AMD are not available at all under the public health system10 – a group of researchers estimated that, had ranibizumab been provided to all clinically eligible patients over the 4 years from 2008 to 2011, over one million individuals would have been entitled to it,10 a situation with massive budgetary implications that will only get worse as the prevalence of AMD rises.
“When data documenting Medicare payments in 2012 were released this week, they showed that one of the most heavily reimbursed procedures – costing a total of $1 billion for 143,000 patients – is for a single treatment for an eye disorder common in the elderly. That treatment is intraocular ranibizumab for age-related macular degeneration.” 11
The costs of modern AMD biologics reflect the scientific innovation and the investment required to support biotechnological research and development. But it puts the treatments beyond the reach of many people. Pursuit of innovative new drugs is clearly of great importance, but so is broadening patient access to established existing treatments. There’s no quick-fix solution but, as AMD biologics start to approach patent expiry, the opportunity arises for other companies to develop less costly versions, which are most commonly known as biosimilars.* As of May 2016, biosimilars of ranibizumab and aflibercept have yet to be developed and licensed in highly regulated markets.
*Also known as follow-on biologics, subsequent-entry biologics (SEBs), and biocomparables, among others.
In contrast to the situation with chemical (small molecule) drugs – which can easily be replicated in a laboratory to generate identical generic versions – biosimilars are not exact copies of originator biologics. Because biologics are produced using living organisms, it is not possible for a new manufacturer to precisely replicate the highly complex and sophisticated production processes involved. However, extensive regulatory requirements are designed to ensure that candidate biosimilars are rigorously compared with their originators both analytically and clinically, to establish that quality, efficacy, and safety are all a very close match. By January 2016, 22 biosimilars in a range of therapy areas had been launched in Europe with no adverse clinical consequences compared with their originators12,13 and have resulted in significant cost savings.14 In Germany, for instance, the use of biosimilar erythropoietin between 2007 and 2011 led to over €600 million in savings.15 Other markets are starting to follow Europe’s example.
The extent of the clinical testing required means that biosimilars can’t be as heavily discounted as chemical generics. The average savings are projected to be around 30%,16 but they could well be higher. For ophthalmic anti-VEGF treatments, these savings will be highly worthwhile, especially since disease activity in neovascular AMD is lifelong1 and repeat treatments are often necessary for continued benefit.8 In addition, the introduction of competition may prompt the manufacturers of originator biologics to reduce their prices and to consider investing in innovative new products as they seek new competitive advantages.
QuintilesIMS is actively supporting the development of AMD biosimilars and we invite you to join us as a clinical investigator. The patients you enroll in these studies will all receive active therapy, either with the originator anti-VEGF agent, or with a biosimilar candidate at no cost to them or to their insurers.
1. Schmidt-Erfurth U, Chong V, Loewenstein A et al. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol (2014) 98:1144–1167.
2. Stone EM. A very effective treatment for neovascular macular degeneration. N Engl J Med (2006) 355:1493–1495.
3. Wong WL, Su X, Li X. 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:e106–116.
4. Yonekawa Y, Miller JW, Kim IK. Age-related macular degeneration: Advances in management and diagnosis. J Clin Med (2015) 4:343–359.
5. Rawson NSB. Including off-label drug indications in HTA jeopardizes patient health and discourages innovation. Canadian Health Policy, January 19, 2016. Toronto: Canadian Health Policy Institute.
6. Steinbrook R. The price of sight: Ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med (2006) 355:1409–1412.
7. Balaratnasingam C, Dhrami-Gavazi E, McCann JT. Aflibercept: A review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration. Clin Ophthalmol (2015) 9:2355–2371.
8. American Academy of Ophthalmology, 20 July 2015. Avastin, Eylea and Lucentis – what’s the difference? http://www.aao.org/eye-health/diseases/avastin-eylea-lucentis-difference. Accessed 30 May 2016.
9. PharmaTimes Online, 19 November 2016. Rationing affecting treatment access in the NHS. http://www.pharmatimes.com/Article/12-11-19/Rationing_affecting_treatment_access_in_NHS.aspx. Accessed 30 May 2016.
10. Tavares Silva Elias F, Nunes da Silva E, Belfort R et al. Treatment options for age-related macular degeneration: A budget impact analysis from the perspective of the Brazilian public health system. PLoS ONE 10(10): e0139556.
11. BU Today, 4 November 2014. Medicare data reveals $1 billion a year for costly eye drug. http://www.bu.edu/today/2014/medicare-data-reveals-1-billion-a-year-for-costly-eye-drug/. Accessed 30 May 2016.
12. Ebbers HC, Crow SA, Vulto AG and Schellekens H. Interchangeability, immunogenicity and biosimilars. Nat Biotechnol (2012) 30:1186–1190.
13. McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther (2012) 91:405–417.
14. Rovira J et al. The impact of biosimilars’ entry in the EU market. Andalusian School of Public Health (2011).
15. Turner M et al. Economic evaluation of epoetin alfa Hexal/Binocrit compared to darbepoetin alfa (Aranesp) in the treatment of chemotherapy-induced anemia (CIA) in Germany. Poster presented at ISPOR 16th Annual European Congress, Dublin, Ireland; 2–6 November 2013.
16. PharmTech.com, 30 September 2014. New report details players and pipelines in the biosimilar space. http://www.pharmtech.com/pharmtech/News/New-Report-Details-Players-and-Pipelines-in-the-Bi/ArticleStandard/Article/detail/855810. Accessed 30 May 2016.