Update on Treatment for Neovascular Age-Related Macular Degeneration
Age-related macular degeneration (AMD) remains the leading cause of irreversible blindness in the industrialized world. Over the last decade, numerous therapeutic options have become available for neovascular AMD, most notably the anti-VEGF medications ranibizumab, bevacizumab and aflibercept. These medicines have proven effective in large clinical trials: Anchor and Marina (ranibizumab), View 1 and 2 (aflibercept), and CATT and IVAN (bevacizumab). While these drugs are far more effective for neovascular AMD than options available previously (with approximately 90% of patients maintaining vision and approximately 40% gaining vision), there remains a need for improved treatments.1-4
In order to be optimally effective, anti-VEGF medications must be used relatively early in the disease process before scar formation. Further, the medications may become less effective with repeated use, a phenomenon known as tachyphylaxis. Intravitreal injections, regardless of the drug used, have well documented risks including infectious endophthalmitis, sterile endophthalmitis, retinal tear, retinal detachment, vitreous hemorrhage, and cataract. Anti-VEGF medications may increase the risk of thromboembolic events in an already susceptible population. Finally, the widespread adaptation of these drugs has placed an increased strain on medical practices both in terms of cash flow management and inventory control. Logistical difficulties exist for providers and patients (e.g. frequent office visits for testing, monitoring and treatment).
So what does the future hold for treatment of neovascular AMD? In the near term, two new compounds have the potential for becoming therapeutic options. Fovista (Ophthotech Corporation) is currently in phase 3 clinical trials. Delivered by intravitreal injection, Fovista prevents platelet-derived growth factor (PDGF) from binding to its natural receptor on pericytes, thus causing pericytes to be stripped from newly formed abnormal blood vessels. Left unprotected, the endothelial cells are then highly susceptible to the effects of anti-VEGF drugs. Because of this unique action, Fovista may work on both immature vessels, as well as later in the disease process on slightly mature vessels.5 A phase 2 study demonstrated that patients who received a combination of Fovista and ranibizumab had a 62% greater improvement in vision compared to ranibizumab alone.6
Another medicine under clinical trial investigation is DARPin by Allergan. A phase 2 study suggested that DARPin has the potential to achieve a longer dosing interval than that observed with ranibizumab. Ongoing studies are exploring the potential benefits of loading doses.7
In the longer term, there are a number of different agents that may show promise for the treatment of neovacular AMD. Topical therapies would have the potential of eliminating many of the risks associated with intravitreal injections. Ohr, a version of squalamine lactate, is an eyedrop which is currently in phase 2 studies; its mechanism of action is intracellular inhibition of angiogenesis.8 Panoptica is testing a small-molecule selective VEGF receptor antagonist, PAN-90806, as a topical treatment for neovascular AMD and diabetic retinopathy.9
A sustained delivery compound or device would have the potential to reduce the number of office visits and treatments. Alcon is in phase 1 trials of EBSA 1008, an extremely potent pan-VEGF-A inhibitor. If successful, this compound could lead to micro volume treatment doses which could be suitable for long term use.10
These newer compounds with mechanisms of action that differ from current anti-VEGF therapies may provide additional weapons in the fight against neovascular AMD.
1. Brown OM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355: 1432-1444.
2. Rosenfeld PJ, Brown OM, Heier JS, et al. Ranibizumab for neovascular ageÂ related macular degeneration. N Engl J Med. 2006;355:1419-1431.
3. Heier JS, Brown OM, Chong V et al. lntravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012 Dec;119(12):2537-48.
4. Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group, Martin OF, Maguire MG. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results. Ophthalmology. 2012 Jul;119(7):1388-98
5. Ophthotech website: www.ophthotech.com
6. Dugel, PU. Phase 2b clinical trial of Fovista anti-PDGF therapy (1.5 mg) in patients with neovascular age-related macular degeneration (wet AMO). Retina Subspecialty Day at the American Academy of Ophthalmology Annual Meeting (AAO) Nov. 10, 2012
7. Callanan, D, Designed Ankyrin Repeat Proteins (DARPins): Proof of Concept Study. Retina Subspecialty Day at the American Academy of Ophthalmology Annual Meeting (AAO) Nov. 15, 2013
8. Ohr Pharmaceutical website: http://www.ohrpharmaceutical.com
9. Panoptica website: http://www.panopticapharma.com
10. EBSA1008 ClinicalTrials.gov Identifier: NCT01849682
About our author(s):
Darren Bell, M.D.
San Antonio, Texas
Michael Singer, M.D.
San Antonio, Texas