OSLI Retina

February 2017

Issue link: http://osliretina.healio.com/i/783801

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February 2017 · Vol. 48, No. 2 101 Practical Retina timally responding despite recurrent injections and marginally acceptable durability of the anti-VEGF class of drugs (especially in year 1) in many patients. Ultimately, the question is why newer, more novel therapeutics have not become available during the past decade despite the remaining unmet need. The answer is not due to a lack of investment into research and development on the part of pharma- ceutical companies and researchers. In fact, despite numerous clinical trials underway the community has been disappointed with repeat failures of highly publicized drugs — most notably the anti–platelet- derived growth factors (anti-PDGFs). Despite these failures, hope remains given numerous other clini- cal trials underway to fill the remaining unmet needs from the anti-VEGFs. THE BASIC SCIENCE BEHIND ANTI-PDGF The process of choroidal neovascularization (CNV) is not solely mediated by VEGF. Rather, it oc- curs as a result of a complex biological orchestra of activity with a number of growth factors involved. As a result, a monotherapeutic approach with anti- VEGFs may lead to incomplete or ineffective treat- ment of neovascular AMD. 7 In the laser-induced CNV model, laser injury promotes the migration and proliferation of pericyte-like cells into the site of CNV formation, where they express markers for smooth muscle actin and PDGF receptor beta. 8 These pericyte-like cells form a scaffold before infiltration of endothelial cells and subsequent formation of new blood vessels. Researchers have demonstrated that targeting these PDGF receptors in combination with VEGF receptors could potently inhibit the formation of the pericyte-like scaffold, with resulting attenu- ation of CNV. 8,9 Therefore, theoretically, treatment with the combination of anti-VEGF and anti-PDGF should provide a more complete and effective way of treating neovascular AMD. EARLY, PROMISING RESULTS CREATE HOPE In 2012, Ophthotech announced its phase 2B data using the anti-PDGF Fovista (pegpleranib; Oph- thotech, New York, NY) in combination with ranibi- zumab at the American Academy of Ophthalmology Retina Subspecialty Day. 10 The company demon- strated that patients receiving the combination of Fovista and ranibizumab gained 10.6 letters versus 6.5 letters in patients receiving ranibizumab mono- therapy at 24 weeks. This was the first trial to show statistical superior efficacy over ranibizumab mono- therapy; for the first time since 2006, a new in class therapeutic for the treatment of neovascular AMD seemed tangible. This success, coupled with other pharmaceutical companies having potential anti-PDGF molecules, caused a boom in research and development target- ing this receptor. Regeneron's rinucumab (an anti- PDGR receptor beta co-formulated with aflibercept) and Allergan's multi-VEGF/PDGF designed ankyrin repeat protein (DARPin) are examples of molecules being explored by some of the larger players in the industry. In addition, smaller companies are look- ing at applying the multitarget approach to different delivery systems. With its agent, X-82, Tyrogenix is looking at an oral anti-VEGF/PDGF formulation that demonstrated positive results in a phase 1 study. 11 Clearside Biomedical is developing axitinib, a com- pound targeting VEGF and PDGF receptors, for injec- tion into the suprachoroidal space for the treatment of wet AMD. The company is planning to submit an investigational new drug application in early 2017 followed by phase 1 and 2 clinical trials. 12 OHR Phar- maceutical's phase 2 IMPACT study of topical Squal- amine Eye Drops (anti-VEGF/PDGF/basic fibroblast growth factor) demonstrated an improvement in vi- sual acuity when used in combination with an anti- VEGF agent versus anti-VEGF monotherapy. Patients receiving combination therapy achieved a mean vi- sion gain in visual acuity of 10.5 letters compared to 5.4 letters in anti-VEGF monotherapy. 13 With all of this activity, it seemed as though anti-PDGF medica- tions were well on their way. 2016: ANTI-PDGF REALITY HITS In 2016, the anti-PDGF momentum finally started to stall. The first clues that there may be some dif- ficulty moving the anti-PDGF story forward came in September of 2016. Regeneron released the phase 2 CAPELLA results, which looked at Regeneron's combination anti-PDGF rinucumab/aflibercept ver- sus aflibercept monotherapy. The combination drug failed to meet the primary endpoint of an im- provement in best-corrected visual acuity (BCVA) at 12 weeks. Patients receiving combination ther- apy showed a 5.8-letter improvement in BCVA at 12 weeks, whereas patients receiving monotherapy with aflibercept showed a 7.5-letter improvement in BCVA at 12 weeks. 14 If anything, this study confirms the efficacy of Regeneron's aflibercept. In November 2016, the data from the phase 2 Oph- thotech study were published confirming the statis- tically significant vision gains in the combination Fovista/ranibizumab cohort over the ranibizumab monotherapy group. 15 However, optical coherence tomography (OCT) findings demonstrated no mean- ingful or statistically significant differences between the groups receiving the combination versus mono-

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