Dual VEGF and PDGF Antagonists to Treat Exudative AMD
Dual VEGF and PDGF Antagonists to Treat Exudative AMD
The identification of the cDNA for human VEGF in the late 1980s and characterization of its physiologic role in the early 1990s facilitated the development and approval of multiple VEGF antagonists, such as ranibizumab, pegaptanib and aflibercept, for the treatment of wet AMD. However, combination therapy with VEGF and PDGF antagonists offers the theoretical benefit of targeting both endothelial cells and pericytes as well as preventing subretinal fibrosis, which is also mediated by PDGF. In this way, dual blockade of VEGF and PDGF has the potential to be a more potent inhibitor of pathologic angiogenesis and prevent the insidious subretinal scarring that occurs following CNV regression. It is the latter that ultimately limits the visual potential in AMD after the CNV has been stabilized. Clinical studies evaluating dual VEGF/PDGF inhibitors in wet AMD are described in Table 1.
Sorafenib is a small molecule that inhibits VEGFR, PDGFR and Raf kinases and is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. In 2008, Diago et al. reported two cases in which addition of oral sorafenib to ranibizumab resulted in marked improvement in patients with wet AMD. Oral sorafenib was administered three-times per week for 1 month following ranibizumab injection. Visual acuity improved from 20/70 to 20/50 in the first patient and stabilized between 20/20 and 20/40 in the second patient. Intraretinal fluid also decreased for both patients by the end of treatment.
Pazopanib (GlaxoSmithKline), a multi-kinase inhibitor, is currently being tested in clinical trials as a topical eye drop and tablet (Clinicaltrials.gov identifiers: NCT01134055, NCT01154062). In a Phase I/II trial, oral pazopanib was delivered to patients with wet AMD for 28 days. Pazopanib was well tolerated and resulted in improvements in vision and retinal edema.
E10030 (Ophthotech), an anti-PDGF pegylated aptamer, is being evaluated in clinical trials as an adjunct to ranibizumab (Clinicaltrials.gov identifier: NCT01089517). Ophthotech has also reported successful completion of Phase I and II trials for E10030. In June 2012, the company announced that co-administration of E10030 with ranibizumab to patients with wet AMD resulted in a 62% increase in visual outcome compared with ranibizumab alone. Patients were administered 0.5 mg of ranibizumab alone or with 0.3 or 0.5 mg of E10030 once every 4 weeks over 24 weeks in a prospective, randomized, fully masked trial. This 2012 announcement is in light of a 2009 ARVO report that E10030 was well tolerated in patients with wet AMD. In this report, E10030 was administered to patients with wet AMD as a single injection or in three monthly injections in conjunction with ranibizumab for 3 months. No drug-related adverse events were observed; the only adverse events were caused by intravitreal injection. Together, results from these trials suggest that E10030 is well tolerated and performs better than ranibizumab alone.
Xcovery Vision recently announced initiation of a Phase I/II trial of an oral VEGFR/PDGFR kinase inhibitor, X-82, in patients with AMD (Clinicaltrials.gov identifiers: NCT01674569). This study will explore safety and preliminary biologic activity at escalating doses of X-82. Prior studies of X-82 in oncology patients suggest a relatively good tolerability profile compared with earlier generation kinase inhibitors. Oral therapy for wet AMD offers significant advantages over existing injectable formulations with regard to patient comfort and ocular safety and has the potential to prevent disease in the fellow eye if conversion to wet AMD has not yet occurred.
Although these isolated cases of sorafenib therapy and early clinical trials with pazopanib and E10030 do not offer conclusive evidence of the benefits of dual VEGF and PDGF inhibition for wet AMD, they do suggest the potential for further development in this area. Basic scientific studies and animal models of diseases clearly suggest these mechanisms are complimentary for inhibition of angiogenesis, and such strategies have proven useful in other therapeutic areas such as oncology. As these programs advance into late-stage clinical trials, we hope to learn more about the prospects of dual VEGF/PDGF inhibition for treatment of wet AMD.
Clinical Data Supporting the Use of Dual VEGF/PDGF Antagonism in the Treatment of Wet AMD
The identification of the cDNA for human VEGF in the late 1980s and characterization of its physiologic role in the early 1990s facilitated the development and approval of multiple VEGF antagonists, such as ranibizumab, pegaptanib and aflibercept, for the treatment of wet AMD. However, combination therapy with VEGF and PDGF antagonists offers the theoretical benefit of targeting both endothelial cells and pericytes as well as preventing subretinal fibrosis, which is also mediated by PDGF. In this way, dual blockade of VEGF and PDGF has the potential to be a more potent inhibitor of pathologic angiogenesis and prevent the insidious subretinal scarring that occurs following CNV regression. It is the latter that ultimately limits the visual potential in AMD after the CNV has been stabilized. Clinical studies evaluating dual VEGF/PDGF inhibitors in wet AMD are described in Table 1.
Sorafenib is a small molecule that inhibits VEGFR, PDGFR and Raf kinases and is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. In 2008, Diago et al. reported two cases in which addition of oral sorafenib to ranibizumab resulted in marked improvement in patients with wet AMD. Oral sorafenib was administered three-times per week for 1 month following ranibizumab injection. Visual acuity improved from 20/70 to 20/50 in the first patient and stabilized between 20/20 and 20/40 in the second patient. Intraretinal fluid also decreased for both patients by the end of treatment.
Pazopanib (GlaxoSmithKline), a multi-kinase inhibitor, is currently being tested in clinical trials as a topical eye drop and tablet (Clinicaltrials.gov identifiers: NCT01134055, NCT01154062). In a Phase I/II trial, oral pazopanib was delivered to patients with wet AMD for 28 days. Pazopanib was well tolerated and resulted in improvements in vision and retinal edema.
E10030 (Ophthotech), an anti-PDGF pegylated aptamer, is being evaluated in clinical trials as an adjunct to ranibizumab (Clinicaltrials.gov identifier: NCT01089517). Ophthotech has also reported successful completion of Phase I and II trials for E10030. In June 2012, the company announced that co-administration of E10030 with ranibizumab to patients with wet AMD resulted in a 62% increase in visual outcome compared with ranibizumab alone. Patients were administered 0.5 mg of ranibizumab alone or with 0.3 or 0.5 mg of E10030 once every 4 weeks over 24 weeks in a prospective, randomized, fully masked trial. This 2012 announcement is in light of a 2009 ARVO report that E10030 was well tolerated in patients with wet AMD. In this report, E10030 was administered to patients with wet AMD as a single injection or in three monthly injections in conjunction with ranibizumab for 3 months. No drug-related adverse events were observed; the only adverse events were caused by intravitreal injection. Together, results from these trials suggest that E10030 is well tolerated and performs better than ranibizumab alone.
Xcovery Vision recently announced initiation of a Phase I/II trial of an oral VEGFR/PDGFR kinase inhibitor, X-82, in patients with AMD (Clinicaltrials.gov identifiers: NCT01674569). This study will explore safety and preliminary biologic activity at escalating doses of X-82. Prior studies of X-82 in oncology patients suggest a relatively good tolerability profile compared with earlier generation kinase inhibitors. Oral therapy for wet AMD offers significant advantages over existing injectable formulations with regard to patient comfort and ocular safety and has the potential to prevent disease in the fellow eye if conversion to wet AMD has not yet occurred.
Although these isolated cases of sorafenib therapy and early clinical trials with pazopanib and E10030 do not offer conclusive evidence of the benefits of dual VEGF and PDGF inhibition for wet AMD, they do suggest the potential for further development in this area. Basic scientific studies and animal models of diseases clearly suggest these mechanisms are complimentary for inhibition of angiogenesis, and such strategies have proven useful in other therapeutic areas such as oncology. As these programs advance into late-stage clinical trials, we hope to learn more about the prospects of dual VEGF/PDGF inhibition for treatment of wet AMD.
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