Anti-VEGF therapy has been one of the most significant breakthroughs in modern medicine, allowing patients the opportunity to improve their vision and stave off blindness over the short term and slow down vision loss over the long term.
But now, patients aren’t satisfied with these short-term gains, and we shouldn’t be either. Not only does anti-VEGF treatment require frequent office visits with injections, but the long-term data show a relentless loss of vision that is unacceptable to our patients who are living healthier, longer lives.1
The two major upgrades being investigated with anti-VEGF therapy include drugs that provide predictable, sustained improvement in visual acuity and treatments that result in fewer clinic visits and injections. To address these unmet needs, the next generation of therapies in clinical trials are exploring agents and combinations that should result in better visual acuity and require fewer injections (Table, page 14).
VEGF Is Not Alone
In addition to VEGF, a number of angiogenic growth factors contribute to the molecular milieu that promotes neovascularization.2 The VEGF family has long been considered one of the main culprits in the formation of neovascularization. The VEGF family consists of VEGF-A, B, C, D and placental growth factor (PIGF), all of which are proteins that interact mainly through VEGFR-2 tyrosine kinase.
VEGFR-2 expression on endothelial cells increases during angiogenesis.3 This has served as the basis for our current therapies, including bevacizumab and ranibizumab (Avastin and Lucentis, Genentech) which target VEGF-A, and aflibercept (Eylea, Regeneron), which targets VEGF-A and B and PIGF.
Many other molecular components are critical for neovascularization. For example, platelet derived growth factor (PDGF) is involved in a wide range of biological processes, including angiogenesis, and may likely contribute to neovascularization in wet AMD.4,5
The PDGF family consists of PDGF-AA, BB, CC and DD. PDGF interacts with PDGFR-α and PDGFR-β tyrosine kinases, which are found in mesenchymal cells. In particular, PDGFR-β is expressed in vascular smooth muscle cells and pericytes.6
Targeting PDGF
Pegpleranib (Fovista, Ophthotech) is an aptamer that binds to PDGF-BB and prevents PDGF from binding to its receptor, PDGFR-β, on pericytes, causing pericytes to be stripped from newly formed abnormal blood vessels.7
Pegpleranib has been used in combination with ranibizumab in a Phase I clinical trial, and shown to be safe. The impression from this Phase I trial was that combination therapy resulted in greater regression of the classic component of choroidal neovascularization than the occult component.8
Based on these observations, a larger Phase II trial investigated monthly pegpleranib and ranibizumab in combination compared with ranibizumab alone for classic-containing neovascular lesions.
After six months, the combination arms had better visual acuity outcomes compared with ranibizumab. This Phase II study set the stage for the on-going Phase III trials to compare the combination of pegpleranib with ranibizumab, bevacizumab or aflibercept, depending on the study, with the anti-VEGF drug alone.
Topline results from these Phase III studies should be known in the fourth quarter this year. Pegpleranib may be one of the first anti-PDGF agents and a component of the first combination therapy approved.
Rinucumab (Regeneron) is a monoclonal antibody intended to bind to the PDGF-β receptor, preventing the action of PDGF.9 This drug is in a Phase II study and is being used in combination with aflibercept in a co-formulated single injection.
X-82 (Tyrogenex) is a small-molecule dual inhibitor of VEGF and the PDGF receptor tyrosine kinases.10 X-82 is in a Phase II study as a once-daily oral formulation in combination with bevacizumab, ranibizumab or aflibercept.
DE-120 (Santen Pharmaceutical) is also a small molecule that inhibits both VEGF and PDGF receptor tyrosine kinases.11 A Phase IIA study is investigating it as intravitreal monotherapy as well in combination with aflibercept.
The ANG Pathway
Angiopoietin (ANG) is involved in another prominent pathway leading to angiogenesis and has been implicated in the pathogenesis of wet AMD. Angiopoietins are protein ligands that control angiogenesis and vascular stability by interacting with Tie1 and Tie2, which are receptor tyrosine kinases that are found on endothelial cells.12,13
Nesvacumab (Regeneron) is a monoclonal antibody directed against ANG 2 and prevents its interaction with Tie2.14 It is currently in a Phase II study and is being used in combination with aflibercept in a co-formulated single injection.
RG7716 (Hoffmann-La Roche) is a bispecific antibody that binds both VEGF A and ANG 2.15 It is in a Phase II study and is being used in combination with ranibizumab.
Target: Tissue Factor
Tissue factor (TF) is another target for wet AMD therapy. TF is well known as a surface receptor for coagulation factor VII, which initiates the extrinsic coagulation pathway.16 TF has been shown to be upregulated in wet AMD17 and cancer, and is believed to also promote angiogenesis.18 Hl-con1 (Iconic Pharmaceuticals) is a factor VII-IgG chimeric protein that binds to TF with the factor VII component, while the IgG component triggers an immunological cascade that destroys the neovascular lesion.19 It is currently in a Phase II study where it is being used as a monotherapy or in combination with ranibizumab.
Other anti-VEGF medications are in clinical trials and being used in combination with current intravitreal medications. Opt-302 (Opthea) is a fusion protein that binds VEGF-C and VEGF-D, blocking their interaction with VEGFR-2 and VEGFR-3.20 This strategy is combined with current medications that primarily target VEGF-A. This drug is in a Phase I/IIA study and is being used as both monotherapy and in combination with ranibizumab.
Two topical therapies are currently in clinical trials. Squalamine (Ohr Pharmaceutical) is a medication that targets intracellular calmodulin to inhibit the downstream effects of VEGF, PDGF and basic fibroblast growth factor (bFGF).21 A topical formulation of this drug is in a Phase III study and is being administered in combination with ranibizumab.
A topical anti-VEGF medication known as PAN-90806 (PanOptica) is being used in combination with intravitreal ranibizumab and is in a Phase I study.22
The Future: Anti-VEGF-Plus
For years to come, intravitreal injections with our current anti-VEGF medications will remain the cornerstone of our treatment strategy. However, combination therapies to reduce the injection frequency and improve visual acuity outcomes show great promise to shake up our current treatment paradigm. RS
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