Future perspectives: 53 agents on the horizon

INTRODUCTION

As demonstrated in the previous chapters of this textbook, retinal pharmacotherapeutics is a rapidly developing area. The enormous burden of disease in an aging population will hopefully be met by significant improvements in our understanding and treatment of disease processes such as age-related macular degeneration (AMD) and diabetic retinopathy.

KEY FEATURES

This chapter will provide some perspectives on select antiangiogenic drugs currently in development, as well as therapies directed against the complement cascade for the treatment of AMD, and an anti-inflam- matory monoclonal antibody for the treatment of diabetic macular edema (DME). One of the exciting possibilities is that the use of a combination of these modalities will enable earlier and more complete control of disease processes. For instance, the use of complement cascade inhibitors in addition to the use of vascular endothelial growth factor (VEGF) inhibition may lead to a reduction in ongoing accumulated damage to the Bruch’s membrane and retinal pigment epithelium (RPE), as well as allowing more complete control over neovascular AMD. The mechanism of action of a number of the discussed drugs differs enough to give the potential to control neovascularization in several different ways, potentially allowing more effective management of this process with fewer treatments.

Multidrug combination therapy is employed throughout medicine, often exploiting synergistic therapeutic effects to allow reduction of dosages, thus minimizing side-effects. Examples are the use of multidrug cocktails of antineoplastic agents in oncology, the use of multiple immunosuppressants in the management of autoimmune disease and transplants, and the use of multidrug therapy to control infectious disease. Fortunately, today’s most commonly used pharmacotherapeutic modality for the treatment of ocular neovascularization and for some causes of macular edema, VEGF inhibition, has had minimal clinically manifested side-effects. However, VEGF inhibition is usually accomplished by intravitreal injection, and this procedure is not without risk. Combination therapy may lead to a reduction in the number of treatments required.

VEGF inhibition has a number of theoretical possible adverse effects on the retina. VEGF is a neurotrophic agent, and there is a possibility that inhibition may lead to loss of retinal tissue. In some conditions where VEGF inhibition is used, such as diabetic retinopathy, obliterative retinal vasculitides, and vein occlusions, VEGF inhibition may potentially place macular capillaries at risk if they are VEGF-dependent.

In the following section, select drugs and categories of drugs (listed in Table 53.1), which are currently under development and which may play an important role in the therapeutic armamentarium for retinal vascular diseases in the future, will be discussed according to the disease processes that they may modulate.

ANGIOGENESIS AND NEOVASCULAR AGE-RELATED MACULAR DEGENERATION

TYROSINE KINASE INHIBITORS

All three VEGF receptors are tyrosine kinases and cause downstream activation of additional tyrosine kinases in a cascade that leads to gene transcription and downstream effects, including leakage, proliferation, migration, and angiogenesis. Thus, blocking this downstream activation is an appealing target. In addition, the receptors for fibroblast growth factor and platelet-derived growth factor (PDGF) are also tyrosine kinases. Thus, tyrosine kinase inhibitors may offer the potential to inhibit angiogenesis via the VEGF pathway and other angiogenic pathways. Inhibition of all three of these receptor tyrosine kinases also raises the possibility of inhibition of the development of subretinal fibrosis associated with choroidal neovascularization (CNV). As an example of this concept, it has been demonstrated that in rats, an inhibitor of these three tyrosine kinases attenuates the development of bleomycininduced pulmonary fibrosis.1 A number of tyrosine kinase inhbitors are under investigation and are discussed below.

Intravitreal injections of AG013764 and AG013711, which inhibit the kinase domains of VEGF receptor 1 (VEGFR-1), receptor 2 (VEGFR-2), and PDGF receptor (PDGFR), have been demonstrated to reduce the area of CNV induced by subretinal injections of a viral vector carrying the gene for the 165-kDa isoform of VEGF (AAV-VEGF(165)).2 Vatalanib (PTK787) inhibits the kinase domain of VEGFR-1, -2, and -3. It is being extensively studied as a chemotherapeutic agent for solid tumors. Oral vatalanib administered daily has undergone a phase I/II study for the treatment of subfoveal CNV secondary to AMD: this study was sponsored by Novartis and was concluded in 2007. The study estimated that it would enroll 47 patients. It was to assess safety over 12 months as well as comparing the effects of vatalanib on visual acuity and retinal anatomic measures with the effects of standard therapy. Initially, patients were randomized to vatalanib or photodynamic therapy with verteporfin. As the standard of care has changed since the study was commenced, the second cohort of patients has been randomized between vatalanib and ranibizumab.

Vatalanib has a high oral bioavailability, which makes the elimination of intravitreal injections with their associated adverse effects a possibility. However, systemic administration would make systemic adverse effects of VEGF inhibition more likely. Vatalanib must be evaluated for the side-effects that have been experienced with systemic bevacizumab and VEGF-Trap, including hypertension, proteinuria, intestinal perforation, reversible posterior leukoencephalopathy syndrome (RPLS), and a trend towards delayed surgical wound healing.3 The CONFIRM-2 trial evaluating vatalanib in the treatment of metastatic colorectal cancer reported adverse effects likely related to VEGF antagonism, including hypertension, thrombotic and embolic events, and RPLS. Other adverse effects that occurred in a higher proportion of vatalanib-treated patients than of those treated with placebo included diarrhea, fatigue, nausea, vomiting, and dizziness.4

Table 53.1  Categories of pharmacologic agents

Neovascular age-related macular degeneration

Tyrosine kinase inhibitors PDGF inhibitors

Integrin inhibitors

Insulin-like growth factor receptor inhibitors Nicotinic acetylcholine receptor antagonists Mammalian target of rapamycin inhibitor Small interfering RNA (siRNA)

Bioactive lipids

Nonneovascular age-related macular degeneration

Complement inhibitors

Diabetic macular edema

Inhibitors of inflammation

Imatinib, which inhibits both the alpha and beta receptors of PDGF, has been proposed as an adjunctive treatment to VEGF inhibition with ranibizumab. A trial of this combination approach is under way. There is now considerable experience with the use of imatinib in oncology. It is generally well tolerated, although less so in blast crises in chronic myeloid leukemia, and is of importance for retinal disease in the elderly. Most of the significant side-effects derive from fluid retention, and pleural effusion, pulmonary edema, renal failure, and congestive cardiac failure may all occur. Rash and muscle cramps also occur. TG100801 is an ocular formulation of the prodrug 4-chloro-3-(5- methyl-3+1,2,4-benzotriazin-7-yl) phenyl benzoate, an inhibitor of the VEGFR-2, Rous sarcoma oncogene (SRC) and Yamaguchi sarcoma oncogene (YES) kinases. Studies from knockout mice suggest that SRC and YES play an important role in vascular permeability. This prodrug has been formulated so as to maximize the drug concentration in the posterior pole resulting from topical administration.5 The formulation has already undergone toxicity studies in healthy volunteers, and is currently under investigation for the treatment of subfoveal CNV secondary to AMD. The study participants are randomized between two doses of the prodrug administered twice daily for 30 days. The effect on central retinal thickness and on visual acuity will be compared.

PDGF INHIBITORS

In addition to the use of tyrosine kinase inhibitors to target the PDGF receptor, E10030 (Ophthotech), a pegylated aptamer which is antagonistic to PDGF function, is in phase I clinical trials in eyes with subfoveal CNV secondary to AMD. PDGF is an appealing target in neovascular AMD since PDGF is required for recruitment of pericytes to developing endothelial cells. Without pericyte recruitment and attachment, neovascular vessels do not mature. Thus, by blocking PDGF a crucial step in the angiogenesis cascade is blocked. The phase I study is an ascendingdose study of intravitreal injections of E10030 used either as monotherapy or in combination with ranibizumab. The endpoints are dose-limiting ocular toxicities and adverse events.6 Although PDGF inhibitors may hold potential in the treatment of CNV, their potential in treating proliferative diabetic retinopathy, where PDGF likely has a pathogenic role,7 is limited by the requirement for PDGF for pericyte retention and recruitment.8

INTEGRIN INHIBITORS

Integrins are adhesion molecules by which cells attach themselves to the extracellular matrix (ECM). They also have a signal transduction

role in that they mediate the effect of the ECM on cellular function. Inhibitors of α5β1,9 αvβ3,10 and αvβ5 11 integrins have all been demonstrated in some systems to have antiangiogenic properties. Only an antagonist of α5β1 integrin (JSM6427) has been demonstrated to have antiangiogenic properties in mouse laser-induced CNV.12 This molecule is now undergoing an ascending-dose phase I trial sponsored by Jerini Pharmaceuticals for the treatment of subfoveal neovascular AMD.

Volociximab is a chimeric monoclonal IgG4 antibody that binds α5β1 integrin. It was developed for the treatment of solid tumors and is being tested for the treatment of CNV by Ophthotech. This molecule has been demonstrated to inhibit endothelial cell proliferation and angiogenesis in in vitro assays. When administered by intravitreal injection concurrently with laser-induced Bruch’s membrane rupture and then weekly, it inhibits the development of laser-induced CNV in cynomolgus monkeys.13

INSULIN-LIKE GROWTH FACTOR

RECEPTOR INHIBITORS

Insulin-like growth factor 1 (IGF-1) has been implicated in the pathogenesis of both diabetic retinopathy and CNV. In rats made diabetic with the use of streptozotocin, intravitreous injections of IGF-1 increased retinal activity ofAkt, JNK, HIF-1α, NF-κB, andAP-1, and also increased retinal VEGF levels, while systemic inhibition of the IGF-1R caused reduction of Akt, JNK, HIF-1α, NF-κB, and AP-1 activity, decreased VEGF levels, decreased retinal vascular leukostasis, and reduced breakdown of the blood–retinal barrier.14 IGF-1 and its receptor (IGF-1R) are expressed throughout the retina and RPE in normal eyes. IGF-1 mRNA and both IGF-1R mRNA and protein have been detected in endothelial cells of CNVs and in associated RPE in a majority of lesions.15 IGF-1 increases VEGF expression by cultured RPE cells from surgically excised CNV lesions.16 The cyclolignan picropodophyllin, an inhibitor of the IGF-1R, reduces the size of laser-induced CNV lesions in mice, and reduces the expression of VEGF in the choroid.17

NICOTINIC ACETYLCHOLINE

RECEPTOR ANTAGONISTS

Nicotinic acetylcholine receptors (nAChr) occur on vascular endothelial cells. Nicotine acts on these receptors to enhance angiogenesis in response to limb ischemia. Nicotine also causes angiogenesis in tumors and atherosclerotic plaques at the concentrations found in the serum of smokers.18 nAChr have been demonstrated on human retinal and choroidal vascular endothelial cells.19 Mecamylamine completely inhibits VEGF-induced angiogenic activity of human retinal and choroidal endothelial cells in an in vivo assay by blocking nAChr. Nicotine increases the size of CNV in mice secondary to laser-induced Bruch’s membrane rupture. This effect is abrogated by inhibition of nAChr by subconjunctival mecamylamine. At least in the cerebral microcirculation, nicotine acts on endothelial cells to alter the distribution of tight junctions, and thus to increase the permeability of the blood–brain barrier.20 Blockade of nAChr inhibits endothelial cell migration induced by both basic fibroblast growth factor and VEGF.21 This raises the possibility that nAChr inhibition may block angiogenesis mediated by other factors in addition to VEGF.

Mecamylamine (Comentis) is a specific inhibitor of nAChr. Studies of the pharmacological distribution of topically administered mecamylamine in the rabbit eye have demonstrated significant retinal and choroidal concentrations and much lower plasma concentrations. A topical mecamylamine formulation (ATG-003) has undergone phase I toxicity studies in healthy volunteers. ATG-003 is currently being evaluated in a phase II clinical trial involving 330 patients with CNV (Optima). Published results are expected in 2010. A more limited phase II safety and efficacy trial in the treatment of DME with endpoints of visual acuity and retinal thickness as measured by optical coherence tomography (OCT) is also under way.

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