Uveitis, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), and Intravitreal Biologics for Ocular Inflammation




Purpose


To provide perspective on the implications of the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) on intravitreal biologic agents in uveitis and retinal diseases in which ocular inflammatory pathways are central to their pathogenesis.


Design


Interpretative essay.


Methods


Literature review and interpretation.


Results


Besides the clear importance of CATT from a patient treatment perspective in age-related macular degeneration (AMD), these data highlight the critical relevance of highly specific protein immunotherapies offered with biologic agents. The CATT trial also provides a reminder regarding the importance of rigorous efficacy and safety monitoring required when administering intravitreal biologic therapy. Within the field of uveitis, systemic and local biologics have been used to effectively treat uveitis, targeting pathways implicated in both angiogenesis and inflammation (eg, tumor necrosis factor-α [TNF-α] and interleukin-2 pathways), and research on intravitreal biologic therapy for uveitis and AMD will continue to expand. With over 25 ongoing clinical trials on intravitreal biologic therapy for AMD, enthusiasm for vanguard biologic therapies should be tempered by judicious monitoring for adverse events.


Conclusion


The importance of the CATT trial encompasses day-to-day treatment decisions for AMD, as well as lessons on how biologics for ocular disease should be implemented into clinical practice. Specifically, the introduction of intravitreal biologic therapies into clinical practice for uveitis, AMD, and other ocular diseases in which inflammation is involved should be guided by a clear understanding of the immunotherapeutic agent and its molecular target and with rigorous monitoring for both patient benefit and patient safety.


In the multicenter, randomized Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) study, the comparative efficacy of the 2 biologic agents ranibizumab (Lucentis; Genentech. South San Francisco, California, USA) and bevacizumab (Avastin; Genentech) was evaluated in a prospective and controlled fashion. The CATT study showed that both monoclonal antibodies targeting vascular endothelial growth factor (VEGF), despite differences in binding affinity, molecular structure, and FDA-approved labels, compared favorably in their ability to improve and stabilize vision at the 1-year time point. The mechanisms underlying age-related macular degeneration (AMD) are incompletely understood, and likely involve angiogenic, inflammatory, and structural wound-healing pathways. The CATT trial illustrates the tremendous impact of specific immunologic targeting of these molecular pathways for retinal disease and answers critical questions in the day-to-day management of AMD. Moreover, the manner in which the trial was conducted provides insight and guidance for future research in another entire category of disease processes—uveitis and ocular immunologic diseases—in which biologic therapies are a mainstay of immunosuppressive therapy. Herein, we discuss the implications of the CATT trial to uveitis, the lessons learned from prior administration of intravitreal biologics, and considerations regarding the manner in which novel intravitreal biologic therapies for uveitis and retinal diseases should be introduced into clinical practice.


Molecular Targeting in Age-Related Macular Degeneration: Vascular Endothelial Growth Factor and Beyond


VEGF is a secreted glycoprotein involved in promoting vascular permeability and angiogenesis and plays a role in mediating tumor angiogenesis, inflammatory conditions including rheumatoid arthritis, psoriasis, and ocular neovascularization. The clinical efficacy of VEGF inhibition with ranibizumab was initially demonstrated in prospective controlled trials for AMD, with subsequent trials for retinal vein occlusions and diabetic retinopathy. Bevacizumab also demonstrated efficacy following its initial systemic intravenous administration for AMD, and then subsequently via intravitreal delivery to patients with AMD. It is notable that despite differences in molecular structure, binding affinity, and biological half-life, bevacizumab was not inferior to ranibizumab in the majority of treatment arms in the CATT study at 1 year.


Ranibizumab is a 48-kDa humanized monoclonal antibody fragment (Fab), which binds to multiple isoforms of VEGF and has a terminal biological half-life of approximately 3 days. Bevacizumab, a 149-kDa humanized full-length monoclonal IgG antibody, is derived from the same murine monoclonal antibody hybridoma as ranibizumab, but has a longer half-life of 9.8 days in human eyes. In addition, because ranibizumab was engineered through the process of in vitro affinity maturation, the affinity improvement of ranibizumab relative to Fab-12 (ie, the Fab fragment of bevacizumab) approaches 100-fold. Moreover, the better retinal tissue penetration of ranibizumab when compared to trastuzumab (Herceptin; Genentech), a full-length 150-kDa monoclonal antibody bearing structural framework similarities to bevacizumab, favored ranibizumab as the preferred therapeutic choice for AMD. With the CATT study results demonstrating comparable efficacy between the 2 medications and no obvious adverse safety signals with bevacizumab, both medications offer effective therapeutic alternatives to consider for both AMD and other off-label indications, including uveitis and other retinal diseases.


Besides biologics inhibiting VEGF in AMD, other molecular pathways relevant to AMD pathogenesis, which may provide rational therapeutic targets, include those involving lipofuscin accumulation, oxidative damage, and chronic inflammation (both complement- and non-complement-mediated). Several biologic therapies relevant to these pathways have been administered previously for uveitis and AMD both systemically and via intravitreal route, and their efficacy and safety warrant discussion.




Intravitreal Biologics for Uveitis: Anti–Vascular Endothelial Growth Factor Agents and Others


While data reporting the efficacy of systemic biologics targeting diffusible cytokines, chemokines, and cell surface receptors for uveitis have been reported frequently in the setting of prospective trials and retrospective series, intravitreal biologic therapy for uveitis is a relatively recent phenomenon, with growing enthusiasm particularly following the successful use of bevacizumab and ranibizumab. Limited studies have reported the intravitreal off-label use of bevacizumab, ranibizumab, infliximab, and rituximab for uveitis and related conditions (eg, vitreoretinal lymphoma).


Specifically, bevacizumab and ranibizumab have been used to treat and stabilize secondary complications of uveitis, which include uveitic macular edema, choroidal neovascularization, and retinal vasculitis, although their use for primary suppression of inflammation has not been established. More recent studies have suggested that a combination of systemic immunosuppression and local anti-VEGF modulation are beneficial for choroidal neovascularization secondary to inflammation-driven processes such as punctate inner choroidopathy and multifocal choroiditis. These data suggest that although anti-VEGF therapies are effective for these conditions, likely owing to their antivasopermeability properties, the complex proteomic milieu of uveitis requires further study to identify appropriate immunologic targets for anti-inflammatory therapy. The use of combination therapy targeting angiogenesis and other pathogenic pathways may be preferred for both AMD and uveitis.


Among systemically administered biologics for uveitis, the anti–tumor necrosis factor-alpha (TNF-alpha) antagonists (eg, infliximab, adalimumab, etanercept) have received considerable attention, showing efficacy for juvenile idiopathic arthritis (JIA), HLA-B27-associated conditions, and Behçet disease. The efficacy of daclizumab, a humanized anti–interleukin-2 receptor (IL-2 receptor), has also been described for birdshot retinochoroidopathy, sarcoidosis, and Vogt-Koyanagi-Harada syndrome. Other biologics with reported efficacy for uveitis include alemtuzumab (anti-CD52 monoclonal antibody) and anakinra (anti-IL-1R). However, systemic side effects may be prohibitive for some of these medications, and the long-term side effect profile is unknown, although retrospective data suggest no increased mortality or cancer risk associated with the anti-TNF-alpha family of medications.


Because of systemic side effects associated with each of these medications, local immunomodulation is a desirable approach; however, it is not clear whether local, transient immunomodulation of soluble factors will prevent the recurrence of inflammation since the mechanisms underlying uveitis are thought to involve systemic T-cell targeting of self-antigen in patients with a genetic predisposition.




Intravitreal Biologics for Uveitis: Anti–Vascular Endothelial Growth Factor Agents and Others


While data reporting the efficacy of systemic biologics targeting diffusible cytokines, chemokines, and cell surface receptors for uveitis have been reported frequently in the setting of prospective trials and retrospective series, intravitreal biologic therapy for uveitis is a relatively recent phenomenon, with growing enthusiasm particularly following the successful use of bevacizumab and ranibizumab. Limited studies have reported the intravitreal off-label use of bevacizumab, ranibizumab, infliximab, and rituximab for uveitis and related conditions (eg, vitreoretinal lymphoma).


Specifically, bevacizumab and ranibizumab have been used to treat and stabilize secondary complications of uveitis, which include uveitic macular edema, choroidal neovascularization, and retinal vasculitis, although their use for primary suppression of inflammation has not been established. More recent studies have suggested that a combination of systemic immunosuppression and local anti-VEGF modulation are beneficial for choroidal neovascularization secondary to inflammation-driven processes such as punctate inner choroidopathy and multifocal choroiditis. These data suggest that although anti-VEGF therapies are effective for these conditions, likely owing to their antivasopermeability properties, the complex proteomic milieu of uveitis requires further study to identify appropriate immunologic targets for anti-inflammatory therapy. The use of combination therapy targeting angiogenesis and other pathogenic pathways may be preferred for both AMD and uveitis.


Among systemically administered biologics for uveitis, the anti–tumor necrosis factor-alpha (TNF-alpha) antagonists (eg, infliximab, adalimumab, etanercept) have received considerable attention, showing efficacy for juvenile idiopathic arthritis (JIA), HLA-B27-associated conditions, and Behçet disease. The efficacy of daclizumab, a humanized anti–interleukin-2 receptor (IL-2 receptor), has also been described for birdshot retinochoroidopathy, sarcoidosis, and Vogt-Koyanagi-Harada syndrome. Other biologics with reported efficacy for uveitis include alemtuzumab (anti-CD52 monoclonal antibody) and anakinra (anti-IL-1R). However, systemic side effects may be prohibitive for some of these medications, and the long-term side effect profile is unknown, although retrospective data suggest no increased mortality or cancer risk associated with the anti-TNF-alpha family of medications.


Because of systemic side effects associated with each of these medications, local immunomodulation is a desirable approach; however, it is not clear whether local, transient immunomodulation of soluble factors will prevent the recurrence of inflammation since the mechanisms underlying uveitis are thought to involve systemic T-cell targeting of self-antigen in patients with a genetic predisposition.




Lessons from Intravitreal Infliximab


The intravitreal delivery of infliximab for AMD, uveitis, and diabetic macular edema was met with considerable interest initially, and early results suggested its possible role in decreasing choroidal neovascularization and treating cystoid macular edema, which is also the most common cause of visual morbidity in uveitis. However, early reports were uncontrolled nonrandomized case series with variable outcomes and limited follow-up. More recent prospective studies evaluating the safety and efficacy of infliximab for diabetic macular edema and AMD were subsequently conducted. However, several concerning reports described electroretinographic abnormalities in patients treated with intravitreal infliximab in addition to severe panuveitis requiring posterior vitrectomy. These adverse events, combined with modest efficacy for the long-term control of uveitis, reduced the initial enthusiasm regarding its intravitreal use outside the confines of a controlled clinical trial.




Lessons from Intravitreal Rituximab


One example of the efficacy of intravitreal therapies with highly specific targeting is the use of rituximab, a chimeric monoclonal antibody targeting CD20, which is a cell surface marker for the uveitis masquerade syndrome B-cell lymphoma. Rituximab, originally marketed for systemic non-Hodgkin lymphoma (NHL), has now been FDA-approved for NHL, rheumatoid arthritis, Wegener granulomatosis, and microscopic polyangiitis. Rabbits given rituximab via intravitreal delivery prior to its use in patients demonstrated no significant clinical or histologic signs of inflammation, although mild vitritis was observed in 1 report. Based on these encouraging data, intravitreal rituximab was administered and was found to effectively eradicate primary vitreoretinal lymphoma (PVRL). Although the reports of its efficacy are encouraging, further evaluation of the efficacy and safety of rituximab for intraocular lymphoma in the context of a prospective clinical trial is needed. Moreover, because 15% of patients with central nervous system (CNS) lymphoma develop PVRL and 65% to 90% of patients with PVRL eventually develop CNS lymphoma, the cooperative efforts of ophthalmologist and oncologist are necessary, as intravitreal chemotherapy may serve as an adjuvant to systemic chemotherapy or radiation.




Future Intravitreal Biologic Considerations


Within the study of uveitis and ocular inflammation, the inflammatory milieu continues to be unraveled, providing numerous cytokines, chemokines, and cell surface markers of immune cell activation and targets for therapy, and biologics provide attractive potential to specifically affect these targets. This group of medications is particularly relevant for patients who are unable to tolerate systemic medications or are unable to have local corticosteroid because of risk of glaucomatous optic neuropathy progression or cataract development. Specifically, the local delivery of biologic agents may minimize the side effects of systemic biologics while concomitantly limiting the cataractogenic and ocular hypertensive risk of periocular and intravitreal corticosteroids. In addition, the further identification of biomarkers within patient serum may help to dictate which patients will respond to specific biologic therapies. Given that uveitis represents a heterogeneous group of ocular inflammatory conditions, it is likely that certain biologics may work better for specific phenotypes.


Recent research on aqueous humor cytokine profiling in patients with AMD and serum and ocular fluid biomarkers in AMD subtypes also highlight the burgeoning interest in biologic therapies for AMD. According to the National Clinical Trials database, there are over 25 trials for AMD in which biologics are being or have been tested for AMD, with safety monitoring requisite prior to the introduction of any new therapeutic. These biologics target integrins, complement, and other inflammatory pathways relevant to both wet and dry AMD and are summarized in the Table . Conducting trials in this prospective manner will help us to adequately assess and safely delivery these medications for wet and dry AMD.


Jan 12, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Uveitis, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), and Intravitreal Biologics for Ocular Inflammation

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