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One biologic response modifier has indication for uveitis; several in development to gain FDA approval
Treatment with a biologic response modifier (BRM) offers a more targeted approach to immunosuppressive therapy for uveitis than standard immunomodulatory drugs.
Reviewed by Eric B. Suhler, MD, MPH
Quoting a line from “Forrest Gump,” Eric B. Suhler, MD, MPH, suggested that use of novel biologic response modifiers (BRMs) for uveitis in the earlier stages of study may be “like a box of chocolates.” “You never know what you are going to get,” explained Dr. Suhler, chief of ophthalmology, VA Portland Health Care System, and professor of ophthalmology and public health, Oregon Health and Science University, Portland, OR.
One BRM is FDA approved for the treatment of uveitis, and it is hoped others will follow. However, more experience with this therapeutic category is needed before BRMs are adopted as first-line options, Dr. Suhler noted.
Compared with standard systemic immunosuppressive drugs, BRMs represent more specific, targeted therapies with the potential for fewer side effects and greater effectiveness. In addition to the approved BRM, a number of biologics are being investigated as treatment for uveitis with some promising results.
Dr. Suhler cautioned, however, that early findings are not always confirmed in larger studies, and with some of the biologics there is a need for more long-term safety information.
Adalimumab (Humira, AbbVie), an anti-tumor necrosis factor Î± (TNF-Î±) monoclonal antibody, was approved by the FDA for the treatment of adults with non-infectious intermediate, posterior, and panuveitis (NIIPP) in July 2016, based on the results of the multinational phase III VISUAL I and VISUAL II trials.
In October 2018, the indication was expanded to include children ages 2 and older based on results of the SYCAMORE study that investigated adalimumab plus methotrexate for uveitis in patients with juvenile idiopathic arthritis. VISUAL I enrolled patients with active uveitis despite systemic corticosteroid treatment and VISUAL II enrolled patients with corticosteroid-dependent, well-controlled disease.
Treatment failure was analyzed as the primary endpoint in both trials. Compared with placebo, adalimumab reduced the risk of treatment failure by 50% in VISUAL I and by 43% in VISUAL II. VISUAL III was an open-label extension study that enrolled patients from the pivotal trials described previously who either had completed these studies successfully over 18 months or who were discontinued after meeting predefined treatment failure criteria.
Results from VISUAL III showed the previously successfully treated cohort had sustained-disease control while being maintained on subcutaneous adalimumab every other week while patients with active disease who started on adalimumab achieved rapid benefit despite tapering of their corticosteroid dose.
“This is a rare example of where the results of an open-label extension study were as compelling or maybe even more compelling than the results of the preceding randomized trials,” Dr. Suhler said.
Off-label TNF-Î± blockers
Infliximab (Remicade, Janssen) is another anti-TNF-Î± treatment that has demonstrated efficacy in the treatment of NIIPP uveitis. Given as an intravenous infusion every 8 weeks after an initial loading phase, infliximab may be an attractive option for patients who are expected to be non-compliant with self-administered subcutaneous injections, Dr. Suhler said.
Limited data provide evidence that two other anti-TNF-Î± agents, certolizumab (Cimzia, UCB) and golimumab (Simponi, Janssen) are also effective treatment for NIIPP uveitis, in contradistinction to the anti-TNF-Î± fusion protein, etanercept (Enbrel, Amgen), which has been shown fairly clearly to not be effective in treatment of uveitis.
More convenient dosing is a feature of certolizumab and golimumab-both are administered monthly as a subcutaneous injection. Because pharmacokinetic data show low to negligible placental transfer of certolizumab, it is also considered as an attractive option for patients who are pregnant or wanting to become pregnant, Dr. Suhler said.
Discussing safety, Dr. Suhler noted that data from the rheumatology literature show treatment with anti-TNF-Î± agents may be associated with increased risks of malignancy and serious infections. The Systemic Immunosuppressive Therapy for Eye Diseases 1 (SITE-1) study also raised safety concerns, showing increased cancer-specific and all-cause mortality.
New information from SITE-2, which was presented later on the same day, however, showed that with increased follow-up from SITE-1, there did not seem to be an increased risk of malignancy in uveitis patients treated with TNFblockers. As a bottom line, the risk of losing sight from uncontrolled uveitis is greater than the risks associated with anti-TNF-Î± treatment.
“All immunosuppressive drugs carry risk, and while there may be a slightly increased arithmetic risk of malignancy or infection with the anti-TNF-Î± drugs, the overall population attributable risk for these events is low, especially in comparison to the risk of vision loss for patients with poorly treated NIIPP uveitis, which is not low,” Dr. Suhler said.
Rituximab (Rituxan, Genentech/Roche) is a commercially available B-cell blocker indicated for treating several diseases that are associated with scleritis, including rheumatoid arthritis and granulomatosis with polyangiitis, and microscopic polyangiitis.
Dr. Suhler noted that it has also demonstrated efficacy for treatment of scleritis and orbital inflammation in case series from his own institution. In addition, rituximab is being used for treating vitreoretinal lymphoma and has demonstrated efficacy in limited series as treatment for uveitis and ocular cicatricial pemphigoid.
Tocilizumab (Actemra, Genentech/Roche), which blocks interleukin-6 (IL-6), has demonstrated efficacy in a case series of patients with juvenile idiopathic arthritis-associated uveitis, and appears to have particular benefit for controlling uveitic macular edema. In the STOPUVEITIS study, tocilizumab was modestly effective for treating uveitis-related vitreous haze.
“Tocilizumab is much more effective for treating macular edema than inflammatory disease, but it may be worth trying tocilizumab to control inflammation when macular edema is present or in any patient with significant macular edema that is refractory to other therapies,” he said.
Results are being awaited from an NEI-sponsored study investigating the IL-12/23 blocker, ustekinumab (Stelara, Janssen), as a treatment for NIIPP uveitis, and an industry-sponsored multicenter randomized clinical trial is also under way investigating filgotinib (Gilead Sciences), a janus kinase 1 (JAK) inhibitor.
“Filgotinib and other JAK inhibitors act at a very upstream point to block the transcription of pro-inflammatory cytokines and are also appealing because they can be given orally,” Dr. Suhler said.
Eric B. Suhler, MD, MPH
This article was adapted from Dr. Suhler’s presentation during Uveitis Subspecialty Day at the 2018 meeting of the American Academy of Ophthalmology. He is a consultant to, receives lecture fees, and/or receives grant support from AbbVie, Aldeyra, EyeGate, EyePoint, Gilead Sciences, and Santen, and received previous support relevant to this article from Centocor and Genentech.