Future of uveitis therapy takes shape with new treatments

July 1, 2014

Potentially effective new drugs are in the pipeline for treating uveitis, in addition to several promising formulations in clinical trials.

 

Take Home

Potentially effective new drugs are in the pipeline for treating uveitis, in addition to several promising formulations in clinical trials.

Dr. Van Gelder

By Lynda Charters; Reviewed by Russell N. Van Gelder, MD, PhD

Seattle-Uveitis therapy seems to have a promising future, with many potentially effective new drugs in the pipeline. To date efficacious local and systemic modalities are currently available to treat non-infectious uveitis, several promising formulations are being evaluated in clinical trials, and numerous agents have potential for off-label use.

This is especially noteworthy, because there has been little change over the past decade with regard to uveitis treatment options. Most patients are treated initially with oral or topical corticosteroids. The steroid-sparing immunomodulating drugs, such as methotrexate, are well established and widely used.

Steroid-sparing drugs are efficacious, according to Russell Van Gelder, MD, PhD. Methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine were all evaluated in the Systemic Immunosuppression Therapy for Eye Disease Study.

“All of the drugs show roughly the same efficacy-about 60% to 70%-for the achieving steroid-sparing dose of less than 10 mg prednisone daily,” said Dr. Van Gelder, the Boyd K. Bucey Memorial Chair, Department of Ophthalmology, University of Washington, Seattle.

Though all of these drugs may have serious adverse effects, they may not be as frequent as many believe, Dr. Van Gelder said.

A new development in uveitis treatment during the past few years is the increased use of tumor necrosis alpha (TNF-α) inhibitors, specifically infliximab (Remicade, Janssen Biotech Inc.) and adalimumab (Humira, Abbott Laboratories). The expert panel review of the American Uveitis Society published in Ophthalmology (2014;121:785-796) recommended these drugs as first-line therapies and as steroid-sparing therapies in patients with Behçet’s disease and that they be used early in the treatment of juvenile idiopathic arthritis in patients for whom methotrexate was not successful, he said.

 

New approved therapies

Difluprednate (Durezol, Alcon Laboratories) is a difluorinated corticosteroid emulsion that was approved to treat anterior uveitis.

“This drug is especially potent,” Dr. Van Gelder said. “It has excellent penetration and can treat uveitic cystoid macular edema even in phakic patients.

“However, it is a two-edged sword in that several recent studies have reported a substantial risk for elevated IOP and cataract formation, especially in children, in whom an IOP elevation of more than 10 mm Hg occurred in about 50% of the children treated with the drug,” he continued. “This drug requires close monitoring.”

Two sustained-release corticosteroid implants have been approved for use in ocular inflammatory disease.

A fluocinolone acetonide intravitreal implant (Retisert, Bausch + Lomb) delivers 0.59 mg of the drug over the course of about 300 days. A dexamethasone intravitreal implant (Ozurdex, Allergan) delivers 0.7 mg between 3 to 6 months.

Both implants are highly potent and are approved to treat intermediate and posterior uveitis. Both also are associated with cataract formation and elevated IOP. The fluocinolone acetonide intravitreal implant carries a greater than 90% risk of cataract formation in phakic patients and about 40% of patients will have to undergo glaucoma surgery after 3 years of drug exposure, according to Dr. Van Gelder.

 

The Multicenter Uveitis Steroid Trial-which compared Retisert with immunomodulation therapies-reported comparable visual acuity outcomes with more control of inflammation in the local therapy arm of the study, but a higher rate of ocular complications with the fluocinolone acetonide intravitreal implant.

Intravitreal methotrexate injection is being studied and several open-label case series have suggested the drug is effective for treating intermediate and posterior uveitis. Corneal toxicity, however, is a possibility with the 0.4-mg dose. The optimal dose remains unknown. A recent study from Moorfields Eye Hospital (Retina. 2013;33:2149-2154) reported that 70% of patients who responded to one methotrexate injection had extended remission of non-infectious uveitis.

Other avenues

Intravitreal TNF-α inhibitors have been studied in diabetic macular edema and Behçet’s disease, and though there was evidence of efficacy, some patients developed severe inflammation after multiple injections. A moratorium on the use of the drugs outside of well-designed, well-monitored clinical trials was advised.

Sirolimus (Santen Pharmaceuticals), a mammalian target of rapamycin inhibitor similar to cyclosporine and tacrolimus, is in a phase III trial for local ophthalmic use. The 6-month results of the Sirolimus as Therapeutic Approach to Uveitis (SAVE) trial showed encouraging results.

Voclosporine (LX211, Lux Biosciences)-a cyclosporine–family calcineurin inhibitor-was tested in a phase III trial of uveitis that required steroid-sparing drugs. The drug did not meet its endpoint of decreased vitreous haze, and the new drug application was withdrawn.

 

Numerous biologics are emerging for treatment of uveitis, including rituximab (anti-CD20, Rituxan, Genentech) for scleritis and granulomatosis with polyangiitis and rheumatoid arthritis, and AIN457 (anti-interleukin 17) (Novartis Pharmaceuticals).

Other biologics that may have off-label uses for uveitis are oclizumab, toclizumab, certolizumab, canakinumab, abatacept, golimumab, and tofacitinib. Dr. Van Gelder said he finds tofacitinib-a small-molecule janus kinase inhibitor-to be especially interesting, as the drug was recently approved to treat methotrexate-resistant rheumatoid arthritis.

“This is a very potent oral immunomodulating drug that may have potential for off-label use in uveitis,” he said. “The next 10 years will be different from the past 10 years in that we will probably have a surplus of treatment options. Determining which of these offers the best comparative efficacy in particular uveitic syndromes will be our greatest challenge.”

 

Russell N. Van Gelder, MD, PhD

E: russvg@uw.edu

Dr. Van Gelder has no personal financial interest in any aspect of this report.  His laboratory in the past has received funding from Alcon Laboratories, Novartis, and Theravance.