sirolimus and Panuveitis

Local therapeutics play an important role in the management of infectious and noninfectious uveitis (NIU) as well as certain masquerade syndromes. This review highlights the established therapeutics and those under investigation for the management of uveitis.. An injectable long-acting fluocinolone acetonide insert was recently approved by the Food and Drug Administration for the treatment of NIU affecting the posterior segment. Intravitreal methotrexate, sirolimus, and anti-vascular endothelial growth factor (VEGF) agents are being evaluated for efficacy in NIU. Intravitreal foscarnet and ganciclovir are important adjuncts in the treatment of viral retinitis as are methotrexate and rituximab for the management of vitreoretinal lymphoma.. Local injectable steroids with greater durability are now available for NIU but comparative efficacy to other treatment modalities remains to be determined. Local steroid-sparing immunosuppressive agents are undergoing evaluation for efficacy in NIU as are anti-VEGF agents for uveitic macular edema. Local antivirals may improve outcomes in cases of viral retinitis. Local chemotherapeutics can help induce remission in vitreoretinal lymphoma.

Topics: Anti-Infective Agents; Drug Implants; Eye Infections, Bacterial; Fluocinolone Acetonide; Glucocorticoids; Humans; Immunosuppressive Agents; Methotrexate; Panuveitis; Rituximab; Sirolimus; Uveitis, Intermediate; Uveitis, Posterior

In recent decades, the treatment paradigm for noninfectious intermediate uveitis, posterior uveitis, and panuveitis, a group of intraocular inflammatory diseases, has included systemic and local (periocular or intraocular) corticosteroids, biologics, and other steroid-sparing immunomodulatory therapy agents. Recently, an intravitreal formulation of sirolimus, an immunosuppressant that inhibits the mammalian target of rapamycin, a key regulator of cell growth in the immune system, was developed. On the basis of this mechanism and the local method of delivery, it was hypothesized that intravitreal sirolimus can improve ocular inflammation in patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis, with minimal systemic exposure and systemic adverse events (AEs). This review summarizes the pharmacokinetics, efficacy, and safety results of intravitreal sirolimus from 3 preclinical studies and 4 phase 1-3 clinical studies. Preclinical studies in rabbits showed that 22 to 220 μg intravitreal sirolimus results in sustained release of sirolimus in the vitreous for 2 months or more, with systemic concentrations below the threshold for systemic immunosuppression (approximately 8 ng/ml). Subsequently, 2 phase 1 studies (n = 50 and n = 30) established that intravitreal sirolimus improves ocular inflammation in humans. Further investigation in phase 2 and 3 studies (n = 24 and n = 347, respectively) suggested that 440 μg has the best benefit-to-risk profile. In the phase 3 study, the proportion of patients who showed complete resolution of ocular inflammation at month 5 was significantly higher in the 440-μg group than in the 44-μg group (22.8% vs. 10.3%; P = 0.025, Fisher exact test). In addition, 47 of 69 patients (68.1%) who were treated with systemic corticosteroids at baseline discontinued corticosteroid use at month 5. No sirolimus-related systemic AEs were reported in phase 1-3 studies. Collectively, these preclinical and clinical study data of intravitreal sirolimus support the therapeutic rationale of treating noninfectious uveitis with a local mammalian target of rapamycin inhibitor and suggest that 440 μg intravitreal sirolimus has the potential to be an effective and well-tolerated anti-inflammatory and corticosteroid-sparing treatment for noninfectious intermediate uveitis, posterior uveitis, and panuveitis.

Topics: Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Immunosuppressive Agents; Intravitreal Injections; Panuveitis; Sirolimus; Uveitis, Intermediate; Uveitis, Posterior