Intravitreal sirolimus for persistent, exudative age-related macular degeneration: a Pilot Study

(2021) 7:11 Minturn et al. Int J Retin Vitr https://doi.org/10.1186/s40942-021-00281-0 ORIGINAL ARTICLE International Journal of Retina and Vitreous Open Access Intravitreal sirolimus for persistent, exudative age‑related macular degeneration: a Pilot Study Robert J. Minturn1, Peter Bracha2, Margaret J. Klein3, Jay Chhablani4, Ashley M. Harless5 and Raj K. Maturi1,5* Abstract Background and objective: To evaluate the safety and efficacy of intravitreal sirolimus for persistent, exudative agerelated macular degeneration (AMD). Methods: This institutional review board approved, registered (NCT02357342), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative Age-related macular degeneration compared intravitreal sirolimus monotherapy (every 2 months) versus monthly anti-vascular endothelial growth factor (VEGF) over six months. Results: 20 subjects were randomized to each arm of the trial. Upon completion of the trial 20 patients were analyzed in the control (anti-vascular endothelial growth factor) group and 17 patients were analyzed in the treatment (sirolimus) group. On average, subjects had 33 previous anti-VEGF injections prior to entry. The primary end-point, mean central subfield thickness (CST), increased by 20 µm in the anti-vascular endothelial growth factor group and decreased by 40 µm in the sirolimus group (p = 0.03). Visual acuity outcomes were similar between groups. Serious ocular adverse events in the sirolimus group included one subject each with anterior uveitis, central retinal artery occlusion and subretinal hemorrhage. Conclusion: Monotherapy with intravitreal sirolimus for subjects with persistent, exudative age-related macular degeneration appears to have a limited positive anatomic benefit. The presence of adverse events in the experimental group merits further evaluation, potentially as an adjuvant therapy. Trial registration This trial was registered with the clinicaltrials.gov, NCT02357342, and was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study. Keywords: Sirolimus, Rapamycin, Anti-vascular endothelial growth factor, Exudative age-related macular degeneration Background and objective In the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT), 53% of patients on monthly ranibizumab and 71% on monthly bevacizumab *Correspondence: 1 Department of Ophthalmology, Indiana University School of Medicine, 10300 N Illinois St, Suite 1060, Indianapolis, IN 46290, USA Full list of author information is available at the end of the article had persistent intra- and/or subretinal fluid at one year, with higher rates in the treat-and-extend arms [1, 2]. Persistent intraretinal fluid and a thicker subretinal tissue complex portend worse visual outcomes [3–5]. Alternate therapies may be of benefit. Sirolimus, the generic name for rapamycin, is a macrolide compound produced by the bacterium Streptomyces hygroscopicus. It has been FDA approved for the © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Minturn et al. Int J Retin Vitr (2021) 7:11 prevention of kidney transplant rejection and coronary stent coating. Previously studied in small pilot studies, rapamycin’s immunosuppressive and anti-proliferative qualities, make it an intriguing option for the treatment of exudative AMD [6–8]. In mouse retinal laser photocoagulation models, oral treatment with sirolimus significantly reduced the extent of neovascularization, in a VEGF-independent manner [9]. In senescence-accelerated OXYS rats, systemic sirolimus reduced the severity of retinopathy in a dose-dependent manner [10]. Intravitreal sirolimus was well-tolerated in rabbits and demonstrated retino-choroidal migration supporting its potential use in chorioretinal disease [11, 12]. In human studies, Sirolimus has been used systemically in a 3 person cohort and demonstrated a decreased number of needed intravitreal Avastin injection per month [6]. Finally, intravitreal sirolimus has undergone two large phase III studies in the treatment of non-infectious uveitis and is currently undergoing a third phase III study [13, 14]. Our desire is to build upon previous research and examine a larger cohort in a randomized monotherapy comparison of anti-VEGF treatments and intravitreal sirolimus for persistent, wet AMD. Patients/materials and methods Study design This prospective, 6-month, subject-masked trial was conducted at a single site. One-year safety monitoring was performed in a subset of subjects—those who were still in the study when the amendment was approved. Each subject provided written informed consent before enrollment. The study site complied with the Health Insurance Portability and Accountability Act and adhered to the tenets of the Declaration of Helsinki. Participants Eligible patients were recruited from the practice of the principal investigator. Inclusion criteria included an age of 50 years or older, best-corrected visual acuity (VA) measured between 5 and 75 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent 20/32–20/800), presence of choroidal neovascularization secondary to AMD, at least 3 previous intravitreal anti-VEGF injections in the past 5 months, and a lack of response to anti-VEGF therapy defined as continued subretinal or intraretinal fluid with a decrease in central subfield thickness of less than 100 µm since the last injection. Ocular exclusion criteria included aphakia, a history of pars plana vitrectomy, a history of major ophthalmic surgery in the past 3 months, any ophthalmic surgery within the past 30 days, a history of significant ocular disease other than exudative AMD, uncontrolled ocular Page 2 of 10 hypertension and the presence of significant epiretinal membrane. Treatment groups and randomization Eligible su (...truncated)