Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease. Current therapies afford clinical improvement, however, they are not curative and elicit significant side-effects. We discovered that the mechanistic target of rapamycin (mTOR) is activated in ?untouched? T cells, which precedes disease flares and underlies abnormal lineage specification in patients with SLE. mTOR is also activated and sirolimus blocks autoimmunity and any sign of disease in lupus-prone mice. Therefore, we initiated a prospective study of rapamycin (sirolimus by generic designation) in SLE patients unresponsive or intolerant to conventional medications. As primary clinical efficacy endpoint, SLEDAI and BILAG scores were progressively reduced over 12 months in 16/29 patients (55%). 19/29 patients (65.5%) met criteria for SLE Responder Index (SRI). Prednisone use was markedly diminished. Sirolimus expanded Tregs and CD8+ memory T cells and inhibited IL-4 and IL-17 production by CD4+ and CD4-CD8- double-negative T cells. To validate the results of this recently completed clinical trial and to address critical knowledge gaps in the responsiveness of individual patients, we propose this R34 planning grant to refine the design and infrastructure in support of a multicenter trial to evaluate the safety, efficacy, and mechanism of action by sirolimus. The primary clinical outcome measure will be the difference in SRI.
The aims for this application include: 1) Bring together lupus investigators in a multi-center study with a coherent management structure and clear communication strategy; 2) Refine the study protocol for determining the safety and efficacy of sirolimus to ensure a clinically meaningful premise, efficient and affordable trial size, and interpretable results; 3) Standardize clinical assessment techniques to ensure reliability of the primary and secondary outcomes; 4) Design and implement a 21 CRF part 11 compliant electronic data capture system; 5) Establish monitoring procedures for data collection and management; 6) Establish standard procedures for the distribution and handling of study drug from SUNY Pharmacy to each participating center; 7) Adopt standard procedures for blood and urine sample collection and transportation to SUNY Laboratories; 8) Establish compliance with regulatory requirements at each center; 9) Develop protocols for sharing of data and future use of stored biospecimen; 10) Address pitfalls in trial planning; and 11) Finalize the Clinical Protocol, DSMP, CRFs, SOPs, Consent Forms, and Investigators Brochure to meet FDA and OHRP policy requirements as well as the Manual of Operations and Procedures as required by NIAID. The preliminary specific aims for the future clinical trial will be to: 1) Confirm safety and determine efficacy of sirolimus relative to placebo in 184 SLE patients (92 patients per arm, with up to 36 additional subjects to be enrolled for titration of sirolimus to tolerance within a dosage range of 1 to 4 mg/day through an initial 3-month open label period) during a 12-month intervention followed by a 1-month washout; 2) Determine whether mTOR blockade and correction of lineage skewing are sustained over 12 months and predict responsiveness to sirolimus. This study will establish the role of sirolimus as a novel, safe, effective, and biomarker-driven treatment for SLE.
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology that affects up to 1.5 million people in the United States. The disease has debilitating and potentially life-threatening consequences with mortality still approaching 10% over 5 years. There is unmet medical need, as current treatments are only partially effective and have significant side effects. As originally uncovered in our laboratory and overwhelmingly confirmed by others, the mechanistic target of rapamycin, a serine/threonine kinase, is prominently overexpressed in T lymphocytes of patients with SLE; this may be a key factor that causes immune system dysfunction and self-destructive autoimmunity. Administration of sirolimus blocks autoimmunity and any sign of disease in lupus prone mouse strains. As evidenced by a recently completed prospective, open-label clinical trial, rapamycin, also called sirolimus, elicits rapid, progressive, and sustained improvement of disease activity by correcting pro-inflammatory T-cell lineage specification in patients with active SLE. This R34 planning grant has been initiated to bring together experienced lupus investigators with a coherent management structure and clear communication strategy to evaluate the safety and clinical efficacy of sirolimus as well as the mechanisms of action and responsiveness over 12 months in a phase II multi-center, randomized, double-blind, placebo-controlled clinical trial, designated as ?Treatment of SLE with sirolimus? (SLESIR), that meets FDA, OHRP and NIAID regulations and policy requirements. The preliminary specific aims for the future clinical trial will: 1) Determine the safety and therapeutic efficacy of sirolimus relative to placebo in SLE patients over 12 months followed by a 1-month washout (future Aim 1). 2) Determine whether the mTOR activation predicts clinical responsiveness and test the hypothesis that the reversal of mTOR activation is sustained and mediate clinical efficacy over 12 months (future Aim 2).