Lulizumab pegol

Several investigational agents are under evaluation in systemic lupus erythematosus (SLE) clinical trials but quantitative frameworks to enable comparison of their efficacy to reference benchmark treatments are lacking. To benchmark SLE treatment effects and identify clinically important covariates, we developed a model‐based meta‐analysis (MBMA) within a latent variable model framework for efficacy end points and SLE composite end point scores (BILAG‐based Composite Lupus Assessment and Systemic Lupus Erythematosus Responder Index) using aggregate‐level data on approved and investigational therapeutics. SLE trials were searched using PubMed and www.clinicaltrials.gov for treatment name, SLE and clinical trial as search criteria that resulted in four data structures: (1) study and investigational agent, (2) dose and regimen, (3) baseline descriptors, and (4) outcomes. The final dataset consisted of 25 studies and 81 treatment arms evaluating 16 different agents. A previously developed (K Goteti et al. 2022) SLE latent variable model of data from placebo arms (placebo + standard of care treatments) was used to describe aggregate SLE end points over time for the various SLE placebo and treatment arms in a Bayesian MBMA framework. Continuous dose‐effect relationships using a maximum effect model were included for anifrolumab, belimumab, CC‐220 (iberdomide), epratuzumab, lulizumab pegol, and sifalimumab, whereas the remaining treatments were modeled as discrete dose effects. The final MBMA model was then used to benchmark these compounds with respect to the maximal efficacy on the latent variable compared to the placebo. This MBMA illustrates the application of latent variable models in understanding the trajectories of composite end points in chronic diseases and should enable model‐informed development of new investigational agents in SLE.

Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m² IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4⁺PD-1⁺ICOS⁺), and proliferating B cells (CD20⁺Ki67⁺) in the lymph nodes. Interestingly, regulatory T cell (CD4⁺CD25⁺CD127^lo) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7⁺CD45RA⁺) and naïve B cells (IgD⁺CD27^-CD20⁺) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p<0.05) and lower antibody-mediated rejection scores compared to control animals. However, all desensitized animals eventually developed AMR and graft failure. Desensitization with CFZ and Lulizumab improves allograft survival in allosensitized NHPs, by transient control of the germinal center and shifting of the immune system to a more naive phenotype. This regimen may translate into clinical practice to improve outcomes of highly sensitized transplant patients.