lulizumab pegol (BMS-931699) / BMS - LARVOL DELTA

Costimulation blockade: the next generation. (PubMed, Curr Opin Organ Transplant) - "The focus in transplantation is shifting toward safer, long-term therapies with greater accessibility. Investigational agents with subcutaneous delivery methods could overcome logistical challenges, improve adherence, and redefine posttransplant care. These advancements in costimulation blockade may enhance long-term graft survival and transform the management of KT recipients."

Journal • Cardiovascular • Transplantation • CD40LG

Treg Modulation With CD28 and IL-6 Receptor Antagonists (clinicaltrials.gov) - P1/2 | N=24 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | N=10 ➔ 24

Enrollment change • Transplantation

Model-based meta-analysis using latent variable modeling to set benchmarks for new treatments of systemic lupus erythematosus. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "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."

Journal • Retrospective data • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Treg Modulation With CD28 and IL-6 Receptor Antagonists (clinicaltrials.gov) - P1/2 | N=10 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Active, not recruiting ➔ Completed

Trial completion • Transplantation

Treg Modulation with CD28 and IL-6 Receptor Antagonists in Kidney Transplant Recipients: Results of CTOT-24, a Prospective Clinical Trial (ATC 2023) - "Subjects received Thymoglobulin (3 mg/kg), LUL+TCZ (mth 0-3), belatacept+ TCZ (mth 3-6), and long-term belatacept (6 mth+) (Fig 1A), along with steroids and MMF/everolimus...The remaining 3 subjects completed the novel regimen without any episodes of acute rejection, and remain on belatacept, MMF, prednisone with excellent graft function (mean GFR 83.9 ml/min/1.73 m 2 ) at the last visit... A novel IS regimen combining lulizumab with tocilizumab in low immunologic risk live donor kidney transplant recipients was associated with a high incidence of acute rejection in this pilot study. Failure of the combination to increase Treg frequencies may underlie the observed lack of efficacy."

Clinical • Late-breaking abstract • Hematological Disorders • Neutropenia • Novel Coronavirus Disease • Transplant Rejection • Transplantation • CD4 • CD8 • FOXP3 • IL6

Selective CD28 Blockade in Renal Transplant Recipients (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | N=54 ➔ 0 | Trial completion date: Oct 2024 ➔ Sep 2022 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Aug 2023 ➔ Sep 2022

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Transplantation

Treg Modulation With CD28 and IL-6 Receptor Antagonists (clinicaltrials.gov) - P1/2 | N=10 | Active, not recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Apr 2024 ➔ Aug 2023 | Trial primary completion date: Apr 2024 ➔ Aug 2023

Trial completion date • Trial primary completion date • Transplantation

Treg Modulation With CD28 and IL-6 Receptor Antagonists (clinicaltrials.gov) - P1/2 | N=10 | Active, not recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial primary completion date: Sep 2022 ➔ Apr 2024

Trial primary completion date • Transplantation

Treg Modulation With CD28 and IL-6 Receptor Antagonists (clinicaltrials.gov) - P1/2 | N=10 | Active, not recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2022 ➔ Apr 2024 | Trial primary completion date: Jun 2022 ➔ Sep 2022

Enrollment closed • Trial completion date • Trial primary completion date • Transplantation

Selective CD28 Blockade in Renal Transplant Recipients (clinicaltrials.gov) - P2; N=54; Not yet recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Clinical • New P2 trial • Transplantation

Treg Modulation With CD28 and IL-6 Receptor Antagonists (clinicaltrials.gov) - P1/2; N=10; Recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Trial primary completion date: Apr 2021 ➔ Jun 2022

Trial primary completion date • Renal Disease • Transplantation

Preoperative Carfilzomib and Lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model. (PubMed, Kidney Int) - "We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model...Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone...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."

Journal • Antibody-mediated Rejection • Immune Modulation • Inflammation • Transplantation • IL7R

[VIRTUAL] Carfilzomib and lulizumab-based desensitization prolongs allograft survival in sensitized non-human primates kidney transplantation model (TTS 2020) - "We previously reported the benefit of desensitization using carfilzomib and belatacept in a non-human primate (NHP) model.  Here we evaluated a desensitization strategy combining carfilzomib (CFZ) with lulizumab (CD28dAb) which, conceptually, has greater immunoregulatory benefit over belatacept by selectively blocking the co-stimulating signal (CD28-B7) whilst preserving the co-inhibitory signal (CTLA4-B7)...All primates received induction therapy with rhesus-specific antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate, and methylprednisolone... Desensitization with CFZ and CD28dAb significantly prolongs allograft survival in allosensitized NHPs by reducing DSA and the germinal center response, likely by promoting a more naive lymphocyte repertoire and increasing the frequency of Tregs. Despite this, the strategy failed to promote durable desensitization, suggesting the need for continuous control of the humoral immune..."

Antibody-mediated Rejection • Immune Modulation • Inflammation • Transplantation • CD14 • CD19 • CD20 • CD27 • ICOS • IL2RA • IL7R • PD-1 • SDC1

CD28 superagonist-mediated boost of regulatory T cells increases thrombo-inflammation and ischemic neurodegeneration during the acute phase of experimental stroke (J Cereb Blood Flow Metab) - "Mechanistically, Treg increased thrombus formation in the cerebral microvasculature. These findings confirm that Treg promote thrombo-inflammatory lesion growth during the acute stage of ischemic stroke."

Clinical • Immunology • Inflammation

Relative Bioavailability of BMS-931699 From Prefilled Syringe Compared to Drug in Vial (clinicaltrials.gov) - P1; N=60; Not yet recruiting; Sponsor: Bristol-Myers Squibb

New P1 trial • Biosimilar

Treg Modulation With CD28 and IL-6 Receptor Antagonists (clinicaltrials.gov) - P1/2; N=10; Not yet recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

New P1/2 trial

Treg Modulation With CD28 and IL-6 Receptor Antagonists (clinicaltrials.gov) - P1/2; N=10; Recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Not yet recruiting ➔ Recruiting

Enrollment open

Dual Targeting Desensitization with Carfilzomib Plus Lulizumab Significantly Prolongs Kidney Transplant Survival in Allosensitized Nonhuman Primates (ATC 2019) - "...Rhesus-specific antithymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone.* T cell flow crossmatch analysis of serum from the CFZ+CD28dAb treated group demonstrated a significant reduction in donor specific antibody after desensitization (ΔMFI -708±83, p<0.05)...Survival in the CFZ+CD28dAb group was significantly improved compared to the control group and similar to our experience using CFZ+Belatacept (see Figure). Dual targeting desensitization with CFZ+CD28dAb leads to increased proportions of naive immune cells and improves allograft survival in allosensitized NHPs. This dual targeting regimen may translate into a clinical desensitization protocol to improve outcomes for highly sensitized transplant recipients."