Objective
The objective of this trial is to assess the safety of tegoprubart and to determine if this experimental agent can prevent graft loss in patients undergoing islet cell transplantation. This is a critical first step in the process of determining whether tegoprubart can replace tacrolimus as the backbone immunosuppressant in patients receiving islet cell transplants. It is hypothesized that tegoprubart would prevent rejection of the engrafted cells at least as well as tacrolimus does, and that tegoprubart would not put the recipient at long term risk of graft loss or of renal dysfunction secondary to tacrolimus toxicity. If this hypothesis is correct, islet transplantation could become a more viable option for poorly controlled T1D patients.
These objectives will be assessed using the following key trial endpoints:
• Incidence of treatment-emergent adverse events (TEAEs)
• Incidence of treatment-emergent serious adverse events (SAEs)
• Incidence of treatment-emergent AEs of special interest (AEoSI).
• Proportion of participants who are insulin-independent at Day 75 and Day 364 post-first and final transplant.
• Proportion of participants with glycosylated hemoglobin (HbA1c) <7.0% (53 mmol/mol) at Day 364 AND free of severe hypoglycemic events (SHEs) from Day 28 to Day 364 post-first and final transplant.
• Proportion of participants with graft failure at Day 364 post final transplant
Background Rationale
Tacrolimus is the main medicine used to prevent rejection in solid organ transplants. It is also a key drug used to prevent rejection of the cells in islet transplant. It works by suppressing the immune response to the new islet cells, but tacrolimus can be directly toxic to the islet cells and to the kidneys, putting recipients at risk for graft loss and kidney dysfunction. An alternative medicine to tacrolimus that effectively prevents the body from rejecting the cells without the side effects, would make improve the outcomes of islet cell transplantation and make this option more broadly available to people suffering with T1D.
Tegoprubart is a monoclonal antibody directed against CD40 ligand (CD40L). Monoclonal antibodies are similar to antibodies your body makes, but these are made in a lab to specifically target something in the body. Tegoprubart targets CD40L, a protein on a class of white blood cells called T cells, which are important cells in the immune system. Blocking CD40L helps turn off two important immune responses to the islet cells, making it more likely that the body will accept the cells. It is hypothesized that tegoprubart could replace tacrolimus as the backbone immunosuppressant medicine in islet cell transplantation, providing similar protection against rejection without the risk of drug induced toxicity to the implanted cells or the kidneys.
This theory has been tested in an animal model of islet cell transplantation where diabetes was induced in the animals, islet cells were transplanted and some animals were treated with tegoprubart and others with tacrolimus. The tegoprubart animals did better than the tacrolimus animals in this study, with better survival, growth and better insulin response to meals with tighter glucose control.
Tegoprubart’s safety has been studied in healthy volunteers and patients with Amyotrophic Lateral Sclerosis. It also currently being studied in patients with kidney disease and in people undergoing kidney transplantation. Because it is designed to block the immune system, the main risk with tegoprubart is infection.
This study is the first study using tegoprubart in patients receiving islet cell transplants. It is designed to primarily assess whether tegoprubart can be safely used for this purpose. In addition, the study will assess how well tegoprubart can prevent rejection of the cells.
Description of Project
Tegoprubart (also known as AT-1501) is an experimental agent being studied in islet cell transplant recipients. Type 1 diabetes (T1D) is a lifelong disease that requires frequent monitoring of blood sugar and treatment with insulin to avoid serious long term complications. T1D is caused by the destruction of the insulin producing islet cells in the pancreas. Transplantation of pancreatic islet cells can provide a functional cure for T1D as the implanted cells produce insulin and restore the physiologic regulation of glucose. Because the implanted islet cells are from a donor, immunosuppression is required to prevent the cells from being rejected (similar to when a kidney is transplanted).
Tacrolimus is the main medicine used to prevent rejection in solid organ transplants. It is also a key drug used to prevent rejection of the cells in islet transplant. It works by suppressing the immune response to the new islet cells, but tacrolimus can be directly toxic to the islet cells and to the kidneys, putting recipients at risk for graft loss and kidney dysfunction. An alternative medicine to tacrolimus that effectively prevents the body from rejecting the cells without the side effects, would make improve the outcomes of islet cell transplantation and make this option more broadly available to people suffering with T1D.
Tegoprubart is a monoclonal antibody directed against CD40 ligand (CD40L). Monoclonal antibodies are similar to antibodies your body makes, but these are made in a lab to specifically target something in the body. Tegoprubart targets CD40L, a protein on a class of white blood cells called T cells, which are important cells in the immune system. Blocking CD40L helps turn off two important immune responses to the islet cells, making it more likely that the body will accept the cells. It is hypothesized that tegoprubart could replace tacrolimus as the backbone immunosuppressant medicine in islet cell transplantation, providing similar protection against rejection without the risk of drug induced toxicity to the implanted cells or the kidneys.
This theory has been tested in an animal model of islet cell transplantation where diabetes was induced in the animals, islet cells were transplanted and some animals were treated with tegoprubart and others with tacrolimus. The tegoprubart animals did better than the tacrolimus animals in this study, with better survival, growth and better islet graft function and insulin response to meals with tighter glucose control.
Tegoprubart’s safety has been studied in healthy volunteers and patients with Amyotrophic Lateral Sclerosis. It also currently being studied in patients with kidney disease and in people undergoing kidney transplantation. Because it is designed to block the immune system, the main risk with tegoprubart is infection.
This study is the first study using tegoprubart in patients receiving islet cell transplants. It is designed to primarily assess whether tegoprubart can be safely used for this purpose. In addition, the study will assess how well tegoprubart can prevent rejection of the cells.
Anticipated Outcome
This is a small, pilot study designed mainly to assess whether tegoprubart could be used safely to prevent rejection of transplanted islet cells. This study will be able to answer that question. Based on the mechanism of action of tegoprubart, it is expected to safely prevent rejection of the implanted islet cells. The anticipated outcome is that tegoprubart will be shown to be safe and well tolerated by this sentinel group of islet cell transplant recipients, and that their engrafted cells all function to reduce or eliminate their need for exogenous insulin without drug related side effects.
Relevance to T1D
This trial is highly relevant to patients with type 1 diabetes (T1D). T1D is a lifelong disease that requires frequent monitoring of blood sugar and treatment with insulin to avoid serious long term complications. T1D is caused by the destruction of the insulin producing islet cells in the pancreas. Transplantation of pancreatic islet cells can provide a functional cure for T1D as the implanted cells produce insulin and restore the physiologic regulation of glucose. Because the implanted islet cells are from a donor, immunosuppression is required to prevent the cells from being rejected (similar to when a kidney is transplanted), and tacrolimus, the main drug to prevent rejection is actually toxic to the implanted islet cells. An alternative medicine to tacrolimus that effectively prevents the body from rejecting the cells without the toxic side effects, would make improve the outcomes of islet cell transplantation and make this option more broadly available to people suffering with T1D. This study is the first one being conducted with tegoprubart, a potential alternative to tacrolimus, in patients undergoing islet cell transplantation. If this drug proves successful it could make islet cell transplantation more available to people with T1D.