Objective
The objective of this extension of the ongoing study is to evaluate the safety of the novel immunomodulatory medication, tegoprubart, and to determine if it can prevent loss and improve the function of islet grafts in patients with type 1 diabetes mellitus undergoing islet cell transplantation.
This is a crucial step in assessing whether tegoprubart can replace tacrolimus as the primary immunosuppressant for patients receiving islet cell transplants.
We hypothesize that tegoprubart will prevent rejection of the transplanted cells at least as effectively as tacrolimus, improve islet graft function compared to historical patients treated with tacrolimus, and minimize long-term risks of graft loss or kidney dysfunction associated with tacrolimus toxicity. If proven effective, islet transplantation could become a more viable option for patients with type 1 diabetes and poor blood glucose control.
The study objectives will be evaluated using the following key endpoints:
• The presence and severity of side effects related to the study treatment.
• The proportion of participants who can completely stop insulin supplementation maintaning optimal blood glucose control (achieving insulin independence) at 75 days and 364 days after their first and final transplants.
• The proportion of patients achieving target blood glucose control (HbA1c <7.0% or 53 mmol/mol) at 364 days, alongside the frequency of severe low blood glucose episodes from 28 to 364 days post-transplant.
• The proportion of participants who lose islet graft function completely by or before 364 days post-final transplant.
Given already the positive preliminary results from the ongoing pilot study with the first three patients, we plan to expand the study to include six additional participants. This larger group will provide more reliable data on the safety, tolerability, and effectiveness of tegoprubart. Our assessment will consider various factors that may influence drug action and outcomes. For example, we will evaluate the following:
• Patient Body Weight: Since tegoprubart is dosed based on body weight, including a higher number of patients will help us better assess safety and tolerability across a broader weight range.
• Patient Sex: We will examine potential differences in outcomes between male and female recipients.
• Concomitant Medications: We will assess how other medications taken during the study, including antimicrobial prophylaxis and those for individual co-morbidities, may influence outcomes.
Additionally, mechanistic studies in collaboration with Dr. Norma Kanyon from the University of Miami will benefit from increased data points, enhancing the statistical power of our findings and informing adjustments to tegoprubart therapy.
The results from these six additional patients will allow us to refine the protocol for optimal outcomes in future participants.
Promising findings from a larger patient group will strengthen our case for potential investors and sponsors, paving the way for the next phase of studies. This could lead to further optimization of the therapy, ultimately benefiting our patients and advancing the search for a cure for diabetes. Notably, the anti-CD40L approach has shown potential in providing transplant recipients with long-term tolerance to the graft, potentially allowing for complete discontinuation of immunosuppression, as demonstrated in nonhuman primate studies.
Background Rationale
Islet transplantation provides patients with Type 1 diabetes with new functional islet cells and allows for optimal blood glucose control without need to external insulin supplementation. However, as islet cells come from another human being (for example deceased donor) patient immune system can recognize transplanted islets and damage them in the process called immunologic rejection. Therefore, patient needs to take anti-rejection medications, which currently have many potentially dangerous side effects.
Tacrolimus is the most potent and key drug used to prevent rejection of islets or any solid organ transplant. It can be also 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 transplantation and make this option more broadly available to people suffering with T1D.
Tegoprubart is a new immunomodulatory medication, which has potential to be as or even more effective than tacrolimus in prevention of the islet graft immunologic rejection, but has no known toxicity towards islets and other organs therefore not causing side effects as tacrolimus.
In currently ongoing pilot study including, we replaced tacrolimus with tegoprubart and already found favorable outcomes in first three patients comparing to historic subjects treated with tacrolimus. First two patients receiving tegoprubart in our pilot study has already developed insulin independence and maintain optimal blood glucose control (HbA1c <5.4%) four and five months after their first islet transplantation, respectively. Moreover, islet function (islet engraftment based on mixed meal tolerance test) ) was 3-5 time better than in historic patients on tacrolimus assessed 1 and 3 months after the first islet transplant. There have been no adverse events related to tegoprubart, no signs of kidney dysfunction or other toxicity characteristic for tacrolimus.
Now, in the current proposal we are planning to expand the study to six more patients to provide more reliable information about Tegoprubart safety, tolerability and effectiveness. Assessment should take into considerations different factors like patient body weight, sex, co-morbidities, which can affect the drug action, interaction with other drugs and outcomes.
Tegoprubart is a monoclonal antibody directed against CD40 ligand (CD40L). Blocking CD40L helps turn off two important immune responses to the islet cells and allows for their acceptance. 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.
In addition, mechanistic studies which we carry on in collaboration with Dr. Norma Kanyon from the University of Miami will also benefit from more data points, which would increase statistical power of findings, which could guide further adjustment in Tegoprubart therapy.
Findings in additional six patients will allow us to adjust the treatment protocol for more optimal outcomes in subsequent patients.
Promising results on higher number of patients are more convincing for potential investors and sponsors to initiate next phase studies and further optimize the therapy for the ultimate benefit of our patients and cure for diabetes, especially that antiCD40L has potential to provide transplant recipient with permanent tolerance towards the graft and complete discontinuation of the immunosuppression as shown in nonhuman primates.
Description of Project
This proposal aims to extend a pilot study currently underway with three patients suffering from type 1 diabetes mellitus. The study investigates the safety and efficacy of a new immunomodulatory agent, tegoprubart, to protect transplanted pancreatic islets, with the ultimate goal of achieving insulin independence in these patients.
Initial results from the first three subjects are promising. The first two patients became insulin-independent in an accelerated manner and have maintained optimal blood glucose control four and five months post-transplant, respectively. The third patient, who underwent transplantation just two weeks ago, is already achieving excellent blood glucose control (99% time-in-range) with over a 70% reduction in insulin requirements (20 units per day, down from 90 units prior to transplant). All three patients have tolerated tegoprubart therapy well, with no related adverse events, infections, or islet rejection. Furthermore, islet function in these patients has been three to five times better than in previous cases treated with standard immunosuppression using tacrolimus.
We now plan to enroll six additional patients to further investigate the safety and efficacy of tegoprubart, focusing on various patient characteristics such as weight, insulin requirements, sex, and co-morbidities.
Tegoprubart (also known as AT-1501) is an experimental treatment being studied for islet transplant recipients. Type 1 diabetes (T1D) is a lifelong condition that requires continuous blood sugar monitoring and insulin therapy to prevent severe long-term complications. T1D results from the destruction of insulin-producing islet cells in the pancreas. Transplanting these cells can provide a functional cure by restoring natural insulin production and glucose regulation. However, since these cells come from donors, immunosuppression is necessary to prevent rejection, much like in kidney transplants.
Tacrolimus is the primary medication used to prevent rejection in solid organ transplants, including islet transplants. While it suppresses the immune response to new islet cells, it can also be toxic to these cells and to the kidneys, increasing the risk of graft loss and kidney dysfunction. A safer alternative that effectively prevents rejection without such side effects would significantly improve transplant outcomes and broaden access to this treatment for individuals with T1D.
Tegoprubart is a monoclonal antibody that targets CD40 ligand (CD40L), a protein on T cells, which are crucial to the immune system. By blocking CD40L, tegoprubart may deactivate two key immune responses that can lead to the rejection of islet cells, thereby enhancing the likelihood of acceptance. This agent has the potential to replace tacrolimus as the primary immunosuppressant in islet cell transplantation, providing protection against rejection without the associated toxicity.
In animal models of islet cell transplantation, those treated with tegoprubart showed better outcomes compared to those treated with tacrolimus, including improved survival, growth, islet function, and glucose control.
Tegoprubart's safety has been evaluated in healthy volunteers and patients with amyotrophic lateral sclerosis (ALS) and kidney disease. While the main risk associated with tegoprubart is infection, over 60 patients have been successfully treated in recent multicenter trials for kidney transplantation, with preliminary results supporting its safety and advantages over standard tacrolimus therapy.
This study is the first to investigate tegoprubart in islet cell transplant patients. It primarily aims to assess the safety of this treatment while also evaluating its ability to promote islet engraftment and survival, ultimately seeking to achieve insulin independence and a functional cure for diabetes.
The Ethics Committee (IRB) at the University of Chicago and the FDA have reviewed and approved the proposed study protocol, allowing for the extension of the study to include six additional patients. Six additional patients meeting the enrollment criteria have been already identified and they are awaiting extension of the study.
Anticipated Outcome
This is extension of the small pilot study involving 3 patients, which is primarily designed to evaluate whether tegoprubart can be used safely to prevent rejection of transplanted islet cells. The study extension on additional 6 patients will be able to answer this question.
Based on tegoprubart’s mechanism of action and preliminary from the first 3 patients, we anticipate it will effectively and safely prevent rejection of the implanted islets. The expected outcome is that tegoprubart will be demonstrated to be safe and well-tolerated by this sentinel group of islet transplant recipients, while their engrafted cells will function to eliminate their need for exogenous insulin.
With the extension of the study on more patients, we aim to obtain more reliable information regarding tegoprubart's safety, tolerability, and effectiveness. This assessment will consider various factors, such as patient body weight, sex, and co-morbidities, which may influence the drug's action, interactions with other medications, and overall outcomes.
Given the promising preliminary results in first 3 patients, we also expect that islet engraftment and function will improve compared to patients who have received tacrolimus as immunosuppressive therapy. It is anticipated that most study participants will achieve and maintain insulin independence following a single islet transplantation, contrasting with the typical requirement of two transplant procedures in patients treated with tacrolimus. Moreover, since no significant toxic side effects have been observed so far, we expect tegoprubart to be safer and better tolerated than tacrolimus in islet transplant recipients.
Additionally, ongoing mechanistic studies are expected to reveal new immunological markers of graft acceptance and rejection, which could inform future modifications to the therapy. These findings hold the potential to lead to complete weaning from immunosuppression, ultimately achieving permanent immunologic tolerance of the graft.
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. Preliminary results in first 2 patients do indicate advantage of Tegoprubart over tacrolimus and now we are seeking funding to extend the study to six more patients to obtain more data to confirm those findings.
In addition, Tegoprubart has potential to induce tolerance to the islet graft as found in non-human primate model, which would allowing stop immunosuppression completely in the future. It would have a great impact on the field and critical step towards a cure for type 1 diabetes.