Objective
Objective:
This extension of our ongoing study aims to evaluate the safety of a novel immunomodulatory medication, tegoprubart, and determine whether it can preserve and improve the function of islet grafts in patients with type 1 diabetes mellitus (T1DM) and chronic kidney disease (CKD) undergoing islet cell transplantation.
This is a critical step toward determining whether tegoprubart can safely replace tacrolimus, the current standard immunosuppressant, which is often unsuitable for patients with CKD due to its kidney toxicity. These patients are typically excluded from islet transplantation because tacrolimus can worsen kidney function.
We hypothesize that tegoprubart will prevent rejection of transplanted islet cells as effectively as tacrolimus, while offering additional benefits:
• Improved islet graft function, compared to historical outcomes in patients treated with tacrolimus.
• Elimination of the risk of kidney function decline related to tacrolimus toxicity.
If proven effective, this strategy could make islet transplantation a viable treatment option for a much broader group of people with type 1 diabetes and poor blood glucose control.
Study Goals and Key Endpoints:
We will evaluate the study objectives using the following measures:
• Safety: Incidence and severity of side effects related to the study treatment.
• Insulin Independence: The proportion of participants able to stop insulin therapy while maintaining optimal blood glucose control at 75 days and 364 days after their first and final islet transplants.
• Glucose Control: The proportion of participants achieving target HbA1c levels (<7.0% or 53 mmol/mol) by day 364, and the frequency of severe low blood sugar (hypoglycemic) episodes between days 28 and 364.
• Graft Function: The proportion of participants who completely lose islet graft function by or before 364 days post-final transplant.
We will assess outcomes in participants receiving tegoprubart in combination with two different anti-rejection medications, seeking to identify synergistic effects that enhance efficacy and minimize side effects.
Based on encouraging preliminary results from the pilot study, we have expanded the study cohort from three to nine patients, with additional enrollment underway. This larger sample size will yield more robust data on the safety, tolerability, and efficacy of tegoprubart. We will also evaluate factors that may influence individual responses to the treatment.
Collaborative and Future Directions:
We are continuing our collaboration with Dr. Norma Kenyon at the University of Miami to conduct mechanistic studies. The expanded dataset from both the pilot and CKD cohorts will strengthen these analyses, improve the statistical power of our findings, and guide refinements to the treatment protocol for future participants.
The promising results in patients with both normal and impaired kidney function will support engagement with potential sponsors and investors, paving the way for the next phase of clinical development. Ultimately, this work may lead to further optimization of immunosuppressive therapy, bringing us closer to a cure for diabetes.
Importantly, anti-CD40L–based therapies like tegoprubart have demonstrated the potential to promote long-term graft tolerance, possibly enabling full withdrawal of immunosuppressive drugs, as seen in nonhuman primate studies.
Background Rationale
Islet transplantation offers patients with type 1 diabetes (T1D) the opportunity to achieve optimal blood glucose control without the need for external insulin. By providing functional insulin-producing cells (islets) from a donor—often a deceased individual—the procedure can restore natural regulation of blood sugar. However, because these islet cells come from another person, the recipient’s immune system can recognize them as foreign and attack them in a process known as immunologic rejection.
To prevent this, transplant recipients must take anti-rejection (immunosuppressive) medications. Unfortunately, these drugs often come with significant side effects. The most commonly used medication, tacrolimus, is highly effective in preventing rejection but can be directly toxic to both the islet cells and the kidneys. As a result, tacrolimus poses a risk of graft failure and kidney dysfunction, especially concerning in people with preexisting kidney disease.
A safer alternative to tacrolimus—one that prevents rejection without causing organ damage—could dramatically improve outcomes in islet transplantation and make it a viable treatment for a broader group of individuals living with T1D.
Tegoprubart is a promising new therapy. It is a monoclonal antibody that targets CD40 ligand (CD40L), a molecule involved in two key immune pathways that lead to rejection of transplanted cells. By blocking CD40L, tegoprubart can help the body tolerate the islet graft without the toxic effects associated with traditional immunosuppressants like tacrolimus.
Unlike tacrolimus, tegoprubart has shown no toxicity to islets or other organs. It has the potential to be just as effective—or even more so—at preventing rejection, while avoiding the harmful side effects of current treatments. No toxic effect toward kidney has been observed.
In our ongoing pilot study, we replaced tacrolimus with tegoprubart in islet transplant recipients. Early results are highly encouraging. Among the first three patients enrolled:
• The first two patients achieved insulin independence and maintained excellent blood glucose control (HbA1c <5.4%) for over 10 months after transplant.
• Islet graft function, measured by mixed-meal tolerance testing, was 2–3 times better than that seen in historical patients treated with tacrolimus at 1 and 3 months post-transplant.
• There were no adverse events linked to tegoprubart and no signs of kidney damage or other organ toxicity.
These positive findings have led us to expand the pilot study from three to nine patients.
While the current pilot study includes only patients with normal kidney function, the proposed study will evaluate the safety and effectiveness of tegoprubart in patients with chronic kidney disease (CKD)—a group with the most to gain from a safer alternative to tacrolimus.
This is a critically important next step. Diabetes is a leading cause of kidney failure, and many patients with long-standing T1D already suffer from CKD. Unfortunately, these patients are typically excluded from islet transplantation because tacrolimus can further damage their kidneys. A successful outcome with tegoprubart could open the door for islet transplantation in this vulnerable population and provide a truly disease-modifying therapy that reverses diabetes without accelerating kidney disease.
Our study will not only advance the safety and accessibility of islet transplantation but also help pave the way for broader application of this therapy to a much larger segment of the diabetes population.
Description of Project
Type 1 diabetes (T1D) is a lifelong condition where the immune system mistakenly attacks and destroys the insulin-producing cells in the pancreas, called islet cells. Without insulin, the body cannot control blood sugar, so people with T1D must take daily insulin injections or use insulin pumps. These treatments help manage the disease but do not offer a cure or prevent long-term complications such as nerve damage, blindness, or kidney failure.
One exciting option is islet cell transplantation, where healthy insulin-producing cells from a donor are transplanted into a person with T1D. This can restore natural insulin production and blood sugar regulation—essentially acting as a functional cure. However, to prevent the body from rejecting the transplanted cells, patients must take medications that suppress the immune system. The most commonly used drug for this is tacrolimus, which has been effective at preventing rejection in organ transplants for years.
Unfortunately, tacrolimus comes with serious side effects. It is toxic to the islet cells themselves and can cause kidney damage over time. As a result, many people, especially those with early signs of kidney disease, are not eligible for islet transplantation. Even for those who are eligible, long-term outcomes are often limited by these side effects. There is an urgent need for safer and more targeted medications that can protect transplanted cells without harming other organs.
Tegoprubart is a promising new therapy that may solve this problem. It is a monoclonal antibody that blocks a specific protein called CD40 ligand (CD40L), which plays a key role in triggering immune responses that lead to transplant rejection. By turning off this immune signal, tegoprubart could help the body accept transplanted islet cells without the toxic effects of tacrolimus.
Animal studies have shown that tegoprubart leads to better survival of islet cells, stronger insulin production, and improved blood sugar control. It has also been tested safely in humans with other diseases, including ALS and kidney disease. More than 60 patients have received tegoprubart in recent kidney transplant trials, with positive results and minimal side effects—mainly a slightly increased risk of infection.
We recently began testing tegoprubart in people with T1D. In our pilot study, three participants with normal kidney function received islet transplants supported by tegoprubart therapy. The outcomes were very encouraging. Two participants became completely insulin-independent within a few months and have maintained excellent blood sugar control for over 10 months. The third participant reduced insulin use by more than 70%, with much better blood sugar levels, and is on track to become insulin-independent after a second transplant. None of these patients experienced serious side effects, infections, rejection, or kidney problems. Their islet function was two to three times better than seen in patients treated with standard tacrolimus-based therapies.
Building on these results, we are enrolling six more patients with normal kidney function. In the new phase of our study, we will expand to 10 patients, including individuals with early-stage kidney disease—who have previously been excluded due to the toxicity of standard treatments. Five participants will receive tegoprubart with mycophenolate acid, and five will receive it with everolimus, to compare the safety and effectiveness of each combination. The study will be conducted at University of Chicago and University of Miami, leading centers in islet transplantation in the US.
Our goal is to develop a safer and more effective treatment plan for islet cell transplantation—one that makes this life-changing therapy available to more people with T1D, including those with kidney disease. If successful, this research could pave the way toward long-term insulin independence and, ultimately, a real cure for type 1 diabetes.
Anticipated Outcome
In the proposed study, we aim to evaluate the safety and effectiveness of a novel immunomodulatory medication, Tegoprubart, in preserving and improving the function of islet grafts in patients with type 1 diabetes (T1D) and chronic kidney disease (CKD) undergoing islet cell transplantation.
This is a critical next step in determining whether Tegoprubart can safely replace tacrolimus, the current standard immunosuppressant, which is often unsuitable for patients with CKD due to its toxic effects on kidney function. Many patients with CKD are currently excluded from islet transplantation because tacrolimus can accelerate kidney damage.
Based on Tegoprubart’s targeted mechanism of action and promising preliminary data from the first three patients with T1D and normal kidney function, we anticipate that Tegoprubart will:
Effectively and safely prevent rejection of transplanted islet cells,
Be well-tolerated by transplant recipients,
Enable restoration of insulin production, eliminating the need for external insulin, and
Improve islet engraftment and function compared to patients treated with tacrolimus.
We expect that most participants will achieve and maintain insulin independence after a single islet transplant, a significant improvement over current protocols that typically require two transplant procedures when using tacrolimus.
Importantly, patients in the pilot study who received Tegoprubart showed no signs of kidney dysfunction, reinforcing its safety profile. In the proposed study, we anticipate stable kidney function in participants with CKD. Furthermore, improved blood glucose control may help slow or potentially reverse diabetes-related kidney damage over time.
These expectations are also supported by early results from Phase 1 and 2 kidney transplant trials with Tegoprubart, where kidney graft function was better preserved compared to control patients receiving tacrolimus-based therapy.
Additionally, our ongoing mechanistic studies are expected to identify immunological markers of graft acceptance and rejection, which could help refine future treatment protocols. These insights may eventually support complete weaning from immunosuppressive therapy, achieving long-term immune tolerance of the transplanted islets—a major breakthrough in the search for a cure for diabetes.
Relevance to T1D
In type 1 diabetes (T1D), the immune system mistakenly attacks and destroys the insulin-producing islet cells in the pancreas. Because these are the body's only source of insulin, people with T1D must rely on insulin replacement to manage their blood glucose. However, even the most advanced technologies—such as artificial pancreas systems and insulin pumps with continuous glucose monitoring—are not able to perfectly mimic the body’s natural insulin regulation. This can lead to episodes of both dangerously low and high blood sugar levels, increasing the risk of long-term complications.
Islet cell transplantation offers a promising solution. By transplanting healthy insulin-producing cells from a donor (usually a deceased donor). This procedure can restore natural blood glucose control and eliminate the need for external insulin. But because the donor cells are recognized as foreign by the recipient's immune system, patients must take immunosuppressive drugs to prevent rejection of the transplanted islets.
The most commonly used immunosuppressant, tacrolimus, is effective at preventing rejection—but it comes with serious drawbacks. Tacrolimus is toxic to both the transplanted islet cells and the kidneys. This makes it particularly risky for patients with preexisting kidney disease and limits the broader use of islet transplantation.
A safer alternative to tacrolimus—one that prevents rejection without damaging the islets or kidneys—could transform islet transplantation into a widely available and durable treatment for people with T1D.
Tegoprubart is an exciting new candidate to fill this role. It is a monoclonal antibody that targets CD40 ligand (CD40L), a key molecule involved in triggering immune responses that lead to rejection. By blocking this pathway, tegoprubart may allow the body to accept the islet graft while avoiding the toxicity seen with traditional drugs.
Unlike tacrolimus, tegoprubart has not shown any toxicity to islet cells or kidneys. Early results suggest it may be equally or even more effective at preventing rejection, and much safer overall.
At the same time, breakthroughs in stem cell-derived islet technology—such as the recent Vertex trials—have shown these lab-grown cells can successfully produce insulin. These stem cell islets could be manufactured in unlimited supply, unlike donor-derived cells, making them a scalable treatment option for the broader T1D population.
If tegoprubart is proven safe and effective, especially in patients with both normal and impaired kidney function, it could become a cornerstone therapy to support stem cell-derived islet transplantation. Ultimately, this combination could allow many more patients with T1D and poor glucose control to benefit from curative therapy.
Moreover, in animal models, a short course of tegoprubart has even induced long-term acceptance of transplanted islets without the need for lifelong immunosuppression. This raises the possibility of achieving permanent immune tolerance—a crucial step toward a true cure for T1D.