Breakthrough - T1DM and Chronic Kidney Disease

This study is funded by Breakthrough T1D (formerly the Juvenile Diabetes Research Foundation) and Emerald Clinical Trials will be acting as the clinical research organization (CRO) for this study, overseeing data integrity, compliance and monitoring clinical trial activity. They will help with development of all regulatory and fully supporting University of Miami.

Islet cells are the specialized cells in the pancreas that produce insulin. In this study, islet cells will be collected from the pancreas of a deceased organ donor in a special laboratory at University of Chicago and then transplanted into the body at the University of Chicago hospital. The goal of this study is to see whether these transplanted islet cells can take over insulin production for the body. The study team will evaluate how well make insulin and how well controlled blood sugar is after the transplant. Islet transplantation has been performed and continuously optimized under clinical studies at the University of Chicago for the past 20 years. During this time, several new, potentially more effective and less toxic combinations of immunosuppressive medications have been evaluated. More recently, Tegoprubart has been tested in a small number of patients with T1D and only mild kidney dysfunction, in combination with mycophenolic acid (Myfortic). Given the promising preliminary results, Tegoprubart is now being studied in pancreatic cell transplantation together with either mycophenolic acid (MPA) or everolimus as part of the immunosuppressive regimen also in patients, who were previously ineligible for islet transplantation due to more advanced kidney dysfunction.

The islet transplant procedure involves inserting a thin, flexible tube called a catheter through a small cut in the upper abdomen. A radiologist uses x-rays and ultrasound to guide the catheter into the portal vein of the liver where the islet cells are delivered. This study of islet transplantation will test to see if islet transplantation is safe and effective; performing this study will help us find if this new medication Tegoprubart, combined with either MPA or everolimus and other medication the provider has been using routinely so far, would protect sufficiently islet transplant from the destruction by the immune system, allowing to stop insulin and have improved blood glucose control. At the same time, the providers will observe if these therapies are safe and other patients participating in the study.

Because these islet cells came from another person, the immune system may recognize them as foreign and attack them. Standard immunosuppressive medicines (Anti-thymocyte globulin [ATG] or Basiliximab and Etanercept) with either MPA or everolimus will be used to help prevent the body from attacking the transplanted islet cells. Immunosuppressive medicines may also be called anti-rejection medicines. Tegoprubart will be given in combination with these standard immunosuppressive medicines to test whether the investigational drug is safe, tolerable, and efficacious. The effect of the combination of Tegoprubart with other immunosuppressant medications has not been previously tested.

Tegoprubart is a monoclonal antibody. Antibodies are Y-shaped proteins that are produced naturally by their immune system to attack and fight foreign substances that cause illness. Monoclonal antibodies are man-made proteins manufactured to serve as substitute antibodies to fight diseases. Monoclonal antibodies can restore, enhance, or mimic (copy) the immune system's attack process; they can also tone down the immune system. Tegoprubart is thought to work by dampening down our immune system so that it will be less likely to attack the transplanted cells. For other types of transplants, like kidneys, a drug called a calcineurin inhibitor is usually used to prevent rejection. That class of drugs can be toxic to islet cells. Tegoprubart is an experimental agent that is anticipated to prevent rejection without harming the islet cells. This study will test this hypothesis. Early results from a recent kidney transplant study using Tegoprubart with Myfortic show that Tegoprubart appears to be less harmful to the insulin-producing cells, the kidneys, and the nervous system compared with tacrolimus and is comparable in prevention of rejection and risk of infectious and developing blood clots in blood vessels.

The Tegoprubart for this study has been provided by Eledon Pharmaceuticals.

Participants are eligible for consideration for the study only if all of the following criteria apply at the time of screening Inclusion:

• Subjects 18-70 years of age.
• A diagnosis of T1D ≥5 years with onset of disease at <40 years of age.
• Ability to provide informed consent.
• Able to comply with study procedures, including the requirement to utilize continuous glucose monitoring (CGM).
• Involvement in appropriate diabetes management in accordance with the standard of care, using an insulin pump or multiple daily injection (MDI) insulin therapy and, unable to achieve acceptable metabolic control because of the occurrence of unexplained SHEs.
• HbA1c level 6.5% to 9.5% inclusive.
• Absence of stimulated C-peptide (<0.3 ng/mL) in response to a mixed- meal tolerance test (MMTT).
• Chronic kidney disease stage 1, 2 or 3a
• Impaired awareness of hypoglycemia based on:

• IAH (HypoA-Q Impaired Awareness Subscale ≥12) and at least one level 3 SHE during the last year or
• IAH and time-below-range (<70 mg/dl) ≥4% with level 2 hypoglycemia (<54 mg/dl) ≥1% (in Diabetes Care, Jan 2025, Patrick Choudhary) or
• Clarke Score >4 or
• Recurrent SHE defined by two or more level 3 SHEs in the year prior to screening
• If female, must be surgically sterile or postmenopausal. Women of childbearing potential may be enrolled if a pregnancy test is negative at screening/baseline. Women of childbearing potential and men with partners that are of childbearing potential must agree to use 2 forms of highly effective methods of contraception from Screening, throughout the study, and while receiving immunosuppressive therapy for the functioning graft after the conclusion of the study. Contraception use must continue for 90 days after the last administration of the study drug (see Appendix 5). Male participants must refrain from donating sperm for the duration of the study and agree to not donate sperm for 90 days after last administration of the study drug.

Exclusion criteria

• Body mass index (BMI) >30 kg/m2.
• Weight ≤40 kg.
• Insulin requirement >60units/day or <15 units/day.
• Untreated and uncontrolled proliferative diabetic retinopathy.
• Blood pressure: systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg.
• Chronic kidney disease stage 3b or above.
• Diagnosis of macroalbuminuria (ACR>300 mg/g creatinine).
• For female participants: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 90 days after discontinuation. For male participants: intent to procreate during the duration of the study or within 90 days after discontinuation or unwillingness to use effective measures of contraception.
• History of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
• History of a thromboembolic event (TE), known hypercoagulable state, or condition requiring long-term anticoagulation:

• Participants with a history of clotted venous access not requiring long- term anticoagulation may be included at the Principal Investigator's discretion if they have no other history of TEs or known hypercoagulable state.
• Patients on aspirin are allowed.
• Receiving treatment for a medical condition requiring chronic use of systemic steroids, except for physiologic replacement for example in Addison disease.
• Presence of ongoing active infection including tuberculosis (TB), human immunodeficiency virus (HIV), hepatitis B, hepatitis C. Laboratory evidence of active infection even in the absence of clinical symptoms of infection is exclusionary.
• Invasive aspergillus, histoplasmosis or coccidioidomycosis infection within one year prior to Screening.
• Negative screen for Epstein-Barr Virus (EBV) by immunoglobulin G (IgG) determination.
• Current treatment with any immunosuppressive regimen, and treatment with biologic immune modulating agents, JAK inhibitors, S1P receptor agonists, azathioprine, 6- MP, or systemic corticosteroids.
• Baseline PRA over 40%
• Previous organ transplant (except failed pancreas or islet transplant)
• Persistent elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value greater than 3 times the upper limit of normal (ULN); elevation of total bilirubin >1.5 ULN.
• Any history of receiving experimental cell or gene therapy. Exposure to any other experimental or investigational agent within 30 days or 5 half-lives; whichever is longer.
• History of substance abuse within the past 6 months.
• Severe cardiovascular disease characterized by any one of these conditions: a) stroke; b) recent myocardial infarction (within past 6 months); c) evidence of ischemia on functional cardiac exam within the last year; d) left ventricular ejection fraction<30%.
• Significant hyperlipidemia despite medical therapy defined as fasting low-density lipoprotein (LDL) cholesterol >130 mg/dL and/ or triglycerides >200 mg/dL.
• Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia (<1,000/µL), neutropenia (<1,500/µL), or thrombocytopenia (platelets <100,000/µL). Participants with lymphopenia are allowed if the Principal Investigator determines there is no additional risk and obtains clearance from a hematologist.
• Administration of live attenuated vaccine(s) within 2 months of Screening.
• Any previous treatment with Tegoprubart or any other anti-CD40L therapy