Breakthrough - T1DM and Chronic Kidney Disease

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

1. Subjects 18-70 years of age.
2. A diagnosis of T1D ≥5 years with onset of disease at <40 years of age.
3. Ability to provide informed consent.
4. Able to comply with study procedures, including the requirement to utilize continuous glucose monitoring (CGM).
5. 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.
6. HbA1c level 6.5% to 9.5% inclusive.
7. Absence of stimulated C-peptide (<0.3 ng/mL) in response to a mixed- meal tolerance test (MMTT).
8. Chronic kidney disease stage 1, 2 or 3a

9. 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
10. 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:

1. Body mass index (BMI) >30 kg/m2.
2. Weight ≤40 kg.
3. Insulin requirement >60units/day or <15 units/day.
4. Untreated and uncontrolled proliferative diabetic retinopathy.
5. Blood pressure: systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg.
6. Chronic kidney disease stage 3b or above.
7. Diagnosis of macroalbuminuria (ACR>300 mg/g creatinine).
8. 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.
9. History of malignancy except for completely resected squamous or basal cell carcinoma of the skin.

10. History of a thromboembolic event (TE), known hypercoagulable state, or condition requiring long-term anticoagulation:

    1. 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.
    2. Patients on aspirin are allowed.
11. Receiving treatment for a medical condition requiring chronic use of systemic steroids, except for physiologic replacement for example in Addison disease.
12. 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.
13. Invasive aspergillus, histoplasmosis or coccidioidomycosis infection within one year prior to Screening.
14. Negative screen for Epstein-Barr Virus (EBV) by immunoglobulin G (IgG) determination.
15. Current treatment with any immunosuppressive regimen, and treatment with biologic immune modulating agents, JAK inhibitors, S1P receptor agonists, azathioprine, 6- MP, or systemic corticosteroids.
16. Baseline PRA over 40%
17. Previous organ transplant (except failed pancreas or islet transplant)
18. 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.
19. 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.
20. History of substance abuse within the past 6 months.
21. 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%.
22. Significant hyperlipidemia despite medical therapy defined as fasting low-density lipoprotein (LDL) cholesterol >130 mg/dL and/ or triglycerides >200 mg/dL.
23. 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.
24. Administration of live attenuated vaccine(s) within 2 months of Screening.
25. Any previous treatment with Tegoprubart or any other anti-CD40L therapy