Eligibility

Eligible Ages

Between 18 Years and 70 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

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