Multiple Ascending Dose (MAD) Study of IMT-002 in HLA-DQ8-positive Type 1 Diabetes

This study is designed to characterize the safety, steady-state pharmacokinetics (PK) of IMT-002, and will serve as a dose range identification for the pharmacodynamic effect of blocking self-antigen presentation in adults with type 1 diabetes (T1D) having the human leukocyte antigen (HLA)-DQ8 gene.

This is a randomized, single-blind, placebo-controlled study that will include 4 ascending dose cohorts: 350 mg twice daily (BID), 1050 mg once daily (QD), 700 mg BID, and 1050 mg BID. Subjects will undergo prescreening for genetic typing and then screening procedures up to 28 days prior to the first dose to determine eligibility. T1D adults between 18 and 45 years of age, inclusive, who are positive for at least one gene encoding for HLA-DQ8 (DQA1\*0301, DQB1\*0302) will be enrolled.

Each cohort will include 6 subjects on active drug, and the study will include 6 subjects total on placebo. Each cohort will participate in a 2-week dosing period. Enrollment of the cohorts will be sequentially staggered such that initial safety data after the first four subjects assigned to active treatment complete one week of treatment in each cohort will be reviewed before the next ascending dose cohort is enrolled. The safety reviews will include cumulative safety data for all subjects to that point. Subjects will have 5 scheduled clinic visits: screening, first day of dosing, 1 week after dosing begins, 2 weeks after dosing begins (end of treatment), and 1 week following the final dose. Subjects will self-administer study drug on non-clinic treatment days. Safety assessments will be conducted at all study visits. Insulin use (dose and frequency) will be monitored.

Pharmacokinetic (PK) assessments will be evaluated at every visit during the treatment period to characterize the following: single dose PK, trough PK and steady PK. Pharmacodynamic (PD) and immunological assessments will be evaluated before, during and after treatment.

Eligibility Criteria:
Inclusion Criteria:

1. Signed the ICF as described in Appendix 3 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2. Man or woman, 18 to 45 years of age inclusive at the time of signing the ICF.
3. Has received a diagnosis of T1D according to the criteria from the American Diabetes Association.
4. Positive for at least one gene encoding for HLA-DQ8 (DQB\*0302).
5. If male, and of reproductive potential, willing to use medically acceptable birth control (Appendix 5), unless the female partner is postmenopausal or surgically sterile, until study completion and for at least 30 days after the last dose of study treatment and refrain from donating sperm during this period.
6. If female: (a) surgically sterile or (b) postmenopausal or (c) if of reproductive potential, willing to use medically acceptable birth control (eg, female hormonal contraception, barrier methods or sterilization (Appendix 5) until study completion and for at least 30 days (one menstrual cycle).

Exclusion Criteria:

1. Inability or unwillingness of a subject to give written informed consent or comply with the study protocol.
2. No HLA-DQ8 gene (DQB\*03:02).
3. Any of the following hematologic abnormalities at the time of screening, confirmed by repeat tests:

   1. Leukopenia (\<3,000 leukocytes/μL)
   2. Neutropenia (\<1,500 neutrophils/μL)
   3. Thrombocytopenia (\<125,000 platelets/μL)
   4. Hemoglobin less than 10 g/dl
4. Evidence of liver dysfunction, with ALT \> 2.5 times the upper limit of normal (ULN) or AST \>3.0 times ULN persistent for 1 week or greater.
5. Evidence of renal insufficiency as indicated by serum creatinine of \>1.5 times ULN, confirmed by a repeat test.
6. Clinically significant abnormal physical examination, vital signs, or 12-lead ECG at screening as deemed appropriate by the investigator.
7. Has a history of or current clinically significant medical illness including, but not limited to, cardiac arrhythmias or other cardiac disease; significant pulmonary disease; neurologic or psychiatric disease; infection; or any other illness that the investigator considers should exclude the subject or that could interfere with the interpretation of the study results.
8. Body mass index (BMI) \> 32 kg/m2.
9. Unstable blood sugar control defined as one or more episodes of severe hypoglycemia (defined as hypoglycemia that required the assistance of another person) within the last 30 days.
10. Use of a treatment that is known to cause a significant, ongoing change in the course of T1D or immunologic status, within 4 weeks prior to participation; this includes high-dose inhaled, extensive topical or systemic glucocorticoids.
11. History of any organ transplant, including islet cell transplant.
12. Pregnant or anticipates pregnancy during the 2-week study period or within 30 days following the last dose of study drug.
13. Use of investigational drugs within 90 days of participation.
14. Currently taking methyldopa (Aldomet) at the time of randomization or taken within the past 3 months.
15. Currently taking ferrous sulfate or ferrous gluconate, which are indicated for the treatment of anemia (hematological disease), or taken within the past 30 days.
16. Unable to avoid medications that affect stomach pH, such as proton pump inhibitors or histamine H2 receptor blockers.
17. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the Investigator, may pose additional risks from participation in the study, may interfere with the subject's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study.
18. Has a history of the human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV; has a history of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or another clinically active liver disease, or tests positive for HBsAg or anti-HCV at Screening.
19. Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.
20. Has preplanned surgery or procedures that would interfere with the conduct of the study.
21. Is an employee of the Investigator or study site, with direct involvement in the proposed study or other studies under the direction of that Investigator or study site, as well as family members of the employees or the Investigator.