A Multiple Ascending Dose Trial Investigating Safety, Tolerability and Pharmacokinetics of NNC0361-0041

A Multiple Ascending Dose Trial Investigating Safety, Tolerability and Pharmacokinetics of NNC0361-0041 Administered Subcutaneously to Patients With Type 1 Diabetes Mellitus

The trial is a placebo-controlled, double-blinded within cohorts, randomized, multiple ascending dose trial with a sequential trial design. The primary outcome is to investigate the safety and tolerability of ascending subcutaneous weekly doses of NNC0361-0041 plasmid in patients with T1D.

A total of 48 patients with T1D are planned to be studied in 4 cohorts of 12 patients (9 on active and 3 on placebo treatment). Within each cohort, sentinel enrollment will occur and safety assessment will occur before remaining participants are enrolled. The treatment period will be 12 weeks with once weekly dosing leading to 12 doses in total. Dose escalation will occur after data safety review (as described in section 4.9.2). An MMTT to assess insulin secretion will be done at baseline, 1, 3, 6, and 12 months. The follow-up (FU) period will be 1 week after the last dose, as well as 4, 6 and 12 months after the first dose.

Inclusion Criteria:

1. Willing to provide Informed Consent
2. Participants must live in a location with rapid access to emergency medical services
3. Age 18-45 years (both inclusive) at the time of signing informed consent
4. Must have a diagnosis of T1D for less than 48 months at randomization
5. Must have at least one diabetes-related autoantibody present (GAD65A; mIAA, if obtained within 10 days of the onset of insulin therapy; IA-2A; ICA; or ZnT8A)
6. Must have stimulated C-peptide levels greater than or equal to 0.2 pmol/ml measured during an MMTT conducted at least 21 days from diagnosis of diabetes and within one month (37 days) of randomization
7. Be willing to comply with intensive diabetes management
8. HbA1c ≤8.5% at screening
9. Subjects who are CMV and/or EBV seronegative at screening must be CMV and/or EBV PCR negative within 37 days of randomization and may not have had signs or symptoms of a CMV and/or EBV compatible illness lasting longer than 7 days within 37 days of randomization
10. Be up to date on recommended immunizations
11. Be at least 6 weeks from last live immunization
12. Be at least 4 weeks from killed vaccine other than flu vaccine
13. Participants are required to receive killed influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available
14. Be willing and medically acceptable to postpone live vaccines during the treatment period and for 3 months following last dose of study drug
15. If participant is female with reproductive potential, she must have a negative pregnancy test at screening and be willing to avoid pregnancy using a highly effective contraceptive method for the 12 months of the study
16. Males of reproductive age must use adequate contraceptive method during the treatment phase and for 3 months following last dose of study drug
17. Participants are required to receive an authorized non-live COVID-19 vaccination and be fully vaccinated, including eligible boosters as indicated, at least two weeks prior to randomization.

Exclusion Criteria:

Potential participants must not meet any of the following exclusion criteria:

1. One or more screening laboratory values as stated

   1. Leukocytes < 3,000/μL
   2. Neutrophils <1,500 /μL
   3. Lymphocytes <800 /μL
   4. Platelets <100,000 /μL
   5. Haemoglobin <6.2 mmol/L (10.0 g/dL)
   6. Potassium >5.5 mmol/L or <3.0 mmol/L
   7. Sodium >150mmol/L or < 130mmol/L
   8. AST or ALT ≥2.5 times the upper limits of normal
   9. Bilirubin ≥ 1.5 times upper limit of normal
   10. Glomerular Filtration Rate (eGFR) value of eGFR < 60 ml/min/1.73 m2 as defined by KDIGO 2012 (43)
   11. Any other laboratory abnormality that might, in the judgment of the investigator, place the subject at unacceptable risk for participation in this trial

2. Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within prior 7 days of screening

3. Use of other immunosuppressive agents including chronic use of systemic steroids. Topical products are acceptable (nasal, conjunctival, skin)

4. Have active signs or symptoms of acute infection at the time of randomization

5. Have current, confirmed COVID-19 infection

6. Chronic active infection other than localized skin infections

7. Have evidence of prior or current tuberculosis infection as assessed by PPD, interferon gamma release assay or by history

8. Have evidence of current or past HIV, Hepatitis B infection

9. Have evidence of active Hepatitis C infection

10. Vaccination with a live virus within the last 6 weeks and killed vaccine within 4 weeks (except 2 weeks for flu vaccine)

11. Be currently pregnant or lactating, or anticipate getting pregnant within the one-year study period.

12. Have severe obesity: adults BMI ≥ 40

13. Have a history of malignancies

14. Untreated hypothyroidism or active Graves' disease

15. History of severe reaction to prior vaccination

16. Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days after last blood draw (or 5 half-lives of investigational drug, whichever is greater) before screening, or currently enrolled in any other clinical trial

17. Subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the trial

18. Supine blood pressure at screening outside the range of 90-139 mmHg for systolic or 50-89 mmHg for diastolic. To exclude white-coat nervousness a single repeat measurement is allowed

19. Have any complicating medical issues or abnormal clinical laboratory results that may interfere with study conduct, or cause increased risk

20. Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results