Diabetes Autoimmunity Withdrawn In New Onset and In Established Patients

The SUNRISE study is a prospective, multi-center, double-blind, randomized,
placebo-controlled trial in subjects aged 18.0 to <41.0 years diagnosed with T1D, as defined
by American Diabetes Association (ADA) criteria, and within 5 years of diagnosis. Time of
diagnosis is defined as the first day of insulin administration. Subjects will be stratified
by duration (zero up to 1 year and 1 year up to five years) to ensure balance of disease
duration across treatment and placebo groups in each strata. Subjects should be randomized no
sooner than 6 weeks after diagnosis, unless blood glucose is adequately controlled for >14
days, defined as 3 consecutive fasting glucose levels by SMBG or lab testing <130 mg/dL.
Screening assessments will include a physical examination, an ophthalmic examination,
chemistry and hematology safety labs, urinalysis, 24-hour urine protein and creatinine,
HbA1c, presence of T1D antibodies, and an MMTT. Approximately 51 qualified subjects who meet
all selection criteria will be randomized in a 2:1 ratio to treatment with TOL-3021 or
placebo and treated for 52 weeks. Subjects will agree to diabetes management during the study
with the goal of maintaining HbA1c levels of approximately 7.0% without frequent episodes of
hypoglycemia.

Inclusion Criteria:

1. Diagnosis of Type 1 Diabetes Mellitus based on American Diabetes Association (ADA)
criteria and ≤100 days since diagnosis, defined as the first day of insulin
administration (subjects must be able to be randomized within the 100-day period from
diagnosis) .

2. Adequate glycemic control for >14 days, defined as 3 consecutive fasting glucose
levels by self-administered blood glucose (SMBG) or lab testing at <130 mg/dL.

3. Age at randomization of 12.0 - <18.0 years (adolescent), 18.0 - <36.0 years of age
(adult) ..

4. HbA1c <10.0% based on point-of-care or local lab measurement.

• Measurement can be repeated every 5-7 days if >10.0%.

5. Presence of antibodies to at least one of the following antigens: GAD-65, IA-2, ZnT8;
or insulin, if obtained within 10 days of the onset of exogenous insulin therapy.

6. Willingness to wear a continuous glucose monitoring (CGM) device for specified periods
of time.

7. Written informed consent, including authorization to release health information and
assent for adolescent subjects.

8. Willingness and ability of subject or adult guardian to comply with all study
procedures of the study protocol, including attending all clinic visits.

Exclusion Criteria:

1. Body Mass Index (BMI) >30 kg/m2 for adults; >95 percentile BMI-for-age for subjects
under 18 years of age.

2. Previous immunotherapy for T1D.

3. Diagnosis of liver disease or hepatic enzymes, as defined by ALT and/or AST ≥2.5 times
the upper limit of normal (ULN).

4. Hematology: white blood cells (WBC) <3 x 109/L; platelets <100 x 109/L; hemoglobin
<10.0 g/dL. (Low WBC values may be repeated every 3-7 days, and results to be
discussed with the Medical Monitor.)

5. Serum creatinine > 1.5 times ULN.

6. History of malignancy, except for cancers in remission >5 years, or basal cell or in
situ squamous cell carcinoma of the skin.

7. Significant cardiovascular disease (including inadequately controlled hypertension,
history of myocardial infarction, angina, use of anti-anginal medicines (e.g.,
nitroglycerin), or abnormal stress test, which, in the opinion of the Principal
Investigator (PI), would interfere with participation in the trial.

8. Immunosuppressive therapy (systemic corticosteroids, cyclosporine, azathioprine, or
biologics) within 30 days of screening.

9. Current or prior (within the last 30 days) use of metformin, sulfonylureas, glinides,
thiazolidinediones, GLP1-RAs, DPP-IV inhibitors, pramlintide, or SGLT-2 inhibitors.

10. Current use of verapamil or α-methyldopa.

11. History of any organ transplant, including islet cell transplant.

12. Active autoimmune or immune deficiency disorder other than T1D or well-controlled
autoimmune thyroid disease (e.g., sarcoidosis, rheumatoid arthritis,
moderate-to-severe psoriasis, inflammatory bowel disease, and other autoimmune
conditions that may require treatment with TNF or other biologics), unless approved by
the Medical Monitor.

13. Thyroid-stimulating hormone (TSH) at screening >2.5 mIU/L.

14. History of adrenal insufficiency.

15. Evidence of infection with HBV (as defined by hepatitis B surface antigen (HBsAg)),
HCV (anti-HCV antibodies), or HIV.

16. Positive urine pregnancy test: Females of childbearing potential must be excluded if
they have a positive urine pregnancy test at screening or randomization or if they are
not using medically acceptable methods of birth control. Acceptable methods of birth
control include oral or transdermal contraceptives, condom, spermicidal foam,
intrauterine device (IUD), progestin implant or injection, abstinence, vaginal ring,
or sterilization of partner. The reason for non-childbearing potential, such as
bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or 1 year or more
postmenopausal; must be specified in the subject's Case Report Form (CRF).

17. Males of reproductive potential who are unwilling to use medically acceptable birth
control, unless the female partner is postmenopausal or surgically sterile.

18. Any social condition or medical condition that would, in the opinion of the PI,
prevent complete participation in the study or would pose a significant hazard to the
subject's participation.

19. Anticipated major surgery during the duration of the trial, which could interfere with
participation in the trial.

20. History of drug or alcohol dependence within 12 months of screening.

21. Psychiatric disorder that would prevent subjects from giving informed consent.

22. Participation in other studies involving the administration of an investigational drug
or device, including the administration of an experimental agent for T1D, at any time,
or use of an experimental device for T1D within 30 days prior to screening, unless
approved by the Medical Monitor.