Safety, Tolerability and Preliminary Efficacy of Sublingual Liraglutide in Patients With Type 2 Diabetes Mellitus

Inclusion Criteria:

1. Males and females aged 18-65 years (inclusive)

2. Body mass index (BMI) 18-35 kg/m2, inclusive

3. Normal blood pressure or well managed hypertension (systolic blood pressure <160mmHg, diastolic blood pressure <100 mmHg)

4. Confirmed diagnosis of T2DM (by repeated laboratory findings) for at least 1 year.

5. Subjects under glycemic control on a stable dose of metformin (within the standardof care dose range up to 2 g daily) for at least 2 months prior to enrolment orthose who manage their condition only by diet/exercise.

6. For subjects on a stable dose of concomitant metformin for at least 2 months priorto enrolment, the subject's dose of metformin will be required to remain constantuntil at least the completion of MMTT on the final dosing day. Subjects whoseconcomitant glucose lowering medication changes during the dosing phase of the studywill be discontinued and may be replaced.

7. For subjects not in receipt of concomitant metformin for at least 2 months prior toenrolment, and who manage their condition only by diet/exercise, documentation ofstable glycemic control under current condition management for at least 2 monthsprior to enrolment, as confirmed by HbA1c. For subjects who meet this criterion, nochange in disease management is permitted until at least the completion of MMTT onthe final dosing day. Any subject who requires a change in disease management,including initiation of any diabetes medication during the study, will bediscontinued from the study and may be replaced.

8. Fasting plasma glucose ≥5.6 mmol/L at screening

9. HbA1c ≥6.5% and ≤9.0% at screening

10. Vital signs after 10 minutes resting supine:

11. 90 mmHg <systolic blood pressure <160 mmHg

12. 40 mmHg <diastolic blood pressure <100 mmHg

13. 40 bpm <heart rate <100 bpm Duplicate assessments will be performed and theaverage of the two assessments of blood pressure will be used.

14. Standard 12-lead ECG parameter results at screening, after 10 minutes resting insupine position, within 120 ms <PR <220 ms, QRS <120 ms, QTcF ≤450 ms (males), QTcF ≤470 ms (females).

15. No history of significant cardiovascular disease over the preceding 3 years or anyother major disease other than T2DM and well managed hypertension, unless permittedat the discretion of the PI.

16. Negative test for selected drugs of abuse at screening (does not include alcohol)and at admission (testing at admission does include alcohol breath test). A positiveresult may be verified by re-testing (up to one false positive result permitted) andmay be followed up at the discretion of the PI.

17. Females must be non-pregnant and non-lactating, and either surgically sterile for aminimum of 6 months (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy,bilateral oophorectomy), or use highly effective contraceptive method (oralcontraceptives pills, long-acting implantable hormones, injectable hormones, avaginal ring or an intrauterine device [IUD]) from screening until study completion,or be post-menopausal for ≥12 months. Post-menopausal status will be confirmedthrough testing of follicle-stimulating hormone (FSH) levels (≥ 40 IU/mL) atscreening for amenorrheic female subjects. Females who are abstinent fromheterosexual intercourse will also be eligible.

18. Women of child-bearing potential (WOCBP) must have a negative pregnancy test atscreening and admission and be willing to have additional pregnancy tests asrequired throughout the study.

19. Males must be surgically sterile (>30 days since vasectomy with no viable sperm),abstinent, or if engaged in sexual relations with a WOCBP, the subject and hispartner must be surgically sterile (e.g. tubal occlusion, hysterectomy, bilateralsalpingectomy, bilateral oophorectomy) or using an acceptable, highly effectivecontraceptive method from screening until study completion. Acceptable methods ofcontraception include the use of condoms and the use of an effective contraceptivefor the female partner (WOCBP), as per Inclusion Criterion #14. Male subjects whosefemale partner is post-menopausal, and subjects who are abstinent from heterosexualintercourse will also be eligible. Male subjects must agree to refrain from donatingsperm from screening until study completion.

Exclusion Criteria:

1. Pregnant or lactating, or intending to become pregnant within 30 days after lastdose of study drug.

2. Participation in a clinical trial within 30 days before enrolment; use of anyexperimental oral therapy within 30 days or 5 half-lives prior to enrolment,whichever is greater; or use of any biologic therapy within 12 weeks or 5 half-livesprior to enrolment, whichever is greater. Subjects who have received an experimentaltherapy that has no half-life, such as a vaccine, should have completed that therapyat least 30 days prior to enrolment.

3. Any vaccine 2 weeks prior to first study drug administration until 2 weeks after thelast dose, with the exception of current seasonal influenza vaccination.

4. Use of any weight loss agent within the preceding 4 weeks.

5. Surgery or hospitalization during the 4 weeks prior to screening.

6. Planned procedure or surgery during the study.

7. Blood transfusion within 8 weeks prior to screening.

8. Donation or loss of blood (excluding the volume of blood that will be drawn duringscreening procedures) as follows: ≥ 300 mL of blood within 30 days prior to studydrug administration.

9. Poor peripheral venous access.

10. Alcohol and/or substance abuse or dependence within the past 2 years.

11. Within the last 2 years, unstable or clinically significant cardiovascular disease (e.g. myocardial infarction, angina pectoris, New York Heart Association Class II ormore cardiac failure).

12. History of pancreatitis

13. History or presence of an abnormal ECG that is clinically significant in the PI'sopinion and/or evidence of prior myocardial infarction within 2 years beforescreening.

14. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmiassuch as structural heart disease, coronary heart disease (symptomatic or withischemia demonstrated by diagnostic testing), clinically significant electrolyteabnormalities (e.g. hypokalemia, hypomagnesemia, hypocalcaemia), or family historyof sudden unexplained death or long QT syndrome.

15. Impaired hepatic function as indicated by screening aspartate aminotransferase (AST)or alanine aminotransferase (ALT) ≥ 2 x or total bilirubin ≥ 1.5 x the upper limitof normal (ULN), which remains above these limits if retested due to a slightlyelevated initial result or abnormalities in synthetic function tests that are judgedby the PI to be clinically significant.

16. Unstable hypo- or hyperthyroidism.

17. Personal or family history of medullary thyroid cancer or multiple endocrineneoplasia syndrome Type 2.

18. Current or history of bulimia or anorexia nervosa.

19. History of severe allergy (requiring hospital care), severe reaction to any drug, orany known or suspected allergies or sensitivities to the study drug constituents.

20. Diagnosis with Type 1 Diabetes Mellitus (T1DM) or any previous episodes of diabeticketoacidosis.

21. History of or ongoing inflammatory bowel disease or diabetic gastroparesis.

22. Severe hypoglycaemia resulting in seizure/unconsciousness/coma/hospitalization inthe last 3 months before screening.

23. Persistent hyperglycaemia not controlled by metformin/diet/exercise.

24. Proliferative retinopathy, nephropathy or renal impairment (<60 mL/min as calculatedby the CKD-EPI equation) if deemed clinically significant by the PI.

25. Any other serious medical condition, or abnormality in clinical laboratory tests,that would preclude the subject's safe participation in and completion of the studyor increase the expected risk of exposure to the investigational product (IP) orwould be expected to interfere with the planned evaluations, in the judgment of thePI.

26. Use of diabetes medication other than metformin at screening and between screeningand Day 1 assessments.

27. Any medication during the treatment period and within 14 days before first dosingunless permitted by the inclusion criteria or permitted at the discretion of the PIand when the intake is unlikely to interfere with insulin/glucose control.

28. Use of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 [GLP-1] agonists,sodium glucose transporter 2 inhibitors, insulin, thiazolenindiones, acarbose in the 3 months prior to study enrolment will not be permitted.

29. Unwilling or unable to follow protocol requirements.