Subcutaneously Administered MD-18 for the Treatment of Obesity and Diabetes

A Multiple Dose, Randomized, Placebo-controlled, Dose-escalating Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered MD-18 for Healthy Subjects With Overweight or Obesity

A Multiple Dose, Randomized, Placebo-controlled, Dose-escalating Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered MD-18 for healthy subjects with overweight or obesity

This study will be conducted as a single center study, at the Sheba Medical Center, Israel. Escalating daily doses of MD-18 or placebo will be administered subcutaneously to each subject over a 4-week period with a 7-day follow-up period. 54 patients will be enrolled across 7 cohorts. Each of the cohorts will enroll 4 active and two placebo subjects, except for the final cohort. Cohort 7 will be comprised of obese subjects and will enroll 12 active and 6 placebo subjects. Starting dose has been determined from the SAD study (CG MD-18-01). Cohorts will receive 74 mg MD-18 three times weekly, (starting dose), 114 mg three times weekly, 227 mg three times weekly, 302 mg once weekly, 302 mg three times weekly or 302 mg daily using 4:2 (active:placebo) randomization; all doses refer to the MD-18 salt. A total of 36 subjects will receive active therapy across seven cohorts (24 in the first six cohorts and 12 in the seventh cohort) and 18 subjects will receive placebo. The study will be conducted on an outpatient basis, with visits performed as shown in the schedule of events.

Inclusion Criteria:

1. Subjects aged 18-70 years, both genders.

2. BMI:

   • Cohorts 1-6: 25-34.9
   • Cohort 7: 30.0-44.9

3. HbA1c <6.5%

4. Healthy as determined by a physician, based on history, medical examination, vital signs, laboratory tests, cardiac monitoring and respiratory function. History must comply with the following:

   1. Absence of clinically significant illness or major surgery within the preceding 12 weeks.
   2. Absence of clinically significant history of neurological, endocrine, cardiovascular, pulmonary, hematological, immunologic, psychiatric, gastrointestinal, renal, hepatic, and/or metabolic disease as per PI decision.

5. Male subjects with female partners of childbearing potential must agree to utilize an approved contraceptive during the study.

6. Female subjects of child-bearing potential with negative urine pregnancy test at screening and who agree to use contraception during the study.

7. Female subjects of non-child-bearing potential (i.e. tubal ligation, hysterectomy, or postmenopausal).

8. Subjects must provide written informed consent and be willing and able to comply with study procedures.

Exclusion Criteria:

1. History of excessive alcohol use (defined as >21 drinks per week for males and >14 drinks per week for females), recreational drug use within the past three months, or failure on urinary drug screen. Note: use of Cannabinoids for medical purposes is allowed.

2. Pregnant or breastfeeding within six months of screening assessment.

3. Substantial changes in eating habits or exercise routine within the preceding three months.

4. Evidence of eating disorders.

5. >5% weight change in the past three months.

6. Bariatric surgery within the past five years.

7. Moderate renal impairment ( Glomerular filtration rate<60 mg/mL/1.73m2)

8. Liver function tests greater than twice the upper limit of normal upon repeated measurements.

9. Diseases interfering with metabolism and or ingestive behavior (e.g., myxedema, Cushing's disease, schizophrenia, major psychoses, unmanaged depression).

10. Use of medications affecting body weight within the past three months, unless on a stable dose, with weight stability in the preceding three months. These medications include:

    1. Drugs approved for the treatment of obesity
    2. Cyproheptadine or medroxyprogesterone
    3. Atypical anti-psychotic drugs
    4. Tricyclic antidepressants
    5. Lithium, MAO's, glucocorticoids
    6. SSRIs or SNRIs
    7. Anti-epileptic drugs

11. Any clinically significant abnormality following the Investigator's review of the physical examination and clinical laboratory tests.

12. A baseline (screening echocardiogram result) prolongation of ventricular activation and recovery interval after repeated measurements of >450 milliseconds; a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsades de pointes, structural heart disease, or a family history of Long QT Syndrome.

13. Use drugs of abuse within the preceding three months.

14. The last dose of an investigational drug in other clinical trial was within the month prior to dosing in the present study. Note: Volunteers from the previous Phase 1a trial (MD-18-01) may be recruited for the current study, provided that at least 12 weeks have passed since their last dose of the investigational product.

15. A positive result for any of the following tests: hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency viruses (HIV) and Treponema pallidum.