A Randomised, Double-Blind, Placebo-Controlled, Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of MTS-201 in Healthy Volunteers and MTS-201 and Multiple Ascending Doses of MTS-201 in Combination with Sitagliptin in Obese, Otherwise Healthy Volunteers,

Exclusion Criteria86

• PART A:
• Known hypersensitivity to the study drug or any of the study drug ingredients.
• History of anaphylaxis or other significant allergy.
• History or presence of clinically significant (CS) cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, psychiatric or neurological disease/disorder including any acute illness, within the past 3 months determined by the investigator to be clinically relevant or could negatively impact the ability to comply with all procedures.
• History of surgery or hospitalisation within 3 months prior to screening, or surgery planned during the study.
• Any surgery on the stomach (such as gastric bypass) or small intestine or colon, excluding appendectomy
• Any history of malignant disease in the last 5 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
• Presence of clinically relevant immunosuppression.
• Diagnosis or treatment of any clinically symptomatic biochemical or structural abnormality of the gastrointestinal tract.
• History of cholecystectomy, gallstones or gallbladder disorders.
• History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia.
• Presence or having sequelae of gastrointestinal tract, liver (including Gilbert’s syndrome), kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
• Elevated Liver function test results
• Renal impairment
• A history of or positive test results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit.
• Positive drugs of abuse test or alcohol breath test results at the screening visit and/or on admission to the study site on Day 1.
• History of alcohol abuse, physical dependence to any opioid, or any history of drug abuse or addiction within 12 months of study enrolment.
• Regular consumption of more than 10 standard alcoholic drinks/week and/or more than 4 standard alcoholic drinks on any one day, where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer. Participants will be required to abstain from the consumption of alcohol for at least 24 hours prior to check-in (Day -1), and while confined to the study site.
• Volunteer smokes more than 5 cigarettes or equivalent nicotine-containing products per week, and/or the volunteer is unwilling to abstain from smoking or the use of nicotine-containing products for 72 hours prior to check-in on Day -1 and throughout the confinement period at the study site.
• Females who are breastfeeding or planning to breastfeed.
• Unable to swallow oral medication.
• Use of any prescription or over-the-counter (OTC) medication (including herbal products, diet aids, vitamins, and hormone supplements) within 10 days prior to the first dose of study drug, except use of contraceptives, the use of paracetamol (up to 2 g per day) for no more than 3 consecutive days and the use of ibuprofen (up to 1.2 g per day) for no more than 3 consecutive days.
• Prior use of GLP-1 or GLP-2 agonist drugs or DPP-4 inhibitor drugs (gliptins).
• Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medication within 10 days prior to first dose of study drug.
• Use of any vaccinations within 30 days prior to screening.
• Donation of blood or plasma within 3 months prior to first dose of study drug, or loss of whole blood of more than 480 mL within 3 months prior to first dose of study drug, or receipt of a blood transfusion within 1 year of the first dose of study drug.
• Participation in another clinical study of an investigational drug or investigational device within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to Day -1.
• Not recorded at least 1 bowel movement prior to study site check-in on Day -1.
• PART B and PART C:
• Known hypersensitivity to MTS-201 or sitagliptin or any ingredient of either study drug.
• History of anaphylaxis or other significant allergy which, in the opinion of the PI (or delegate), would interfere with the volunteer’s ability to participate in the study.
• History or presence of CS cardiovascular, pulmonary (excluding resolved childhood asthma, at the discretion of the PI or delegate), hepatic, renal, haematological, GI, endocrine, immunologic, dermatologic, psychiatric (excluding non-hospitalised depression and anxiety, at the discretion of the PI or delegate), or neurological disease/disorder (excluding migraine, at the discretion of the PI or delegate), including any acute illness, within the past 3 months determined by the PI (or delegate) to be clinically relevant or could negatively impact the ability to comply with all procedures.
• History of surgery or hospitalisation within 3 months prior to screening, or surgery planned during the study.
• Unable to swallow oral medications.
• History of Type 1 diabetes or Type 2 diabetes, or glycated haemoglobin (HbA1c) >6.5 % or fasting plasma glucose >126 mg/dl at screening.
• Has obesity due to an endocrine disorder (e.g., Cushing’s syndrome) or a genetic form of obesity (e.g., Melanocortin 4 Receptor deficiency or Prader–Willi Syndrome).
• Weight change >5% in the past 3 months or >10% in the past 6 months (increase or decrease).
• History of bariatric surgery or related procedures for weight loss (excluding liposuction or abdominoplasty if performed >1 year before screening).
• Extreme dieting or participation in an organized weight loss program (e.g., Weight Watchers) or vigorous physical exercise habits (e.g., exercising more than 1 hour daily) within 4 months of the study start visit.
• Any condition that prevents normal gastrointestinal digestion, absorption and function including prior surgery on the stomach or small intestine or colon, excluding appendectomy.
• Any CS symptomatic abnormality of the GI tract, including, but not limited to, an adenomatous polyposis syndrome, gastroparesis or severe gastroesophageal reflux disease.
• History of cholecystectomy or CS gallbladder disorders.
• Presence or having sequelae of GI tract, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
• Liver function test results elevated >2-fold above the ULN for GGT, bilirubin (total, conjugated and unconjugated), ALP, AST or ALT. Persons with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the PI (or delegate), if the levels are unaccompanied by clinical signs and are assessed to be consistent with normal variants.
• History of acute or chronic pancreatitis.
• History of malignant disease in the last 5 years (excluding surgically resected skin squamous cell or basal cell carcinoma).
• Presence of clinically relevant immunosuppression from, but not limited to, chronic immunodeficiency conditions such as common variable hypogammaglobulinemia.
• History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known CS arrhythmia.
• Renal impairment defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula).
• A history of or positive test results for HIV-1 or -2, HBsAg or HCV antibodies at the screening visit.
• Positive test for drugs of abuse or positive alcohol breath test results at the screening visit and/or on admission to the study site on Day -2.
• History of alcohol abuse, physical dependence to any opioid, or any history of drug abuse or addiction within 12 months of study enrolment.
• Regular consumption of more than 10 standard alcoholic drinks/week and/or more than 4 standard alcoholic drinks on any one day, where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer (4.9% alcohol [Alc]/ volume [Vol]), 100 mL wine (12% Alc/Vol), or 30 mL spirit (40% Alc/Vol). Participants will be required to abstain from the consumption of alcohol for at least 24 hours prior to check-in (Day -2), and while confined to the study site.
• Smokes more than 5 cigarettes or equivalent nicotine-containing products per week, and/or is unwilling to abstain from smoking or the use of nicotine-containing products for 72 hours prior to check-in on Day -2, and throughout the confinement period at the study site.
• Note: 1 average cigar = approx. 5 average cigarettes; 1 average pipe session = approx. 5 average cigarettes; 1 average nicotine liquid vape session = 1 average e-cigarette = 1 average cigarette.
• Females who are breastfeeding or planning to breastfeed.
• Use of any prescription OTC medication (including herbal products, diet aids, vitamins) within 14 days or 5 half-lives of the medication (whichever is longer) prior to the first dose of study drug, except as follows:
• a. Use of contraceptives, the use of paracetamol (up to 2 g per day) for less than 3 consecutive days and the use of ibuprofen (up to 1.2 g per day) for less than 3 consecutive days is acceptable.
• b. Use of anti-hypertensive medications is acceptable, if on a stable dose and regimen for at least 3 months prior to screening and the blood pressure at screening is <140 mm Hg systolic and <90 mm Hg diastolic.
• NOTE: Anti-hypertensive drugs that are susceptible to significant CYP3A4-mediated drug-drug interactions are not allowed.
• c. Use of anti-dyslipidaemia medications (e.g., statins, ezetimibe) are acceptable, if on a stable dose and regimen for at least 3 months prior to screening, and the screening lipid panel meets both of the following thresholds:
• o Low density lipoprotein cholesterol (LDL-c) less than or equal to 100 mg/dL
• o Fasting triglycerides less than or equal to 200 mg/dL
• NOTE: Anti-dyslipidaemia drugs that are susceptible to significant CYP3A4-mediated drug-drug interactions are not allowed.
• Use of any GLP-1 receptor agonist or DPP-IV inhibitor (“gliptins”) within 6 months prior to screening.
• Known intolerance to or contraindications to use of GLP-1 RA or DPP-IV inhibitor drugs or to sitagliptin.
• Has a known self or family history (first-degree relative) of multiple endocrine neoplasia type 2A or type 2B, thyroid C-cell hyperplasia, or medullary thyroid carcinoma.
• Use of medications (OTC or prescription) that can cause significant weight-loss, within 3 months prior to screening. Examples of such drugs include, but are not limited to:
• Saxenda® (liraglutide)
• Wegovy (semaglutide)
• Xenical®/Alli® (orlistat)
• Meridia® (sibutramine)
• Acutrim® (phenylpropanolamine)
• Sanorex® (mazindol)
• Adipex® or LomairaTM (phentermine)
• BELVIQ® [lorcaserin]
• QsymiaTM (phentermine/topiramate combination)
• Contrave® (naltrexone/bupropion)
• Use or history of treatment with medications within 3 months of screening that may cause significant weight gain including, but not limited to, tricyclic antidepressants, atypical antipsychotics, and mood stabilizers.
• Long-term use of drugs that affect metabolism (e.g., steroids, but excluding topical, intraocular, intranasal, single intraarticular injection, or inhaled preparations) or affect GI motility.
• a. Thyroid hormone replacement therapy may be acceptable (at the discretion of the PI or delegate) if patient is euthyroid and has been on a stable dose and regimen for at least 12 weeks prior to the study, and the dose is not anticipated to change during the trial.
• Current infection requiring systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medication within 10 days prior to first dose of study drug.
• Received any vaccinations within 30 days prior to screening.
• Donation of blood or plasma within 3 months prior to first dose of study drug, or loss of whole blood of more than 480 mL within 3 months prior to first dose of study drug, or receipt of a blood transfusion within 1 year of the first dose of study drug.
• Participation in another clinical study of an investigational drug or investigational device within 90 days or 5 half-lives of the investigational drug (whichever is longer) prior to Day -2.
• Any other condition or prior therapy that in the opinion of the PI (or delegate) would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.