| Eligibility |
Inclusion Criteria:
l. Understand the trial procedures and agree to participate by providing written informed
consent.
2. Be willing and able to comply with all trial procedures and restrictions, including
following study diet requirements.
3. Be healthy between 18 to 60 years of age, inclusive, at the Screening Visit.
4. Have a Body Mass Index (BMI) =27.0 and <35.0 (kg/m2) at the Screening Visit.
5. Be weight stable (<5% variation) over the last 3 months.
6. Be a nonsmoker who has not used tobacco or nicotine-containing products (e.g. nicotine
patch, e-cigarettes, vapes) for at least 3 months before administration of the initial dose
of trial drug and agrees to abstain from smoking tobacco or the use of nicotine-containing
products while on study.
7. Be judged to be in good health by the Investigator, based on clinical evaluations
including laboratory safety tests, medical history, physical examination, 12-lead ECG, and
vital sign measurements performed at the Screening Visit and before administration of the
initial dose of trial drug.
8. Meet the following requirements:
1. Is a male who agrees to all of the following:
- To use an appropriate method of contraception, including a condom with or without
spermicidal cream or jelly, from the first dose of study drug until 14 days after
the last dose of study drug. A male subject who had a vasectomy procedure must
follow the same restrictions as a non-vasectomized man.
- If partner is pregnant, to use a condom
- To not donate sperm from the first dose of study drug until 14 days after the
last dose of study drug.
OR
2. Is a female who is of non-childbearing potential defined by at least 1 of the
following criteria:
- Postmenopausal (aged >45 years and with a minimum of 12 months of spontaneous
amenorrhea with a Screening serum follicle-stimulating hormone (FSH) level >30
mIU/mL).
- Post hysterectomy, bilateral oophorectomy or bilateral salpingectomy, based on
the subject's recall of their medical history.
Exclusion Criteria:
1. Has participated in another interventional investigational study within 30 days of the
Screening Visit. The window will be derived from the date of the last study procedure
and/or AE related to the study procedure in the previous study to the Screening Visit
of the current study. If the subject received an investigational medication in the
prior study, at least 5 half-lives (or longer if required by local regulations) must
have passed between the last dose of the investigational product and the Screening
Visit.
2. Is an employee or immediate family member (e.g., spouse, parent, child, sibling) of
the Sponsor or study site.
3. Has a history of multiple significant and/or any severe allergies (e.g., food, drug,
latex allergy) or has had an anaphylactic reaction or significant intolerance to
prescription or nonprescription drugs or food.
4. Has a known hypersensitivity or contraindication to any component of K-757 (all
Panels), sitagliptin (Panel C only), or K-833 (Panels D and E only), related compounds
or their excipients.
5. Has a positive alcohol or drug screen at Screening or admission.
6. Has a positive pregnancy test.
7. Is a lactating/nursing female.
8. Has a positive test result for hepatitis B surface antigen (Ag), hepatitis C virus
antibody, or human immunodeficiency (HIV) antibody, at the Screening Visit. Note:
Subjects with positive hepatitis B virus or hepatitis C virus serology may be enrolled
if quantitative polymerase chain reaction for hepatitis B virus or hepatitis C virus
ribonucleic acid is negative.
9. Does not meet study site COVID-19 admission/study participation restrictions.
10. Has a fever (>38°C)*.
11. Had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4
weeks prior to the Screening Visit*.
12. Is unable to refrain from the use of prohibited prescription or non-prescription drugs
including vitamins, herbal and dietary supplements (including St John's Wort) within 7
days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever
is longer) prior to the first dose of study medication through completion of study
participation. Allowable concomitant medications are limited to
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), =2
permissible anti-hypertensive agents, and post-menopausal hormone replacement therapy
(HRT). Statin doses must have been stable with reported compliance of at least 80% for
=3 months prior to the Screening Visit. Anti-hypertensive and HRT doses/regimens must
have been stable for =1 month prior to the Screening Visit.
13. Has been on any GLP-1 receptor agonist, any dipeptidyl peptidase IV (DPP-4) inhibitor,
or any approved or investigational medications known to cause weight loss in the prior
3 months.
14. Has excessive consumption of alcohol within 6 months prior to screening (>14
drinks/week for men and >7 drinks/week for women, where l drink= 5 ounces [150 mL] of
wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) or use of
soft drugs (such as marijuana) within 3 months prior to Screening, or hard drugs (such
as cocaine) within 6 months prior to Screening.
15. Is unwilling or unable to refrain from consuming alcohol from 7 days prior to the
first dose of study medication through the completion of study participation.
16. Is unable or unwilling to refrain from consumption of Seville oranges, grapefruit,
grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids from 2 weeks prior
to administration of the first dose of study drug, throughout the study, and until the
Follow-up Visit.
17. Is unwilling to refrain from the mustard green family (eg, kale, broccoli, watercress,
collard greens, kohlrabi, Brussels sprouts, and mustard) or charbroiled meats
beginning approximately 48 hours prior to admission to the clinic, if possible (if
subject has consumed any of these items prior to admission, the subject may be
included in the study and the food and amount should be recorded in the source
documents). Subjects will not consume any of the above foods while in the clinical
research unit and until the poststudy visit.
18. Has a substance abuse disorder.
19. Had a previous major psychotic disorder.
20. Has a corrected QT interval to Fridericia's formula (QTcF) >450 milliseconds (msec)
for males and >470 msec for females at screening or on Day 1 predose.
21. Has a mean value for triplicate semi-recumbent systolic blood pressure >150 mmHg
and/or diastolic blood pressure (BP) >90 mmHg measured after at least 10 minutes at
rest at the Screening Visit.
22. Has a screening estimated glomerular filtration rate (eGFR by Modification of Diet in
Renal Disease [MDRD]) <60 mL/min/1.73 m2.
23. Has alanine aminotransferase or aspartate aminotransferase (ALT or AST) of >1.0X upper
limit of normal (ULN) or total bilirubin >1.2X ULN (isolated bilirubin >1.2X ULN is
acceptable if bilirubin is fractionated and direct bilirubin is within the laboratory
normal range) at the Screening Visit and Day -1. (Note: Subjects who do not meet this
criterion during screening or check-in [Day -1] may not be rescreened/retested).
24. Has serum amylase or lipase >1.2X the ULN at the Screening Visit.
25. Has a recent history (within past 3 years) or current diagnosis of any of the
following GI (gastro-intestinal) related diseases: intestinal obstruction, GI
perforation, GI motility disorders, adhesions, Clostridium difficile colitis or have
had recent unexplained GI bleeding within 3 months prior to screening.
26. Has any history of pancreatitis (acute or chronic), gastroparesis, ischemic colitis,
inflammatory bowel disease (IBD), celiac disease, irritable bowel syndrome (IBS), or
colitis.
27. Has any past surgical history of gastric banding or bariatric surgery or bowel
resection.
28. Has a history of clinically significant endocrine disease including T2DM, a screening
HbA1c =6.5%, or a history of clinically significant gastrointestinal, cardiovascular,
hematological, hepatic, immunological, renal, respiratory, neurologic disorder,
neoplastic, or genitourinary abnormalities or diseases.
29. Has a history of unexplained arthralgias (Panel C only).
30. Has a history of bullous pemphigoid (Panel C only).
31. Has a history of any illness that, in the opinion of the study investigator, might
confound the results of the study or poses an additional risk to the subject by their
participation in the study.
note-* Subject may be included if they are able to return to the site within 7 days of
initial screening and the exclusion criterion is no longer met.
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