A First-In-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of K-645 in Healthy Volunteers

Exclusion Criteria34

• Has participated in another investigational study within the following time period: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer or based on local regulations) prior to 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.
• Is an employee of the Sponsor or study site or an immediate family member (eg, spouse, parent, child, sibling) of any employee of the Sponsor or study site.
• Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or food.
• Has a known hypersensitivity or contraindication to any component of K-645, its excipients, or related compounds.
• Has a positive alcohol or drug screen at Screening or admission.
• Has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency 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.
• Has a fever at screening* or has a positive COVID-19 test or has a fever at Period 1 Day -1.
• Had major surgery or donated or lost 1 unit of blood or blood products (approximately 500 mL) within 4 weeks prior to Period 1 Day -1.
• Is unable to refrain from the use of 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 and through the completion of study participation at the Follow-Up visit. Exceptions are noted below:
• Exceptions:
• The occasional use of non-steroidal anti-inflammatory agents (e.g. ibuprofen) that do not include paracetamol/acetaminophen is allowed. Note: chronic routine use of NSAIDs prior to the screening visit is exclusionary.
• Influenza vaccination and COVID vaccination are allowed.
• Other exceptions can be made, case by case, if the Investigator and Kallyope Medical Monitor agree that the medication in question will not interfere with the study procedures, compromise subject safety, or otherwise undermine study goals.
• Note: CYP3A4 inhibitors and inducers, and P-glycoprotein (P-gp) inhibitors are strictly prohibited due to potential for drug interactions with K-645.
• Has excessive consumption of alcohol within 6 months prior to screening (greater than 14 drinks/week, 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.
• Is unwilling or unable to refrain from study alcohol restrictions:
• Subjects will refrain from consuming alcohol from 5 days (at least 120 hours) prior to check-in through discharge from the unit in each period, and from 5 days (at least 120 hours) prior to the Poststudy visit.
• At all other times, alcohol consumption is limited to less than or equal to 14 drinks/week, where 1 drink equals to 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor.
• 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.
• Is unwilling/unable to refrain from consumption of mustard green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, and mustard) or charbroiled (charcoal cooking) meats beginning approximately 48 hours prior to admission to the clinic in Period 1, 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.
• Is unable or unwilling to refrain from consuming caffeinated beverages 24 hours prior to check-in through discharge from the unit in each period, and 24 hours prior to the follow up visit.
• Has a substance abuse disorder.
• Had a previous major psychotic disorder.
• Has a mean triplicate value for corrected QT interval to Fridericia's formula (QTcF) greater than 450 milliseconds (msec) at screening or on Period 1 Day 1.
• Has a mean value for triplicate semi-recumbent systolic blood pressure (SBP) greater than 140 mmHg and/or diastolic blood pressure (DBP) greater than 90 mmHg measured after at least 10 minutes at rest at the Screening Visit or on Period 1 Day -1. If a subject’s BP is over the limits, then one triplicate repeat may be taken after at least another 10 minutes of rest.
• Has an estimated glomerular filtration rate (eGFR by the Chronic Kidney Disease Epidemiology [CKD-EPI]) less than 70 mL/min/1.73m2 at the Screening Visit or Period 1 Day -1.
• Has alanine aminotransferase or aspartate aminotransferase (ALT or AST) of greater than 1.0X upper limit of normal (ULN) or total bilirubin greater than 1.5X ULN upper limit of normal (ULN) (total bilirubin greater than 1.5X ULN is acceptable if bilirubin is fractionated and direct bilirubin is within the laboratory normal range) at the Screening Visit and Period 1 Day -1.
• Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, neurologic, neoplastic, or genitourinary abnormalities or diseases.
• Note: Self-limited conditions/events that occurred and resolved greater than or equal to 1 year prior to screening are not exclusionary if both the Investigator and Kallyope Medical Monitor agree that these conditions were self-limited and do not compromise subject safety, or otherwise undermine study goals.
• Family history of congenital hypogonadotropic hypogonadism in a first-degree relative unless a specific genetic cause has been confirmed which does not involve mutation of TAC3R (the NK3R gene) or TAC3 (the neurokinin B gene).
• 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.
• Is biological female.
• Has a pregnant partner.
• A 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.