Single and Multiple Ascending Dosing Administration of MF-300 in Healthy Participants

Phase 1 Study of Single and Multiple Ascending Dosing Administration of MF-300 in Healthy Participants

The study will consist of 2 parts, Study Parts 1 (1a: single ascending dose [SAD] Phase; and 1b: Food Effect Phase) and Part 2 (multiple ascending dose [MAD] Phase). The SAD and MAD phases will evaluate separately non-elderly (≥ 18 to ≤ 65 years of age) and elderly (> 65 to ≤75 years of age) healthy adult subjects.

Part 1a is a double blind, randomized, placebo controlled, sequential SAD trial in healthy male or female volunteers. Volunteers will receive oral study drug (MF-300 or placebo) single dose administration. The dose levels will be tested sequentially until safety evaluation identifies a non-tolerated dose in the investigated population or when sustained MF-300 plasma levels are reaching the exposure supported by the available preclinical toxicokinetic data. Approximately 5 dose groups (non-elderly population) will provide a series increasing dose levels. An additional SAD dose group will evaluate an elderly population, with a dose selected based on safety and PK data from the 5 non-elderly SAD cohorts but not higher than what has been determined as generally safe and tolerated in the non-elderly population. Overall, no less than 48 subjects (assuming 6 cohorts of 8 subjects each) may complete the SAD study.

One tolerated dose completed in Part 1a will be selected for the evaluation of food effect (Part 1b). The dose will be selected on the basis of accumulated safety and PK information from the SAD phase. Food effect assessment is to be performed using the non-elderly population only. The food effect study is a randomized, 2-period, 2-sequence, open-label, crossover study. Approximately 12 subjects will be randomly assigned to 1 of the 2 treatment sequences (6 subjects per sequence) in which they receive MF-300 following a 10-hour fast or following a high-fat breakfast.

Part 2 is a double blind, randomized, placebo controlled, sequential MAD trial in healthy male or female volunteers. Volunteers will receive oral study drug (MF-300 or placebo) daily for 5 days as anticipated to achieved MF-300 steady state. The frequency of administration (once daily (QD)) and the duration of therapy required to achieve steady state (5 daily doses) were selected on the basis of allometric modeling from available toxicokinetic data but may be adapted based on MF-300 PK observed in the SAD cohorts previously completed. Three dose groups (non-elderly population) will provide a series increasing dose levels. The start of the MAD and SAD parts will be staggered, and a MAD dose cohort may be initiated when the corresponding SAD cohort at the next higher MF-300 dose has been cleared as safe and the food effect cohort has been completed. A fourth MAD dose group will be evaluated in the elderly population.

Inclusion Criteria:

Non-Elderly Cohorts:

1. Healthy male or non-pregnant, non-lactating female subjects ≥ 18 to ≤ 65 years of age at time of first dosing.

2. Body mass index (BMI) within the range ≥ 18.0 to ≤ 35.0 kg/m2.

3. Subjects in the food effect cohort must be willing to eat a high fat breakfast, including butter and turkey bacon or sausage.

4. Female subjects must either:

   1. have no childbearing potential by reason of surgery (e.g., hysterectomy, bilateral oophorectomy, salpingectomy in documented medical history) or be at least 1 year post-menopausal (e.g., 12 months without menstrual period without other medical cause), and have menopause confirmed with follicle-stimulating hormone level of >40 IU/L at screening in women not taking hormone contraceptive or hormone replacement therapy. Note: Documentation can come from the study center personnel's: review of the subject's medical records, medical examination, or medical history interview.
   2. if of child-bearing potential, must be truly abstinent of heterosexual intercourse as their usual and preferred lifestyle practicing abstinence and agree to remain abstinent for the duration of the study or subject's heterosexual partner is non-fertile (e.g. at least 90 days post-vasectomy from screening) or subjects are using and willing to continue using two medically acceptable forms of birth control for at least 30 days prior to screening (at least 90 days for oral and transdermal contraceptives) and at least 30 days after the last study drug administration. Acceptable forms of contraception include: bilateral tubal ligation or occlusion, oral or injectable hormonal contraceptives, contraceptive patch, hormonal and non-hormonal intra uterine devices, vaginal hormonal rings, vaginal diaphragm, or cervical caps, in addition to having their male partner use a condom plus spermicide agent.

5. Male subjects must be non-fertile, vasectomized (vasectomy performed 4 months or more prior to the first dosing), or truly abstinent of heterosexual intercourse as their usual and preferred lifestyle and agree to remain abstinent for duration of study and for 90 days from last administration of study drug or heterosexual partner is not of child bearing potential or subject is willing to continue using two medically acceptable form of birth control from Day -1 until at least 90 days after the last administration of study drug. Highly effective contraceptive methods include:

   1. Use of a condom plus spermicide agent from the time of informed consent until 90 days after the last administration of study drug.
   2. Subject's sexual partner is of non-childbearing potential, i.e., post-menopausal or surgically sterilized
   3. If subject's partner is of childbearing potential, she is using an acceptable form of contraception such as: bilateral tubal ligation or occlusion, oral or injectable hormonal contraceptives, contraceptive patch, hormonal and non-hormonal intra uterine devices, vaginal hormonal rings, vaginal diaphragm, or cervical caps

6. Male subjects must agree not to donate sperm from the first dosing until 90 days after the last dose.

7. Capable of giving signed informed consent that includes agreement to comply with the requirements and restrictions listed in the ICF and in this protocol.

Elderly Cohorts:

To be eligible for this study, subjects must meet all of the following inclusion criteria:

1. Healthy male or non-pregnant, non-lactating female subjects > 65 to ≤ 75 years of age at time of first dosing. Subjects with a history of and/or current well-controlled medical conditions may be enrolled so long as the investigator, in consultation with the medical monitor, are of the opinion that such conditions will not interfere with the safety of the subjects and that the subjects are otherwise in good general health. Some examples of allowable well-controlled medical conditions, in otherwise healthy subjects, include, but are not limited to the following:

   1. Well-controlled hypertension, for which, if on medication, are on a stable dose for at least 3 months prior to screening with no history of cardiac arrhythmia
   2. Well-controlled pre-diabetes/non-insulin dependent type 2 diabetes managed by diet and exercise. If treated with metformin, on a stable metformin dose for at least 3 months prior to screening
   3. Well-controlled hyperlipidemia, for which, if on medication, are on a stable dose for at least 3 months prior to screening
   4. Overweight/Obesity not requiring medication

2. Body mass index (BMI) within the range ≥ 18.0 to ≤ 35.0 kg/m2.

3. Female subjects must have no childbearing potential by reason of surgery (e.g., hysterectomy, bilateral oophorectomy, salpingectomy in documented medical history) or be at least 1 year post-menopausal (e.g., 12 months without menstrual period without other medical cause), and have menopause confirmed with follicle-stimulating hormone level of >40 IU/L at screening in women not taking hormone contraceptive or hormone replacement therapy. Note: Documentation can come from the study center personnel's: review of the subject's medical records, medical examination, or medical history interview. Female subjects who do not meet a follicle-stimulating hormone level of >40 IU/L at screening must be truly abstinent of heterosexual intercourse as their usual and preferred lifestyle and agree to remain abstinent for the duration of the study, or subject's heterosexual partner is non-fertile (e.g. at least 90 days post-vasectomy from screening), or agrees to use a condom plus spermicide agent from screening to end of study.

4. Male subjects must be non-fertile, vasectomized (vasectomy performed 4 months or more prior to the first dosing), or truly abstinent of heterosexual intercourse as their usual and preferred lifestyle and agree to remain abstinent for duration of study and for 90 days from last administration of study drug or heterosexual partner is not of child bearing potential or subject is willing to continue using two medically acceptable form of birth control from Day -1 until at least 90 days after the last administration of study drug. Highly effective contraceptive methods include:

   1. Use of a condom plus spermicide agent from the time of informed consent until 90 days after the last administration of study drug.
   2. Subject's sexual partner is of non-childbearing potential, i.e., post-menopausal or surgically sterilized
   3. If subject's partner is of childbearing potential, she is using an acceptable form of contraception such as: bilateral tubal ligation or occlusion, oral or injectable hormonal contraceptives, contraceptive patch, hormonal and non-hormonal intra uterine devices, vaginal hormonal rings, vaginal diaphragm, or cervical caps

5. Male subjects must agree not to donate sperm from the first dosing until 90 days after the last dose.

6. Capable of giving signed informed consent that includes agreement to comply with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

Non-Elderly Cohorts:

Subjects who meet any of the following criteria will be excluded from participating in the study:

1. History of or current clinically significant medical illness including, but not limited to, any cardiovascular disease (including blood pressure or rhythm disturbance requiring constant monitoring), hematologic disease, coagulation disorders, lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease and diabetes mellitus, hepatic or renal insufficiency, thyroid disease, neurologic or psychiatric disease, or any other illness that the Investigator considers should exclude the subject or that could interfere with the safety of the subjects, or might confound the study results.
2. Has cancer (Note: subject with history of cancer that is in complete remission and not requiring treatment for at least 5 years, including basal cell carcinoma, squamous cell skin cancer, or melanoma in situ superficial skin lesions that have been successfully removed, will not be exclusionary).
3. Has acute or chronic GI conditions (e.g., gastroesophageal reflux disease, peptic ulcer, active and chronic colitis, cholecystectomy, small or large bowel resection, gastric bypass or equivalent) that would interfere with drug tolerance or absorption.
4. Has history of migraine headaches requiring medical attention or active treatment within the past 6 months from screening.
5. Has visible sunburn at admission
6. Has a history of hypersensitivity/photosensitivity dermatosis within the past 5 years,
7. Has another active dermatological pathology at screening or admission excluding dry skin or acne, deemed clinically significant by the Investigator.
8. Has a history of or active ocular pathology or clinically significant findings in the Investigator opinion on ophthalmology exam at screening (Note: normal slit exam (glaucoma, cataract) will be sufficient to exclude sensitivity to phototoxicity).
9. Clinically significant abnormalities in results of laboratory tests, such as clinically significant abnormal hematology, clinical chemistry, thyroid, or urinalysis at screening or at the time of admission, as per Investigator's judgment; Note: Repeat testing is allowed at Investigator discretion.
10. Liver impairment defined as AST and/or ALT > ULN; or kidney impairment defined as eGFR < 90 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation
11. Clinically significant abnormal physical examination or vital signs as determined by the Investigator.
12. Clinically significant, abnormal 12 lead ECG as determined by the Investigator, including average QTcF > 450 ms for males and >470 ms for females. Note: Repeat testing is allowed at Investigator discretion.
13. Blood pressure less than 90/40 mmHg or greater than 140/90 mmHg. Heart rate lower than 40 bpm or higher than 99 bpm. Subjects should be seated or semi-supine for a minimum of 5 minutes. Vital signs may be repeated once (once at screening and once at admission) at the discretion of the PI or designee.
14. History of or positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2) antibody.
15. Active bacterial or viral infection at screening or the time of admission or COVID 19 test positive at admission
16. Excessive use of caffeine-containing foods including coffee, tea, cola, energy drinks or chocolates, exceeding 500 mg caffeine/day (approximately 5 cups of coffee or 10 cups of tea), in the opinion of the Investigator during the 7 days before the first administration of the study drug.
17. Use of or unable to refrain from prescribed medication (with the exception of hormone contraceptives for women of child bearing potential) or over-the-counter (OTC) medicine (including vitamins, and herbal and dietary supplements, such as St John's Wort) during the 14 days or clearance of 5 half-lives (whichever is longer) before the first administration of the study drug and throughout the study.
18. Participation in another investigational drug, biologic, or device study, with less than 30 days or less than 5 half-lives from the last dose of investigational product to admission, whichever is longer, except for observational studies.
19. Use of nicotine-containing products (gum, patch, etc.) within 3 months of Screening (as confirmed by urine cotinine test) and throughout the study; Presence or history within 2 years of screening of smoking or vaping nicotine and throughout the study.
20. Subject has a presence or history, within 2 years of screening, of alcohol abuse or illicit substance abuse as judged by the Investigator or consumes alcohol or an illicit substance within 48 hours prior to admission and throughout the study.
21. Presence or history of marijuana use (including prescribed marijuana) within 30 days of Screening and throughout the study
22. Positive result in the urine alcohol and/or drug screen at screening or at the time of admission.
23. Veins unsuitable for repeated venipuncture.
24. Blood donation or blood loss of more than 500 mL within 7 days prior to screening.
25. In the Investigator's opinion, subject is unable to understand the nature of the study and any risks involved in participation, and unwilling to cooperate and comply with the clinical study protocol procedures, restrictions (dietary or physical activity), and requirements, or is unsuitable for any other reason.

Elderly Cohorts:

Subjects who meet any of the following criteria will be excluded from participating in the study:

1. Any acute or chronic clinically significant medical condition that is poorly controlled and in the judgement of the Investigator (in consultation with the Sponsor Medical Monitor) could interfere with the safety of the subject or might confound the study results.
2. Has cancer (Note: subject with history of cancer that is in complete remission and not requiring treatment for at least 5 years, including basal cell carcinoma, squamous cell skin cancer, or melanoma in situ. Superficial skin lesions that have been successfully removed, will not be exclusionary).
3. Has acute or chronic GI conditions (e.g., gastroesophageal reflux disease, peptic ulcer, active and chronic colitis, cholecystectomy, small or large bowel resection, gastric bypass or equivalent) that would interfere with drug tolerance or absorption.
4. Has history of migraine headaches requiring medical attention or active treatment within the past 6 months from screening.
5. Has visible sunburn at admission
6. Has a history of hypersensitivity/photosensitivity dermatosis within the past 5 years,
7. Has another active dermatological pathology at screening or admission excluding dry skin or acne, deemed clinically significant by the Investigator.
8. Has a history of or active ocular pathology or clinically significant findings in the Investigator opinion on ophthalmology exam at screening (Note: normal slit exam (glaucoma, cataract) will be sufficient to exclude sensitivity to phototoxicity). Participants with a history of cataracts that have been corrected may be enrolled, just so long as the corrective procedure took place ≥1 yr prior to screening, and current exam shows no active pathology on screening exam.
9. Clinically significant abnormalities in results of laboratory tests, such as clinically significant abnormal hematology, clinical chemistry, thyroid, or urinalysis at screening or at the time of admission, as per Investigator's judgment; Note: Repeat testing is allowed at Investigator discretion.
10. Liver impairment defined as AST and/or ALT > ULN; or kidney impairment defined as eGFR < 75 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation at screening.
11. Clinically significant abnormal physical examination or vital signs as determined by the Investigator.
12. Clinically significant, abnormal 12 lead ECG as determined by the Investigator, including average QTcF > 450 ms for males and >470 ms for females. Note: Repeat testing is allowed at Investigator discretion.
13. Blood pressure less than 90/40 mmHg or greater than 140/90 mmHg. Heart rate lower than 40 bpm or higher than 99 bpm. Subjects should be seated or semi-supine for a minimum of 5 minutes. Vital signs may be repeated once (once at screening and once at admission) at the discretion of the PI or designee.
14. History of or positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2) antibody.
15. Active bacterial or viral infection at screening or the time of admission or COVID 19 test positive at admission
16. Excessive use of caffeine-containing foods including coffee, tea, cola, energy drinks or chocolates, exceeding 500 mg caffeine/day (approximately 5 cups of coffee or 10 cups of tea), in the opinion of the Investigator during the 7 days before the first administration of the study drug.
17. Use of or unable to refrain from prescribed medication or over-the-counter (OTC) medicine (including vitamins, and herbal and dietary supplements, such as St John's Wort) during the 14 days or clearance of 5 half-lives (whichever is longer) before the first administration of the study drug and throughout the study. Subjects taking daily prescription medications for management of acceptable chronic medical conditions (as defined in inclusion criteria #1) will be allowed to continue on these medications but must be on a stable dose, as defined by no change in dose for the 3 months prior to the first dose of study medication and no planned changes during the conduct of the study.
18. Participation in another investigational drug, biologic, or device study, with less than 30 days or less than 5 half-lives from the last dose of investigational product to admission, whichever is longer, except for observational studies. This reference is specific to participation in a different study involving another investigational drug. This does not apply to the current study where a participant in the SAD phase of the study can also participate in the MAD phase of the study provided they continue to meet all eligibility criteria and a sufficient washout period of 5 half-lives (minimum of 96 hours) takes place between the first dose of the SAD and first dose of the MAD phases.
19. Use of nicotine-containing products (gum, patch, etc.) within 3 months of Screening (as confirmed by urine cotinine test) and throughout the study; Presence or history within 2 years of screening of smoking or vaping nicotine and throughout the study.
20. Subject has a presence or history, within 2 years of screening, of alcohol abuse or illicit substance abuse as judged by the Investigator or consumes alcohol or an illicit substance within 48 hours prior to admission and throughout the study.
21. Presence or history of marijuana use (including prescribed marijuana) within 30 days of Screening and throughout the study
22. Positive result in the urine alcohol and/or drug screen at screening or at the time of admission.
23. Veins unsuitable for repeated venipuncture.
24. Blood donation or blood loss of more than 500 mL within 7 days prior to screening.
25. In the Investigator's opinion, subject is unable to understand the nature of the study and any risks involved in participation, and unwilling to cooperate and comply with the clinical study protocol procedures, restrictions (dietary or physical activity), and requirements, or is unsuitable for any other reason.