A Phase 1 Safety and Tolerability Study of TML-6 in Healthy and Elderly Volunteers for Alzheimer's Disease Treatment

Healthy adults: Subject's age is ≥18 years old and ≤55 years old at screening Healthy elderly adults: Subject's age is ≥60 years old and ≤80 years old at screening

Inclusion criteria

• Healthy male and female volunteers
• For Parts 1, 2, and 4 (Cohorts 1-5 and 7-8): Subject's age is ≥18 years old and ≤55 years old at screening.

For Parts 3 and 5 (Cohorts 6 and 9): Subject's age is ≥60 years old and ≤80 years old at screening.

• For Parts 1, 2, and 4 (Cohorts 1-5 and 7-8): Subjects whose body mass index (BMI) at screening is within a range of ≥18.5 kg/m2 and <30.0 kg/m2 For Parts 3 and 5 (Cohorts 6 and 9): Subjects whose BMI <30.0 kg/m2 Note: BMI = Body weight (kg) / [Height (m)]2; Body weight is not less than 50 kg at screening and admission.
• Subjects who are deemed to be satisfactory health by the investigator through an assessment of their medical history, physical examinations, and routine laboratory tests.
• Female subjects of child-bearing potential show negative pregnancy test results at screening and admission.
• Female subjects of child-bearing potential, committing to practicing sexual abstinence or using and continue to use 2 highly effective contraceptives of birth control for at least 30 days prior to screening (that period will extend to 90 days for oral contraceptive use) and for at least 30 days after the last dose of investigational product (IP).

For a subject to be considered not to be of child-bearing potential, she must have been amenorrheic for at least 12 months with confirmed follicle-stimulating hormone (FSH) level (within postmenopausal range) at screening, or must have had a hysterectomy, a bilateral tubal ligation, and/or a bilateral oophorectomy (as determined by the medical history).

The male partner of a female study subject with childbearing potential must use a condom and ensure that his partner uses a highly effective contraception as outlined below.

The highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject.
• Combination of the following listed methods (d.1+d.2):

d.1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception, intrauterine device (IUD), or intrauterine system (IUS).

d.2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps).

• Subjects must demonstrate willingness to comply with all requirements, instructions and restrictions stated in the protocol, and must provide the written informed consent form after thorough understanding.

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Exclusion criteria

• Subjects with any properly diagnosed disease within 30 days prior to the first dose of the IP.
• Subjects who have a QTcF interval >450 msec (male) or >470 msec (female) (Fridericia's correction) at screening. The assessment may be repeated once during the screening period.
• Systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg at screening and admission, irrespective of anti-hypertensive medication status for the subject. The assessments may be repeated for confirmation after resting for approximately 10 to 30 minutes.
• Any laboratory values with the following deviations at screening and admission. The laboratory test may be repeated once during the screening period and Day -1.

• White blood cell count (WBC) < 3000/μL
• Hemoglobin < 10 g/dL
• Platelet count < 100000/μL
• Creatinine > upper limit of normal (ULN)
• Alanine Aminotransferase (ALT) > ULN
• Aspartate Aminotransferase (AST) > ULN
• Total bilirubin > ULN of the reference range * If agreement is obtained per the investigator's discretion, exceptions may be made for isolated ALT or AST elevation <1.5× ULN and bilirubin values that are above the ULN for subject has an underlying diagnosis of Gilbert's syndrome.
• Subjects who have been tested positive for the following tests:

• Human immunodeficiency virus (HIV)

• Hepatitis B virus (HBV)

• Hepatitis C virus (HCV)
• Female subjects who are lactating or with a positive pregnancy test at the screening visit and/or admission.
• Subjects had a history of substance use disorders according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V) criteria.
• Subjects with positive urine drug test (including cotinine detection) or positive blood alcohol test at screening and on Day -1 (and on Day 15+ in Cohort 2).
• Subjects with underlying medical, mental, or psychological conditions that may impede study compliance, or, at the discretion of the investigator, preclude participation in the study.
• The medical history indicates contraindications or hypersensitivity to the use of test medications [TML-6 or any components of the IP].
• Subjects took any of the following systemically-absorbed medications in the specified durations:

• Any medications (excluding vitamins, food supplements, and hormonal contraceptives for birth control) within 14 days prior to the first dose of the IP, unless in the opinion of the investigator and sponsor, the medication will not interfere with the study or compromise subject's safety.

• Any known enzyme inducers/inhibitors or agents that significantly alter hepatic or renal clearance (e.g., erythromycin, cimetidine, barbiturates, phenothiazine, clarithromycin, troleandomycin, ketoconazole, miconazole, fluconazole, itraconazole) within 30 days prior to the first dose of the IP.
• Subjects had participated in investigational drug trials and took any investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the first dose of the IP.
• Subjects had blood loss or blood donation of more than 250 and 500 mL within 60 and 90 days, respectively prior to the first dose of the IP.
• Subjects who cannot stop caffeine-intake for 48 hours prior to the first study dose and during the entire study period.
• Subjects who are smokers or former smokers who have used nicotine-containing products within 3 months prior to the first dose of the IP.
• Unwilling or unable to comply with the lifestyle instructions described in the protocol.
• Subjects appears to have poor venous access.
• Subjects have any other condition which, in the opinion of the investigator, precludes the subject's participation in the study.

Additional exclusion criteria for the healthy adult subjects in Cohorts 1-5 and 7-8:

• Subjects with a clinically significant hematological, endocrine, cardiovascular, hepatic, renal, gastrointestinal, pulmonary, immunologic, metabolic, urologic disorder, and/or malignancy as judged by the investigator; subjects with any predisposing condition that might interfere with the absorption, distribution, metabolism, and excretion of drugs; subjects who has had any previous gastrointestinal surgery, except appendectomy if performed >90 days prior to the first dose of the IP.

Additional exclusion criteria for the healthy elderly subjects in Cohorts 6 and 9:

• Subjects with a clinically significant hematological, endocrine, cardiovascular, hepatic, renal, gastrointestinal, pulmonary, immunologic, metabolic, urologic disorder, and/or malignancy that is not well managed and stable, as judged by the investigator; subjects with any predisposing condition that might interfere with the absorption, distribution, metabolism and excretion of drugs; subjects who has had any previous gastrointestinal surgery, except appendectomy if performed >90 days prior to the first dose of the IP.
• Subjects with estimated Glomerular Filtration Rate (eGFR, calculated based on Cockcroft-Gault formula) of <60 mL/min/1.73 m2 during screening period. If the eGFR exceeds the limits above, the assessment may be repeated once during the screening period.

Additional exclusion criteria for the subjects in Cohorts 7-9:

• If the subject has history of suicidal attempt as an adult or suicide ideation in the past year that resulted in pharmacologic treatment or hospitalization, the subject will be excluded if he/she meets any of the following criteria.

• Answer of "yes" on items 4 or 5 of the Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening if the ideation occurred in the previous 6 months.
• Answer of "yes" on any item of the Suicidal Behavior section of the C-SSRS, except for the Non-Suicidal Self injurious Behavior if this behavior occurred in the previous 2 years.

Additional exclusion criteria for the subjects in Cohort 9:

• The subject with clinically significant abnormal finding in the lumbar X-ray examination that is considered incompatible with lumbar puncture (LP) by the investigator at screening.
• The subject has had CSF collection performed within 30 days prior to Day -1.
• The subject has a history of clinically significant back pain and/or injury (e.g., clinically significant degenerative disease, spinal deformity, or spinal surgery) that may predispose to complications or technical difficulty with LP, as judged by the investigator.
• The subject has developed signs and symptoms of spinal radiculopathy, including lower extremity pain and paresthesias.
• The subject has evidence or history of significant active bleeding or coagulation disorder or have received drugs that affect coagulation or plate function within 14 days prior to LP procedure.
• The subject has a local infection at the puncture site.
• The subject has any focal neurological deficit that might suggest an increase in intracranial pressure.
• The subject has any abnormal finding on ophthalmological assessment/fundoscopy indicative of raised intracranial pressure (i.e., optic disc swelling/edema, or uncontrolled hypertensive retinopathy).
• The subject has abnormal coagulation tests (prothrombin time [PT]/international normalized ratio [INR], and partial thromboplastin time [PTT]) at screening. The assessment may be repeated once during the screening period.
• The subject regularly suffers from moderate-to-severe headaches requiring analgesics.
• Subject's medical history shows hypersensitivity to the anesthetic, or its derivatives used during CSF collection or any medication used to prepare the area of LP procedure.

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