A Study to Evaluate the Safety, Tolerability, and Efficacy of TML-6 in Participants With Early Alzheimer's Disease

An Exploratory Phase 2 Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Investigate the Safety, Tolerability, and Efficacy of TML-6 in Early Alzheimer's Disease

The primary purpose of the study is to assess if treatment with TML-6 for 52 weeks will be effective in slowing, stopping, or improving cognitive and functional decline in participants with early Alzheimer's Disease (AD) as compared to participants receiving placebo.

TML-6 is a novel, orally active, synthetic curcumin analog. it is an investigational oral small molecule which demonstrated multiple mechanisms of action for the treatment of AD and is different from the currently common antibody-based approaches. TML-6 uses a first-in-class upstream autolysosomal targeting approach, which may enable a multi-target approach in AD. There remains a significant unmet need for safe and effective disease-modifying therapies in AD as disease-modifying agents offer the greatest potential to alter the course of disease progression. TML-6, a curcumin analog with multi-targeted biological activity, is under investigation as a potential disease-modifying therapy for AD.

TML-6 has demonstrated biological activity, including antioxidative, anti-inflammatory, autolysosomal, and anti-amyloid effects. TML-6 exhibits multiple biological effects to anti-aging to improve metabolism and to reduce amyloid levels and inflammation. This study is designed to evaluate the safety, tolerability, and efficacy of TML-6 in participants with early AD.

Inclusion Criteria:

1. Male participants or post-menopausal female participants (defined as women who have not had a menstrual period for at least 12 consecutive months, without the influence of medications known to cause amenorrhea) aged 60 to 85 years (inclusive) at the time of informed consent. If the male participant is sexually active with a female partner of childbearing potential, he must be willing and able to comply with the protocol-specified contraception and reproductive risk management requirements and agree to refrain from sperm donation, in accordance with the protocol.

2. Screening of blood biomarkers: local p-Tau217 or p-Tau181 should meet the National Institute of Aging - Alzheimer's Association (NIA-AA) core clinical criteria, Revised Criteria for Diagnosis and Staging of Alzheimer's Disease, 2024 Updated.

3. Have a clinical diagnosis of Mild Cognitive Impairment (MCI) due to AD - intermediate likelihood (Alzheimer's Association International Conference [AAIC] Stage 2 to 3):

   1. Meet the NIA-AA core clinical criteria for MCI due to AD.

   2. Blood biomarkers cut-off value (any one of the following):

      • Simoa® ALZpath p-Tau217: high cut-off value greater than or equal (>=) 0.551 picograms per milliliter (pg/mL)
      • Fujirebio Lumipulse® p-Tau217: high cut-off value >=0.34 pg/mL
      • C2N Diagnostics PrecivityAD2™ blood test: percentage (%) p-Tau217 cut point >=4.2%
      • Roche Elecsys® p-Tau181: high cut-off value >=0.934 pg/mL

   3. Mini-Mental State Examination (MMSE) score of 24 to 28 (inclusive) at screening.

   4. CDR-Global Score of 0.5 at screening. OR

4. Have a clinical diagnosis of mild AD dementia (Alzheimer's Association International Conference Alzheimer's Disease [AAIC AD] staging 4):

   1. Meet the NIA-AA core clinical criteria for probable AD dementia.

   2. Blood biomarkers cut-off value (any one of the following):

      • Simoa® ALZpath p-Tau217: high cut-off value >=0.551 pg/mL
      • Fujirebio Lumipulse® p-Tau217: high cut-off value >=0.34 pg/mL
      • C2N Diagnostics PrecivityAD2™ blood test: %p-Tau217 cut point >=4.2%
      • Roche Elecsys® p-Tau181: high cut-off value >=0.934 pg/mL

   3. MMSE score 20 to 26 (inclusive) at screening.

   4. CDR-Global Score of 0.5 or 1 at screening.

5. Report a history of subjective memory decline or decline in other cognitive domains (that is, executive functioning, visuospatial abilities, language functions) with gradual onset and slow progression over ≥ 6 months before screening.

6. Body mass index 17 to 35 kilograms per square meter (kg/m^2) at screening.

7. If receiving an approved AD treatment, such as acetylcholinesterase inhibitors (AChEIs), or memantine, or both for AD, medium chain triglyceride, Souvenaid, any nutraceutical, herb, or vitamin utilized as a cognitive enhancer must be on a stable dose for at least 13 weeks prior to baseline. Otherwise, these treatments are exclusionary. Treatment-naïve participants for AD can be entered into the study but must be agreeable to not start approved AD treatment throughout their study participation. Unless otherwise stated, participants must have been on stable doses of all other (that is, non-AD-related) permitted concomitant medications for at least 4 weeks prior to baseline.

8. Have an identified study partner who in the opinion of the investigator, has contact with the participant for 10 hours or more per week. The study partner must provide separate written informed consent. In addition, this person must be willing and able to provide follow-up information on the participant throughout the course of the study. For study partners not residing with the participant, the investigator has to be satisfied that the participant can contact the study partner readily during the times when the study partner is not with the participant. If in doubt about whether a participant's care arrangements are suitable for inclusion, the investigator should discuss this with the medical monitor. Study partners need to participate in person for visits where clinical assessments take place.

9. Be able to provide written informed consent.

10. Willing and able to comply with all aspects of the protocol.

11. Participants who received treatment or participated in a clinical trial with curcumin and ginkgo can be enrolled after 1 month of treatment discontinuation. In addition, participants who received treatment or participated in a clinical trial with noncurcumin, non-ginkgo or have been enrolled in a clinical trial for any type of cognitive treatment can only be enrolled after 3 months or 5 half-lives (whichever is longer) of treatment discontinuation.

12. Have adequate premorbid literacy, and current adequate vision, hearing, and motor skills to complete neuropsychological testing in the opinion of the investigator. Corrective aids are allowed.

Exclusion Criteria:

1. Female participants who are not yet menopausal or have not reached 1-year post-menopause are excluded.

2. Any participant who has received anti-amyloid therapy.

3. Any laboratory values with the following deviations at screening and admission. The laboratory test may be repeated once during the screening period.

   1. Alanine aminotransferase (ALT) greater than (>) upper limit of normal (ULN)

   2. Aspartate aminotransferase (AST) >ULN

   3. Total bilirubin (TBL) >ULN of the reference range

      * If predefined agreement is established in this protocol and, in the opinion of the investigator, the findings are clinically non-significant, exceptions may be made for

      • Isolated ALT and/or AST elevation less than (<) 1.5*ULN.
      • Bilirubin values that are above the ULN when the participant has an underlying diagnosis of Gilbert's syndrome.
      • Such cases should be documented in the participant's source records and may be reviewed by the Sponsor during routine monitoring.

   4. Absolute neutrophil count <1500 unless if it can be demonstrated that this is the participant's normal values.

   5. Hemoglobin <12 grams per deciliter (g/dL)

   6. Estimated glomerular filtration rate of <50 milliliters per minute per 1.73 square meters (mL/min/1.73m^2) (calculated by either the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] or Modification of Diet in Renal Disease [MDRD] by the method used at an International Organization for Standardization or Taiwan Accreditation Foundation-accredited hospital is accepted).

   7. Total cholesterol >=240 milligrams per deciliter (mg/dL)

4. Participants who have been tested positive for the following tests:

   1. Human Immunodeficiency Virus (HIV)

   2. Hepatitis B virus

      o Hepatitis B surface antigen (HBsAg)

   3. Hepatitis C virus (HCV) if confirmed by a positive polymerase chain reaction test or ever receiving anti-HCV treatment.

5. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's AD. (This would include but not be limited to vascular dementia, Lewy body dementia, Frontotemporal dementia, Parkinson's disease, traumatic brain injury, strokes, seizure disorder or any other neurological condition that could produce a decline in cognitive functioning).

6. History of transient ischemic attacks, stroke, or seizures within 12 months of screening.

7. Current psychiatric disorders, including schizophrenia and other psychotic disorders, major depression, or bipolar disorder according to the Diagnostic and Statistical Manual of Psychiatric Disorders, Edition V, text revision (DSM-V-TR) or (DSM-V).

8. GDS Short Form score >=8 at screening or any prior suicide attempt.

9. Having contraindications to MRI scanning, including cardiac pacemaker/defibrillator and ferromagnetic metal implants (for example, in skull and cardiac devices, other than those approved as safe for use in Magnetic Resonance Imaging [MRI] scanners).

10. Evidence of other clinically significant lesions on the brain MRI at screening that could indicate a dementia diagnosis other than AD.

11. Other significant pathological findings on the brain MRI at screening, including but not limited to: >=4 microhemorrhages (defined as <=10 millimeter [mm] at the greatest diameter); a single microhemorrhage >10 mm at the greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular territory; cerebral small vessel diseases; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and are <1 centimeter [cm] at their greatest diameter and with no mass effect need not be exclusionary).

12. Have a Modified Hachinski Ischemia Scale score of >=4 and a Fazekas score of 3.

13. Hypersensitivity to curcumin or any curcumin-based product.

14. Any immunological disease which requires treatment with biologic drugs during the study.

15. Participants with a bleeding disorder that is not under adequate control (including a platelet count <100,000 per microliters [/μL] or international normalized ratio >1.5).

16. Have thyroid stimulating hormone above normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator. This applies to all participants whether or not they are taking thyroid replacement.

17. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or electrocardiogram (ECG) at screening or baseline which, in the opinion of the Principal Investigator (PI), require further investigation or treatment or which may interfere with study procedures or safety.

18. Participants with malignant neoplasms within 3 years of screening (except for basal or squamous cell carcinoma in situ of the skin or localized prostate cancer in male participants). Participants who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before screening need not be excluded, if in the clinical opinion of the investigator, in remission.

19. At screening, participants with evidence of a serious risk for suicide based on the C-SSRS, answers "yes" to suicidal ideation questions 4 or 5 within 6 months prior to screening, or participants with a history of hospitalization or treatment for suicidal behavior prior to screening will be excluded.

20. Known or suspected history of drug or alcohol abuse or dependence within 2 years before screening or a positive urine drug test at screening. Participants who test positive for benzodiazepines or opioids in urine drug testing need not be excluded if, in the clinical opinion of the investigator, this is due to the participant taking prior/concomitant medications containing benzodiazepines or opioids for a medical condition and not due to drug abuse.

21. Any other medical conditions (for example, cardiac, respiratory, gastrointestinal, renal disease) which are not stable and adequately controlled, or which in the opinion of the investigator(s), could affect the participant's safety or interfere with the study assessments.

22. Any gastrointestinal condition that could impact the absorption of TML-6, for example, gastric bypass, inflammatory bowel disease, etc.

23. Have any reasons that prevent the participant from stopping the taking of supplements containing curcumin and ginkgo in the 1 month prior to the current trial (screening).

24. Participants who have known sensitivity to amyloid tracing agents or have contraindications to Positron Emission Tomography (PET) will be excluded from the PET sub-study; however, exclusion from the PET sub-study does not preclude participation in the main study at participating study site.

25. Have a history of clinically significant multiple or severe drug allergies, or severe posttreatment hypersensitivity reactions that, in the investigator's opinion, could interfere with the study Participants who have a history of anaphylaxis or a history of multiple drug allergies.

26. Participants who have a QTcF interval >450 millisecond (msec) (male) or >470 msec (female) and >480 for participants with a Bundle Branch Block or an MRI compatible pacemaker. (Fridericia's correction) at screening (as determined at the investigational site). The assessment may be repeated once during the screening period.