TML-6 for Alzheimer’s Disease

Overseen By Clare Ting-Yi Hou

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Merry Life Biomedical Co., Ltd.

Must not be taking: Enzyme inducers/inhibitors

Disqualifiers: Hypertension, HIV, Hepatitis, substance use, others

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effects of a new treatment called TML-6 for Alzheimer’s disease. Researchers aim to determine how the body handles different doses and whether eating affects the drug's performance. The trial will compare TML-6 to a placebo (a harmless pill with no active drug) across several groups. Healthy adults aged 18-55 and healthy seniors aged 60-80 who meet specific health criteria are eligible to participate. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding how it works in people.

Will I have to stop taking my current medications?

Participants must stop taking any medications (except vitamins, food supplements, and hormonal contraceptives) within 14 days before the first dose of the study drug, unless the investigator and sponsor agree that the medication won't interfere with the study or compromise safety.

Is there any evidence suggesting that TML-6 is likely to be safe for humans?

Research shows that TML-6 looks promising in early studies. It is considered safe and absorbs well in the body. Detailed information about side effects in humans is not yet available, but the treatment is currently undergoing early human trials. This phase focuses on safety, indicating that lab and animal tests deemed it safe enough to proceed. So far, these studies have not identified any major safety issues. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Most treatments for Alzheimer's disease, like donepezil and memantine, work by managing symptoms rather than altering disease progression. But TML-6 is unique because it is being explored for its potential to target underlying disease mechanisms. Researchers are particularly excited about its novel oral granule format, which may offer easier administration and better patient compliance compared to existing treatments. Additionally, TML-6 is being studied for its effects on both younger and elderly populations, which could provide broader insights into its efficacy and safety.

What evidence suggests that TML-6 might be an effective treatment for Alzheimer's?

Research shows that TML-6, which participants in this trial may receive, is a promising treatment for Alzheimer's disease. Studies have found that TML-6 improves memory and thinking skills in mice with Alzheimer's. It reduces the buildup of harmful proteins in the brain, such as amyloid-beta and tau. This treatment also aids in learning and decreases brain inflammation. These findings suggest that TML-6 could potentially help people with Alzheimer's by addressing several aspects of the disease. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for healthy adults and elderly volunteers who are interested in helping to find new treatments for Alzheimer's disease. Participants should not have any serious health issues that could interfere with the study.

Inclusion Criteria

Subjects who are deemed to be in satisfactory health by the investigator through an assessment of their medical history, physical examinations, and routine laboratory tests.

I am a healthy volunteer.

I am of child-bearing age and my pregnancy tests are negative.

Exclusion Criteria

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 underlying medical, mental, or psychological conditions that may impede study compliance, or, at the discretion of the investigator, preclude participation in the study.

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Single-ascending Dose (SAD)

5 cohorts of subjects are planned to be orally dosed, ranging from 100 mg - 1000 mg

3 days per cohort

Multiple visits for dosing and safety assessments

Food Effect

Subjects from Cohort 2 of Part 1 receive the same dose under fed and fasting conditions

48 hours

Visits for dosing and PK sampling

Multiple-ascending Dose (MAD)

2 cohorts of subjects are dosed once daily for 7 consecutive days, ranging from 400 mg - 800 mg

7 days

Daily visits for dosing and PK sampling

Elderly Cohort

One cohort of elderly subjects receives a single dose of IP within the safe range defined in the SAD study

3 days

Visits for dosing and safety assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 days

Safety assessments post-dose

What Are the Treatments Tested in This Trial?

Interventions

• TML-6

Trial Overview

The study is testing TML-6, a potential treatment for Alzheimer's. It will look at how people handle different doses, how food affects it, and what happens to TML-6 in the body over time compared to a placebo.

How Is the Trial Designed?

Group I: TML-6 Granules Experimental Treatment 1 Intervention

This study consists of 5 parts, Part 1 (SAD): 5 cohorts of subjects are planned to be orally dosed, ranging from 100 mg - 1000 mg. Part 2 (Food effect): All subjects in Cohort 2 of Part 1 will constitute Period 1 of Part 2 and will move to Period 2 to receive the same Investigational Product (IP) dose as in Period 1. Part 3 (Elderly): One cohort of elderly subjects will receive a single dose of IP. A dose level of IP within the safe range defined in the Part 1 SAD study will be chosen Part 4 (MAD): 2 cohorts of subjects are planned to be orally dosed once daily for 7 consecutive days, ranging from 400 mg - 800 mg. Part 5 (MAD+Cerebrospinal Fluid, CSF PK): One cohort of elderly subjects will receive orally once daily for 7 consecutive days of IP. The dose level of IP defined in the Part 4 MAD study will be chosen.

Group II: Placebo Placebo Group 1 Intervention

Placebo

Who Is Running the Clinical Trial?

Merry Life Biomedical Co., Ltd.

Lead Sponsor

Trials

1

Recruited

70+

Published Research Related to This Trial

In the TRAILBLAZER-ALZ study, treatment with donanemab, an amyloid-lowering drug, significantly delayed disease progression in Alzheimer's disease by approximately 5.3 months according to the Integrated Alzheimer's Disease Rating Scale and 5.2 months according to the Clinical Dementia Rating Sum of Boxes.

Expressing treatment effects as 'months saved' provides a clearer understanding of the clinical relevance of donanemab's efficacy compared to traditional metrics, making it easier for patients and clinicians to interpret the benefits of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

'Time Saved' As a Demonstration of Clinical Meaningfulness and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings. Dickson, SP., Wessels, AM., Dowsett, SA., et al.[2023]

The TREM1 variant rs2234246A is significantly associated with amyloid-β deposition in Alzheimer's disease, as shown in a study of 522 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

This variant influences amyloid pathology specifically in individuals with mild cognitive impairment and Alzheimer's disease, suggesting its role in the progression of AD-related brain changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Common Variant in TREM1 Influencing Brain Amyloid Deposition in Mild Cognitive Impairment and Alzheimer's Disease. Liu, YS., Yan, WJ., Tan, CC., et al.[2022]

The TREML2 gene, located on chromosome 6p21.1, is associated with an increased risk of late-onset Alzheimer's disease (AD), suggesting it plays a role in the disease's susceptibility and development.

Recent studies indicate that TREML2 may influence immune responses in the brain, highlighting its potential involvement in the pathogenesis of AD and pointing to future research opportunities to explore its mechanisms further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of TREML2 in Alzheimer's Disease. Wang, SY., Gong, PY., E, Y., et al.[2021]

The anti-human TREM2 agonistic antibody AL002c showed promising effects in mouse models of Alzheimer's disease by reducing amyloid plaques and improving microglial response, indicating its potential to mitigate disease pathology.

In a phase I clinical trial, a variant of AL002c was found to be safe and well tolerated in humans, successfully engaging the TREM2 receptor, which suggests it could be a viable therapeutic option for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. Wang, S., Mustafa, M., Yuede, CM., et al.[2021]

In a 24-week study involving 268 patients with mild to moderately severe Alzheimer's disease, donepezil at a dose of 5 mg/day significantly improved cognitive performance and clinical assessments compared to placebo, as shown by various efficacy measures.

The safety profile of donepezil was favorable, with only 10% of patients experiencing drug-related adverse events, primarily mild gastrointestinal symptoms that resolved with continued treatment or temporary discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer's disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group. Homma, A., Takeda, M., Imai, Y., et al.[2018]

The study identified that using the Functional Activities Questionnaire and the Clinical Dementia Rating Sum of Boxes as endpoints can detect significant changes in Alzheimer's disease progression, particularly in patients with Late Mild Cognitive Impairment, suggesting these measures are effective for future trials.

Composite measures showed even greater sensitivity, indicating that using a combination of endpoints could enhance the success rate of Alzheimer's clinical trials by better capturing the disease's progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The importance of endpoint selection: How effective does a drug need to be for success in a clinical trial of a possible Alzheimer's disease treatment? Evans, S., McRae-McKee, K., Wong, MM., et al.[2019]

Recent discussions among physicians emphasize that evaluating Alzheimer's disease treatments should go beyond just cognitive improvements to include functional abilities, behavior, caregiver burden, quality of life, and resource utilization, as these factors significantly impact patients and caregivers.

Cholinesterase inhibitors have been shown to provide meaningful long-term benefits across multiple domains in Alzheimer's patients when using these expanded criteria for treatment success, highlighting their efficacy in improving overall patient well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of Alzheimer's disease: is there a need to redefine treatment success? Winblad, B., Brodaty, H., Gauthier, S., et al.[2022]

Hippocampal sclerosis of aging, affecting over 20% of individuals older than 85, is a significant condition that mimics Alzheimer's disease and is linked to cognitive impairment, highlighting the need for better disease classification.

The review discusses genetic risk factors and pathogenetic influences related to TDP-43 pathology, proposing a new term 'cerebral age-related TDP-43 and sclerosis' (CARTS) to better describe this condition and improve diagnostic accuracy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"New Old Pathologies": AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS). Nelson, PT., Trojanowski, JQ., Abner, EL., et al.[2020]

In a study of 1,306 individuals from the Alzheimer's Disease Neuroimaging Initiative, the TREML2 rs3747742 mutation was found to significantly influence cerebrospinal fluid (CSF) total-tau levels in Alzheimer's disease patients, suggesting a role in neurodegeneration.

The mutation did not show associations with other Alzheimer's biomarkers like amyloid-β or phosphor-tau, indicating that TREML2 may specifically affect tau-related neurodegeneration rather than overall Alzheimer's pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TREML2 Mutation Mediate Alzheimer's Disease Risk by Altering Neuronal Degeneration. Song, YN., Li, JQ., Tan, CC., et al.[2020]

Early diagnosis of Alzheimer's disease is crucial for initiating treatment with cholinesterase inhibitors, which can help stabilize or reduce cognitive and functional decline in patients with mild-to-moderate Alzheimer's disease.

Cholinesterase inhibitors like rivastigmine, donepezil, and galantamine are recommended as first-line therapies, while memantine can be used alone or with these inhibitors for moderate to severe cases, emphasizing the importance of tailored pharmacologic management based on disease stage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective pharmacologic management of Alzheimer's disease. Farlow, MR., Cummings, JL.[2022]

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TML-6 (1.05, 2.09, 3.14, 4.19 μg/mL; 24 h) reduces the production of Aβ40 and Aβ42 between 1.05, 2.09 and 3.14 μg/mL (equal to 2, 4 and 6 μM) in a dose- ...

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