Study to Evaluate the Efficacy and Safety of KDS2010 in Patients With Alzheimer's Disease With Mild Cognitive Impairment and Mild Dementia Due to Alzheimer's Disease

A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Phase 2a Clinical Trial to Evaluate the Efficacy and Safety of KDS2010 in Patients With Alzheimer's Disease With Mild Cognitive Impairment and Mild Dementia Due to Alzheimer's Disease

A randomized, double-blind, placebo-controlled, dose-finding Phase 2a clinical trial will be conducted to evaluate the efficacy and safety of KDS2010 in patients with Mild Cognitive Impairment (MCI) due to Alzheimer's disease (AD) and mild dementia due to Alzheimer's disease.

Based on preliminary efficacy observed in the Phase 1 clinical trial, a clinical trial will be conducted in Korea. Eligible patients diagnosed with MCI or mild Alzheimer's disease will be stratified by disease stage (MCI/mild AD) prior to randomization. Subjects will be randomly assigned in a 1:1:1 ratio to either Treatment Group 1, Treatment Group 2, or the Control Group. The investigational product will be administered orally once daily for a duration of 24 weeks. Approximately 114 subjects will be enrolled, including an estimated 20% dropout rate, with 38 subjects assigned to each group (Treatment Group 1, Treatment Group 2, and Control Group).

The objectives of the study are as follows:

1. Efficacy Objectives: Efficacy will be evaluated through changes in cognitive function, self-management, and daily living activities before and after administration of KDS2010. Biomarker analysis in plasma and in cerebrospinal fluid (CSF; optional) will also be conducted to explore treatment efficacy.
2. Safety Objectives: The safety and tolerability will be evaluated after administration of KDS2010.
3. Exploratory Objectives: The efficacy of Treatment Groups 1 and 2 compared to the Control group will be explored through cognitive endpoints (the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and the Mini-Mental State Examination (MMSE)), stratified by demographic information, tauopathy, and ApoE4 genes.

Based on nonclinical and Phase 1 clinical data, KDS2010 will be administered orally once daily at two dose levels: 60 mg and 120 mg.

This Phase 2a, randomized, double-blind, placebo-controlled, dose-finding clinical trial is designed to evaluate the efficacy, safety, and pharmacokinetics of KDS2010, a novel investigational product, reversible monoamine oxidase-B (MAO-B) inhibitor, in patients with Alzheimer's Disease (AD) with Mild Cognitive Impairment (MCI) and Mild Dementia due to Alzheimer's Disease. The clinical trial is conducted at selected sites in Korea.

A total of 114 subjects are planned for the study, with 38 subjects in each of the three groups: two treatment groups (receiving different doses of KDS2010) and a placebo control group. Subjects will be randomized in a 1:1:1 ratio, and the study is designed to allow for a 20% dropout rate. Inclusion criteria require that participants be aged between 50 and 85 years, diagnosed with MCI or mild AD, and amyloid-positive as confirmed by PET scans. Eligible participants must also demonstrate cognitive impairment as indicated by a CDR score between 0.5 and 1.0 and an MMSE score between 21 and 30.

Key exclusion criteria include individuals with cognitive impairment caused by conditions other than AD, those with a history of serious medical conditions such as cardiovascular disease or cancer, and individuals who have used AD-modifying agents or CNS-active drugs within 12 weeks prior to screening.

The primary efficacy endpoint is the change in cognitive function, assessed through the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Alzheimer's Disease Assessment Scale-Cognitive 13 (ADAS-Cog13) scores. Secondary efficacy endpoints include changes in daily living activities (measured by the Activities of Daily Living Scale and the Alzheimer's Disease IADL Questionnaire), as well as biomarkers such as tauopathy and Apo-E4. Exploratory endpoints will assess cognitive decline and specific changes in brain imaging (e.g., PET scans) and cerebrospinal fluid biomarkers.

Safety will be evaluated through monitoring adverse events (AEs), vital signs, laboratory tests, ECGs, and psychological assessments, including the Columbia-Suicide Severity Rating Scale (C-SSRS). Pharmacokinetic parameters (AUCtau, Cmax,ss, Cmin,ss, Cav,ss, Tmax,ss, T1/2, and PTF, etc.) will be measured to assess systemic exposure to KDS2010.

Subjects must be aged between 50 and 85 years, diagnosed with MCI or mild AD, and amyloid-positive based on PET scan results. Inclusion criteria also require cognitive impairment as indicated by a CDR score between 0.5 and 1.0 and an MMSE score between 21 and 30. Major exclusion criteria include conditions other than AD that cause cognitive impairment, uncontrolled systemic diseases, and recent use of AD-modifying agents.

The primary aim of the study is to determine the potential of KDS2010 to slow cognitive decline in individuals with early-stage Alzheimer's disease, with secondary and exploratory objectives focused on safety, quality of life, and understanding the drug's pharmacokinetic profile. This study aims to provide important insights into the potential therapeutic benefits of KDS2010 in treating Alzheimer's disease at the early stages of cognitive decline.

The total duration of the study is expected to be approximately 30 months from IRB/IEC approval, with individual subject participation lasting up to 9 months. This trial aims to evaluate the safety, efficacy, and pharmacokinetics of KDS2010 as a potential treatment for early stages of Alzheimer's disease, with the goal of advancing the development of KDS2010 in the treatment of AD.

Inclusion Criteria:

• Male and female adults aged ≥50 and ≤85 years at the time of written consent
• Patients with MCI or mild AD confirmed at screening according to the 2024 diagnostic criteria (APPENDIX 1) of the National Institute on Aging-Alzheimer's Association (NIA-AA)
• Subjects whose total CDR score (CDR-GS) is 0.5 to 1.0 at screening (however, CDR memory score is ≥0.5)
• Subjects with a Mini-Mental State Examination (MMSE) score of 21 to 30 at screening
• Subjects who test positive for amyloid on Positron Emission Tomography (PET) during screening
• Subjects who have a caregiver capable of providing accurate information about the subject's cognitive and functional abilities and appropriate for the planned assessments in the study, as judged by the investigator
• Subjects (or their legal representatives) who have voluntarily agreed to participate in this study and have given written consent

Exclusion Criteria:

• Cognitive impairment or dementia due to causes other than Alzheimer's disease

  • Vascular dementia, central nervous system infections (e.g., HIV, syphilis, etc.), head trauma, Creutzfeldt-Jakob disease, Pick's disease, Huntington's disease, Parkinson's disease, subdural hematoma, normal pressure hydrocephalus, brain tumor, thyroid disorders, parathyroid disorders, Vitamin B12 deficiency, folic acid deficiency, other metabolic and nutritional deficiencies, etc.
  • Alcohol or drug abuse, dependence

• Subjects with cognitive impairment due to hypothyroidism, nutritional deficiencies, Vitamin B12 or folic acid deficiency as assessed during screening

• Subjects confirmed during screening to have had the following medical history:

  • Malignant tumors within five years prior to screening except for basal cell carcinoma, cutaneous squamous cell carcinoma, thyroid cancer, or carcinoma in situ that has not recurred in over three years and is considered successfully treated by the investigator
  • History of alcohol or drug abuse within two years prior to screening
  • Loss of consciousness of unknown cause, or seizure within the past 52 weeks before screening
  • Unstable and clinically significant cardiovascular diseases despite appropriate treatment (acute coronary syndrome (ACS), tachycardia, clinically significant arrhythmias, cardiomyopathy, angina of at least CSS III, heart failure of NYHA II-IV, or clinically significant valvular heart disease) within 24 weeks before baseline
  • Severe or active infectious diseases requiring antibiotics or antivirals within four weeks before baseline
  • A history of stroke involving a major vascular area, transient ischemic attack (TIA), epilepsy, or severe head trauma with loss of consciousness
  • Hypersensitivity or allergy to any components of the investigational product

• Subjects confirmed during screening to have had the following accompanying disease:

  • Clinically significant neurological diseases or serious pathological findings affecting cognitive function as confirmed by brain imaging studies within 52 weeks prior to screening, including multiple sclerosis, normal pressure hydrocephalus, brain tumor (however, exceptions are allowed for lesions diagnosed as benign and with a maximum diameter of less than 1 cm), spinal cord infarction, major hemorrhage (defined as having a diameter > 1 cm in MRI) or subdural hemorrhage, cerebral vascular malformation, communicating hydrocephalus, inflammatory demyelinating diseases, etc.

  • Uncontrolled hypertension despite appropriate treatment at screening or baseline (SBP ≥160 mmHg or DBP ≥100 mmHg)

  • Dizziness or fainting when standing due to orthostatic hypotension that may affect the evaluation according to the judgment of the investigator

  • Uncontrolled diabetes (HbA1c > 9%) during screening, despite appropriate treatment

  • Bleeding disorders (Platelet <50,000/mm³) during screening, despite appropriate treatment

  • Patients with severe hepatic impairment (Child-pugh class C) at screening

  • Following laboratory test values at screening:

    • AST or ALT > 2.5 x ULN
    • total bilirubin > 1.5 x ULN (however, in case of Gilbert syndrome, > 3.0 mg/dL)
    • MDRD eGFR < 30 mL/min/1.73 m²

  • QTcF interval >450 msecs for male or 470 msecs for female(12-lead ECG) during screening

  • Gastrointestinal diseases that may affect oral administration or absorption (celiac disease, Crohn's disease, intestinal resection, etc.)

  • Gastrointestinal diseases, including gastric and duodenal ulcers, that may affect the safety evaluation according to the judgment of the investigator

  • Psychiatric diagnosis or symptoms that may interfere with the study (uncontrolled major depression, uncontrolled schizophrenia, uncontrolled bipolar affective disorder, etc.), as assessed by the investigator

  • Positive responses to items 4 or 5 on the Columbia University Suicide Severity Rating Scale (C-SSRS) during screening

  • Other conditions deemed by the investigator to potentially affect the outcome of the study

• Subjects who have undergone or require treatment with the following:

  • AD disease-modifying agents (aducanumab, lecanemab, donanemab, gantenerumab, solanezumab, blarcamesine, simufilam, tricaprilin, valiltramiprosate, etc.) within 12 weeks before screening
  • Medications that may improve cognitive abilities or affect AD treatment (AChEIs, donepezil, galantamine, rivastigmine, tacrine, memantine, etc.) within 12 weeks before screening, except if the subject has been on a stable dose for at least 12 weeks before baseline and maintains the same composition/dosage/method of administration during the study period
  • CNS-active drugs or those affecting cognitive function antidepressants other than serotonergic drugs [e.g., bupropion], sedatives [e.g., carbamazepine], dopamine antagonists [e.g., antipsychotics, metoclopramide], amfepramone, mazindol) within 12 weeks before screening
  • Central anticholinergics and sedating H1-antihistamines within 12 weeks before screening.

However, exceptions are allowed for one-time use of the drugs, such as second-generation H1 antihistamines (e.g., cetirizine, levocetirizine, etc.) or peripheral anticholinergics with no central action (e.g., trospium for treating overactive bladder). But the use is prohibited for at least 3 days from the date of cognitive function evaluation.

• Other investigational products or clinical trial devices within four weeks before baseline or five times the half-life of the drug (whichever is longer, and patients can be enrolled after wash-out)

• Monoamine oxidase inhibitors (MAOIs) and linezolid within two weeks before baseline or five times the half-life of the drug (whichever is longer, and patients can be enrolled after wash-out)

• Opioids (pethidine, tramadol, tapentadol, etc.) within two weeks before baseline or five times the half-life of the drug (whichever is longer, and patients can be enrolled after wash-out)

• Cyclobenzaprine and St. John's wort within two weeks before baseline or five times the half-life of the drug (whichever is longer, and patients can be enrolled after wash-out)

• The following serotonergic drugs within two weeks before baseline or five times the half-life of the drug (whichever is longer, and patients can be enrolled after wash-out),

  • selective serotonin (5HT1) agonists
  • lithium
  • lamotrigine
  • ritonavir
  • dapoxetine
  • Selective serotonin reuptake inhibitors (SSRIs)
  • dapoxetine
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs)
  • Tricyclic or tetracyclic antidepressants
  • triazolopyridine antidepressant However, amitriptyline ≤ 50 mg/day, trazodone ≤ 100 mg/day, citalopram ≤ 20 mg/day, and sertraline ≤ 100 mg/day are allowed without washout.

• Use of sympathomimetics (ephedrine, methylphenidate, amphetamine, methamphetamine, lisdexamfetamine, etc.) during the screening period

• Use of Dextromethorphan during the screening period

• Use of CYP3A4 strong inducer, CYP3A4 strong inhibitor, CYP2D6 strong inducer, and CYP2D6 strong inhibitor during the screening period

  • Inability to undergo MRI or PET scans

  • Pregnant or breastfeeding women

  • Fertile women or men who are unwilling to use effective contraception* from the date of written consent until 12 weeks after the last administration of the investigational product

    *Effective contraception is defined as follows, and at least one method should be used:

    • Hormonal contraception (oral, injectable, implantable, etc.)
    • Intrauterine device (IUD) or system (IUS)
    • Sterilization or surgical procedures (vasectomy, bilateral tubal ligation/surgery, hysterectomy)
    • Dual contraception methods: Simultaneous use of barrier methods (male condoms) with the methods listed above
    • Absolute abstinence: Total abstinence from sexual intercourse is recognized if the investigator deems the subject's age, occupation, lifestyle, or sexual orientation assures contraception. However, periodic abstinence (calendar method, mucus method, and symptothermal method), withdrawal, and coitus interruptus are not recognized as effective contraception methods.

  • Other conditions deemed by the investigator to be unsuitable for participation in the study