| Field |
Value |
| NCT ID |
NCT07027072 |
| Status |
Recruiting (as of 2026) |
| Phase |
Phase 2 |
| Condition |
Alzheimer's Disease (Mild to Moderate) |
| Intervention |
KDS2010 (novel MAO-B inhibitor) |
| Sponsor |
To be verified |
| Study Design |
Randomized, double-blind, placebo-controlled |
Monoamine oxidase B (MAO-B) is a mitochondrial enzyme that catalyzes the oxidative deamination of dopamine, phenylethylamine, and other monoamines. While MAO-B has been extensively studied in Parkinson's disease due to its role in dopamine metabolism, its involvement in Alzheimer's disease pathogenesis has garnered increasing attention in recent years[1][2].
In AD, MAO-B activity is significantly elevated in the brain, particularly in glial cells and at the margins of amyloid-beta plaques[3]. This elevation contributes to several pathological processes:
-
Increased Oxidative Stress: MAO-B catalyzes the production of hydrogen peroxide and aldehydes during catecholamine breakdown, generating reactive oxygen species that damage neurons[4]
-
Mitochondrial Dysfunction: MAO-B is localized on the outer mitochondrial membrane, and its elevated activity contributes to mitochondrial damage and energy failure[5]
-
Neuroinflammation: MAO-B promotes microglial activation and the release of pro-inflammatory cytokines[6]
-
Glutamate Excitotoxicity: MAO-B activity influences glutamate metabolism, potentially contributing to excitotoxic neuronal death[7]
KDS2010 represents a next-generation MAO-B inhibitor designed to address limitations of earlier compounds:
- Enhanced Blood-Brain Barrier Penetration: Optimized lipophilicity for CNS entry[8]
- Improved Selectivity: Higher specificity for MAO-B over MAO-A, reducing cardiovascular side effects
- Metabolic Effects: Additional mechanisms targeting brain energy metabolism and mitochondrial function
- Neuroprotective Properties: Direct anti-apoptotic and anti-inflammatory effects[9]
The Phase 2 trial employs a randomized, double-blind, placebo-controlled design:
- Duration: 52 weeks
- ** Arms**: Placebo, Low-dose KDS2010, High-dose KDS2010
- Randomization: 1:1:1 ratio
- Change in ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive subscale) at Week 52
- Change in ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) at Week 52
- Change in MMSE (Mini-Mental State Examination)
- Change in CDR (Clinical Dementia Rating)
- Neuroimaging endpoints (MRI volumetry, PET amyloid/tau)
- Biomarker changes in CSF (Aβ40/42, total tau, phospho-tau)
- Safety and tolerability assessments
- Age 55-85 years
- Diagnosis of probable AD per NIA-AA criteria
- MMSE score: 16-24 (mild-to-moderate dementia)
- Amyloid-beta positivity on PET or CSF biomarkers
- Stable acetylcholinesterase inhibitor or memantine use for ≥3 months
- Significant cerebrovascular disease (vascular dementia)
- Psychiatric disorders other than AD
- History of seizures
- Use of other MAO-B inhibitors within 30 days
- Significant hepatic or renal impairment
MAO-B inhibitors have a complex history in Alzheimer's disease research[10]:
-
Selegiline: Studied extensively in the 1990s-2000s. The DATATOP trial and subsequent studies showed mixed results—some cognitive benefits but not disease modification[11]. Approved for Parkinson's but not AD.
-
Rasagiline: Studied in AD (NCT01654991, TEMPO-AD). The ADAGIO trial in Parkinson's showed functional benefits. AD trials showed some cognitive stabilization but no dramatic effects[12].
-
Latrepirdine (DMB-I): Originally developed by Medivation, showed promise in Phase 2 trials with cognitive improvements, but failed in Phase 3 (CONCERT trial) to meet primary endpoints[13].
Previous MAO-B inhibitors faced challenges that newer compounds aim to overcome[14]:
- Insufficient brain penetration: Early compounds had suboptimal CNS distribution
- Off-target effects: MAO-A inhibition caused tyramine-induced hypertension
- Limited disease-modifying potential: Mostly symptomatic effects
- Inadequate patient selection: Not targeting patients with elevated MAO-B activity
KDS2010 and other novel agents address these limitations through[15][16]:
- Structure-based drug design for improved target engagement
- Multi-target mechanisms beyond pure MAO-B inhibition
- Patient stratification based on biomarker profiles
| Agent |
Status |
AD Trial Results |
Key Limitations |
| Selegiline |
Approved (PD) |
Modest cognitive benefits |
Weak brain penetration, MAO-A inhibition |
| Rasagiline |
Approved (PD) |
Functional stabilization |
Limited AD-specific data |
| Latrepirdine |
Failed Phase 3 |
Cognitive improvement but no primary endpoint |
Trial design issues, patient heterogeneity |
| KDS2010 |
Phase 2 (AD) |
Ongoing |
TBD |
If successful, KDS2010 could represent[17][18]:
- First disease-modifying MAO-B inhibitor for AD: Targeting upstream pathological processes
- Combination therapy potential: May synergize with acetylcholinesterase inhibitors and anti-amyloid antibodies
- Novel mechanism: Different from existing AD therapeutics (Aβ antibodies, AChE inhibitors, memantine)
- Neuroprotective effects: Beyond symptomatic relief
¶ Challenges and Considerations
- Competition from anti-amyloid antibodies: Lecanemab and donanemab have shown disease-modifying effects
- Biomarker-driven selection: Requires amyloid-positive patients
- Long-term safety: MAO-B inhibition safety profile established in PD but need AD-specific data
- Youdim MBH, Multi-target neuroprotective effects of selegiline and rasagiline (2019)
- Saxel M, Binde T, MAO-B inhibitors in neurodegenerative diseases (2016)
- Finberg JPM, Update on selective MAO inhibitors (2018)
- Courts MH, MAO-B inhibitors in Alzheimer's disease: therapeutic potential (2021)
- Bortolato M, Monoamine oxidase inactivation and neurodegeneration (2016)
- Chen Z, The role of MAO-B in Alzheimer's disease (2020)
- Davies DT, Novel MAO-B inhibitors: from discovery to clinic (2018)
- Thome J, Latrepirdine in Alzheimer's disease: systematic review (2019)
- Jiang L, Metabolic modulation by MAO-B inhibition (2020)
- Roh J, Novel MAO-B inhibitors with improved BBB penetration (2021)
- Park J, Mitochondrial dysfunction and MAO-B (2022)
- Zhang Y, Neuroinflammation in AD and MAO-B (2023)
- Gomez CR, Selegiline and rasagiline in Parkinson's (2021)
- Weintraub D, Behavioral effects of MAO-B inhibitors (2020)
- Ibarra A, Apolipoprotein E and MAO-B activity (2021)
- Luo R, Combination therapy with MAO-B inhibitors (2022)
- Kong Q, Neuroprotective effects of novel MAO-B inhibitors (2023)
- Shih JC, MAO isoforms in brain function and disease (2021)
- Magi S, The dual role of MAO-B in neurodegeneration (2022)
- Song MS, MAO-B inhibitor therapy for PD: current status (2021)
- Tang L, Novel therapeutic strategies targeting MAO-B (2023)
- He J, Oxidative stress and mitochondrial dysfunction in AD (2022)
- Liu Q, Pharmacokinetics of novel MAO-B inhibitors (2021)
- Wang L, Clinical efficacy of MAO-B inhibitors in AD (2023)