AGB101 for Mild Cognitive Impairment

Overseen By Carrie Wagandt

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AgeneBio

Must be taking: Cholinesterase inhibitors, Memantine

Must not be taking: Anticonvulsants, Anti-amyloids

Disqualifiers: ApoE4 allele, Severe renal impairment, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 78 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called AGB101 (a form of the drug Levetiracetam) for individuals with mild cognitive impairment (MCI) due to Alzheimer's Disease. The goal is to determine if AGB101 can slow memory and thinking problems by reducing brain cell damage. Participants will take either AGB101 or a placebo (a pill with no active medicine) daily for 78 weeks. The trial seeks individuals with memory issues who can still perform daily activities and do not have one or more E4 alleles related to Alzheimer's. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that certain medications be at a stable dose for a specific period before and during the study. If you are taking medications with potential pro-cognitive effects, antidepressants, or antipsychotics, they must be stable for at least 3 months before screening. Other medications like estrogen replacement therapy, Ginkgo biloba, and vitamin E must be stable for at least 4 weeks before screening. Some medications, such as anticonvulsants and certain psychotropics, are not allowed.

Is there any evidence suggesting that AGB101 is likely to be safe for humans?

Research has shown that AGB101 is generally safe for people with mild cognitive impairment (MCI). Earlier studies found its safety profile similar to its use in healthy aging and MCI. Other studies suggest that levetiracetam, the main ingredient in AGB101, is well-tolerated by patients with Alzheimer's disease and MCI. Common side effects include sleepiness and fatigue, but these are not serious. Overall, evidence suggests that AGB101 is a safe option for those considering participation in clinical trials for mild cognitive impairment due to Alzheimer's disease. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

AGB101 is unique because it specifically targets mild cognitive impairment, a condition often considered a precursor to Alzheimer’s disease. Unlike standard treatments for cognitive disorders, which mainly focus on symptom management, AGB101 targets the underlying mechanisms of cognitive decline. Researchers are excited about AGB101 because it contains a new formulation of levetiracetam, a known anti-seizure medication, which is repurposed here to potentially slow down the progression of cognitive impairment by modulating abnormal brain activity. This approach could offer a more proactive and potentially more effective path to managing early cognitive issues.

What evidence suggests that AGB101 might be an effective treatment for mild cognitive impairment?

Research has shown that AGB101, which participants in this trial may receive, might help slow memory and thinking problems in people with mild cognitive impairment due to Alzheimer's. The HOPE4MCI study found that AGB101 worked better in individuals without the specific genetic marker (APOE ε4) linked to Alzheimer's disease. Another study indicated that AGB101 might improve brain function by calming overactive areas affected by Alzheimer's. This treatment uses a low dose of levetiracetam, a drug originally used for epilepsy, which might positively affect memory and thinking. These promising results suggest AGB101 could be a helpful option for slowing mental decline in Alzheimer's-related conditions. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for individuals with mild cognitive impairment due to Alzheimer's, who can consent and participate for 78 weeks. They should have at least an eighth-grade education or equivalent work history, adequate sensory abilities for testing, a study partner to assist them, MMSE scores of 24-30, and a specific memory complaint.

Inclusion Criteria

I have someone who knows me well to attend major clinic visits and assess my memory changes.

You are able to provide consent and commit to the study's duration.

You have completed at least eight years of schooling, or possess a work record that indicates an absence of mental impairment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either AGB101 or placebo once daily for 78 weeks

78 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AGB101

Trial Overview The trial tests AGB101 (220 mg daily) against a placebo to see if it slows down cognitive decline in Alzheimer's patients over 78 weeks. It measures the reduction in neuronal injury and assesses clinical progression using dementia rating scales.

How Is the Trial Designed?

Group I: AGB101 220 mg tablet Experimental Treatment 1 Intervention

Single 220 mg AGB101 tablet once daily, taken orally, for 78 weeks.

Group II: Placebo Oral Tablet Placebo Group 1 Intervention

Matching placebo to AGB101 tablet once daily, taken orally, for 78 weeks

AGB101 is already approved in United States, European Union, Canada, China for the following indications:

Approved in United States as Levetiracetam for:

• Partial onset seizures
• Myoclonic seizures
• Tonic-clonic seizures

Approved in European Union as Levetiracetam for:

• Epilepsy
• Partial onset seizures
• Myoclonic seizures
• Tonic-clonic seizures

Approved in Canada as Levetiracetam for:

• Partial onset seizures
• Myoclonic seizures
• Tonic-clonic seizures

Approved in China as Levetiracetam for:

• Epilepsy
• Partial onset seizures
• Myoclonic seizures
• Tonic-clonic seizures

Who Is Running the Clinical Trial?

AgeneBio

Lead Sponsor

Trials

3

Recruited

250+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

Levetiracetam (LEV) effectively increases seizure latency and reduces the severity of seizures and mortality in a pilocarpine-induced seizure model in mice, indicating its potential as a strong adjunctive therapy for partial seizures.

LEV appears to modulate cholinergic activity by reversing the downregulation of muscarinic acetylcholine receptors, particularly enhancing the inhibitory effects of the M2 subtype, which may help explain its anticonvulsant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of levetiracetam effects on pilocarpine-induced seizures: cholinergic muscarinic system involvement. Oliveira, AA., Nogueira, CR., Nascimento, VS., et al.[2018]

Hippocampal hyperactivity is linked to age-related cognitive decline and may play a significant role in the progression of late-onset Alzheimer's disease (LOAD), highlighting it as a potential therapeutic target.

Initial studies suggest that the antiepileptic drug levetiracetam can reduce this hyperactivity, potentially improving cognitive function and slowing the accumulation of pathology associated with LOAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. Haberman, RP., Branch, A., Gallagher, M.[2019]

Levetiracetam (LEV) was found to be well tolerated and safe for patients with epilepsy, cognitive disorders, and anxiety, based on safety data from 3347 patients in clinical trials, with common adverse effects being somnolence, asthenia, and dizziness primarily occurring in the first month of treatment.

The incidence of adverse effects was slightly higher in epilepsy patients compared to those with cognitive or anxiety disorders, but overall, the adverse effects reported were similar to those in placebo groups, indicating that while LEV is generally safe, long-term and rare side effects remain uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. French, J., Edrich, P., Cramer, JA.[2022]

In patients with amnestic mild cognitive impairment (aMCI), elevated hippocampal activation was linked to cognitive impairment, but treatment with a low dose of the antiepileptic drug levetiracetam successfully reduced this activation to normal levels seen in healthy controls.

The reduction in hippocampal activation with levetiracetam also led to significant improvements in memory performance during cognitive tasks, suggesting that targeting excessive hippocampal activity could be a promising therapeutic approach for aMCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Bakker, A., Krauss, GL., Albert, MS., et al.[2022]

In a study of 25 patients with advanced Alzheimer's disease and new-onset seizures, 72% achieved seizure freedom for at least one year while on levetiracetam (LEV) monotherapy at doses of 1000-1500 mg.

The study also noted that 16% of participants discontinued treatment due to intolerability, indicating a need for further controlled studies to evaluate the safety and efficacy of LEV as a first-choice treatment for seizures in Alzheimer's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Belcastro, V., Costa, C., Galletti, F., et al.[2022]

Levetiracetam, an FDA-approved antiepileptic drug, effectively reduces seizure frequency in patients with epilepsy while preserving cognitive functions, making it a safe option for these individuals.

The drug shows potential cognitive improvement in patients with Alzheimer's disease and in animal models of cognitive decline, suggesting it may be beneficial for preventing or treating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam might act as an efficacious drug to attenuate cognitive deficits of Alzheimer's disease. Xiao, R.[2019]

Levetiracetam (LEV) did not negatively affect cognitive function in normal and amygdala-kindled rats, unlike traditional antiepileptic drugs such as sodium valproate (VPA), which impaired learning performance.

LEV also showed no impact on long-term potentiation (LTP) in hippocampal slices, suggesting it may be a safer option for cognitive function in epileptic patients compared to other AEDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of negative impact of levetiracetam on cognitive function and memory in normal and amygdala-kindled rats. Lamberty, Y., Margineanu, DG., Klitgaard, H.[2010]

Levetiracetam is an effective antiepileptic drug that significantly reduces seizure frequency in both pediatric and adult patients with refractory partial-onset seizures compared to placebo, and it is also effective as monotherapy for newly diagnosed partial-onset seizures.

The drug has a unique mechanism of action involving binding to synaptic vesicle protein 2A and inhibiting excessive neuronal activity, while also showing a favorable safety profile with mild to moderate side effects and no significant cognitive impairment or weight gain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on levetiracetam in epilepsy. Lyseng-Williamson, KA.[2021]

In a study involving 219 patients with refractory epilepsy, levetiracetam (LEV) was found to be well tolerated, with a high retention rate of 81.7% and limited adverse events, primarily occurring during dose increases.

LEV significantly reduced seizure frequency, with 48.2% of patients experiencing a >50% reduction in seizures, and 13.6% achieving complete seizure freedom during the evaluation period, indicating its efficacy as an adjunctive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label study of levetiracetam at individualised doses between 1000 and 3000 mg day(-1) in adult patients with refractory epilepsy. Abou-Khalil, B., Hemdal, P., Privitera, MD.[2019]

Levetiracetam (LEV) has been shown to reduce reactive gliosis and the expression of the interleukin-1 beta (IL-1 beta) system in the hippocampus and piriform cortex of chronic epileptic rats, suggesting an anti-inflammatory effect in the brain during epilepsy.

In contrast to valproic acid, LEV specifically targets the IL-1 beta system, indicating a unique mechanism of action that may contribute to its efficacy in treating seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam inhibits interleukin-1 beta inflammatory responses in the hippocampus and piriform cortex of epileptic rats. Kim, JE., Choi, HC., Song, HK., et al.[2018]

Levetiracetam (Keppra) significantly reduced partial seizure frequency in adult patients with refractory partial epilepsy, with both 1000 mg and 2000 mg doses showing better results than placebo, particularly at the higher dose.

The medication was well-tolerated, with no significant withdrawal effects reported, indicating it can be safely used as an adjunctive therapy without causing rebound seizures after discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy. Boon, P., Chauvel, P., Pohlmann-Eden, B., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10865488/

The HOPE4MCI study: A randomized double‐blind ... This trial, HOPE4MCI (Hippocampal Overactivity Prevention in the Elderly with MCI due to AD), was conducted to assess the efficacy of AGB101.

2. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70004

The HOPE4MCI study: AGB101 treatment slows progression ... The HOPE4MCI study showed that APOE ε4 non-carriers treated with AGB101 demonstrated a substantially more favorable treatment effect compared to carriers.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0011393X25000232

Cognitive Effect of Levetiracetam in Patients with ... The results of this systematic review suggest that LEV may have a positive effect on cognitive function in patients with MCI or AD. Supporting this, Lippa et al ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03486938

NCT03486938 | Study of AGB101 in Mild Cognitive ... The primary objective of the study is to evaluate the efficacy of AGB101 on slowing cognitive and functional impairment as measured by changes in the Clinical ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10664284/

Levetiracetam for the treatment of mild cognitive impairment in ... This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative ...

6. alzdiscovery.org alzdiscovery.org/uploads/cognitive_vitality_media/Levetiracetam_UPDATE_%28drug%29.pdf

Levetiracetam Cognitive benefits with levetiracetam have been observed in people with epilepsy, MCI, and brain injury. Side effects include drowsiness, fatigue, irritability, ...

7. agenebio.com agenebio.com/pipeline/agb101-for-amnestic-mild-cognitive-impairment-amci/

AGB101 Development To Treat Amnesia Disorder AGB101 is in development to treat mild cognitive impairment due to Alzheimer's disease (MCI due to AD) and to control progression to Alzheimer's dementia.