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

Trial Summary

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.

What evidence supports the effectiveness of the drug AGB101 for mild cognitive impairment?

Levetiracetam, a component of AGB101, has been shown to improve cognitive deficits in Alzheimer's disease and mild cognitive impairment by reducing excess neural activity in the brain, which is linked to memory loss. Additionally, it does not negatively impact cognitive function in patients with epilepsy, suggesting it may be beneficial for cognitive health. ^{1 2 3 4 5}

Is AGB101 (Levetiracetam) safe for humans?

Levetiracetam, also known as AGB101 or Keppra, has been studied extensively for epilepsy and is generally considered safe for humans. Most side effects are mild to moderate, and it does not impair cognitive function or cause weight gain, though some people may experience behavioral changes. ^{3 6 7 8 9}

How does the drug AGB101 (Levetiracetam) differ from other treatments for mild cognitive impairment?

AGB101 (Levetiracetam) is unique because it targets excess neural activity in the hippocampus, which is linked to cognitive decline in conditions like mild cognitive impairment and Alzheimer's disease. Unlike other treatments, it reduces this hyperactivity without negatively impacting cognitive function, potentially improving memory and slowing disease progression. ^{2 3 4 10 11}

What is the purpose of this trial?

The primary objective of the study is to evaluate the efficacy of AGB101 on slowing cognitive and functional impairment as measured by reduction in neuronal injury in participants with mild cognitive impairment due to Alzheimer's Disease. Participants will be randomized to receive placebo or AGB101 (220 mg), once daily for 78 weeks. Secondary objectives are to assess the effect of AGB101 compared with placebo on clinical progression as measured by the Clinical Dementia Rating Scale- Sum of Boxes and Memory Box score.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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) 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, 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]

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 (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]

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]

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]

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]

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]

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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Levetiracetam inhibits interleukin-1 beta inflammatory responses in the hippocampus and piriform cortex of epileptic rats. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Absence of negative impact of levetiracetam on cognitive function and memory in normal and amygdala-kindled rats. [2010]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Spotlight on levetiracetam in epilepsy. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy. [2022]

9. England 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. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. [2022]

11. Ireland pubmed.ncbi.nlm.nih.gov

Evaluation of levetiracetam effects on pilocarpine-induced seizures: cholinergic muscarinic system involvement. [2018]