GSK4527226 for Early Alzheimer's Disease

(PROGRESS-AD Trial)

Recruiting in Palo Alto (17 mi)

+107 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: GlaxoSmithKline

Must not be taking: Antipsychotics, Antidepressants, Opiates, others

Disqualifiers: Stroke, CNS trauma, Alcohol use, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The aim of this study is to assess the efficacy and safety of GSK4527226 in participants with early Alzheimer's Disease (AD) (including mild cognitive impairment \[MCI\] and mild dementia due to AD) of 2 dose levels of GSK4527226 compared to placebo.

Will I have to stop taking my current medications?

You may need to stop certain medications, like anticoagulants and systemic immunosuppressive therapy, before joining the study. If you're on medications for Alzheimer's symptoms, they must be stable for at least 4 to 12 weeks before the study and should not change during the study.

What data supports the effectiveness of the drug GSK4527226 for early Alzheimer's disease?

There is no direct data on the effectiveness of GSK4527226 for early Alzheimer's disease, but research suggests that targeting certain genetic pathways and proteins, like calcineurin, may help reduce Alzheimer's symptoms. Tacrolimus, a drug that targets calcineurin, has shown reduced Alzheimer's prevalence in organ transplant recipients, indicating potential benefits of similar approaches. ^{1 2 3 4 5}

What safety data exists for GSK4527226 (AL101) in humans?

The research articles provided do not contain specific safety data for GSK4527226 (AL101) in humans. ^{6 7 8 9 10}

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility Criteria

This trial is for adults with early Alzheimer's Disease, including mild cognitive impairment and mild dementia. They must have certain scores on memory and cognition tests, evidence of amyloid in the brain, stable medication regimens if taking Alzheimer's drugs, a body weight between 45-120 kg with specific BMI limits, and not be pregnant or breastfeeding. Participants need to use contraception and have a study partner who can provide information about their condition.

Inclusion Criteria

I am not pregnant or breastfeeding and will follow the study's birth control requirements.

You need to have a positive result from a PET scan or a CSF test showing evidence of amyloid positivity.

Participants must also meet the following criteria for clinical severity:

Exclusion Criteria

Your folate levels are too low or your thyroid-stimulating hormone levels are too high.

History of primary psychiatric diagnosis that the investigator considers may interfere with study assessments.

You have had serious thoughts of suicide, engaged in suicidal behavior, or have been at risk of suicide in the past 6 months.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive GSK4527226 or placebo via intravenous infusion

76 weeks

Regular visits for infusion and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• GSK4527226 (Monoclonal Antibodies)

Trial Overview The trial is testing GSK4527226 (AL101) at two dose levels against a placebo to see how effective and safe it is for people with early-stage Alzheimer's Disease. The participants will be randomly assigned to receive either the drug or placebo.

Participant Groups

Group I: GSK4527226 Dose 2 Experimental Treatment 1 Intervention

Participants will receive GSK4527226 Dose 2

Group II: GSK4527226 Dose 1 Experimental Treatment 1 Intervention

Participants will receive GSK4527226 Dose 1

Group III: Placebo Placebo Group 1 Intervention

Participants will receive placebo.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

GSK Investigational Site Verdun, Canada

GSK Investigational Site Greenfield-Park, Canada

GSK Investigational Site Lake Worth, FL

GSK Investigational Site West Long Branch, NJ

More Trial Locations

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4834

Patients Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Alector Inc.

Industry Sponsor

Trials

11

Patients Recruited

1,300+

Findings from Research

A systematic review and meta-analysis of 820 studies identified significant genetic markers associated with Alzheimer's Disease (AD), specifically highlighting SNPs rs3865444 (CD33), rs7561528 (BIN1), and rs1801133 (MTHFR) as risk factors.

The research underscores the need for consistent genetic data in AD studies, as previous findings lacked reliability across different populations, emphasizing the importance of identifying robust drug targets for effective therapeutic development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Untangling huge literature to disinter genetic underpinnings of Alzheimer's Disease: A systematic review and meta-analysis. G N S, HS., Marise, VLP., Satish, KS., et al.[2021]

In a study examining the SNP rs3740058, which was significantly associated with late-onset Alzheimer's disease in Japanese populations, no such association was found in a large Caucasian American cohort, indicating potential ethnic differences in genetic risk factors for Alzheimer's.

The analysis included a large case-control cohort for the primary SNP and a smaller subset for the other five SNPs, but none showed significant associations, suggesting that these genetic markers may not be universally applicable across different populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No association of dynamin binding protein (DNMBP) gene SNPs and Alzheimer's disease. Minster, RL., DeKosky, ST., Kamboh, MI.[2022]

Tacrolimus (FK506), an FDA-approved calcineurin inhibitor, can be safely delivered to APP/PS1 mice using time-release pellets, leading to normalization of calcineurin activity and significant reduction of Alzheimer's disease (AD) pathologies such as synapse loss and neuroinflammation.

The treatment with FK506 not only alleviated cognitive impairment and neuroinflammation but also preserved normal immune responses, suggesting it could be a promising early intervention for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response. Stallings, NR., O'Neal, MA., Hu, J., et al.[2023]

In a study of 103 Alzheimer's disease (AD) cases and 96 cognitively preserved nonagenarians, rare variants of the ADAM10 gene were found in 15.5% of AD cases, particularly in early-onset cases, but these variants did not correlate with lower levels of ADAM10 protein in cerebrospinal fluid (CSF).

The research suggests that while certain rare intronic variants of ADAM10 are more common in early-onset AD, they do not significantly affect the overall protein levels or the risk of developing AD, indicating that ADAM10 exonic variants are rare in AD cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels. Agüero-Rabes, P., Pérez-Pérez, J., Cremades-Jimeno, L., et al.[2023]

A novel locus on chromosome 10 has been identified that is linked to increased levels of plasma amyloid beta protein (Abeta42), which is associated with late-onset Alzheimer's disease (LOAD), based on studies involving 10 and 12 extended LOAD families.

The gene VR22, located at this locus, contains SNPs that significantly associate with plasma Abeta42 levels, suggesting that variations in VR22 may influence the risk of developing LOAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Ertekin-Taner, N., Ronald, J., Asahara, H., et al.[2018]

In an 11-week study involving 181 patients with mild to moderate Alzheimer's disease, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid modulator LY451395 did not show significant improvement in cognitive function compared to placebo, as measured by the ADAS-Cog scale.

While there were some marginal improvements in neuropsychiatric symptoms after 8 weeks of treatment, the overall safety profile was similar between LY451395 and placebo, with most adverse events being mild.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AMPA potentiator treatment of cognitive deficits in Alzheimer disease. Chappell, AS., Gonzales, C., Williams, J., et al.[2022]

Aducanumab, an antiamyloid antibody, showed modest efficacy in a phase 3 trial for Alzheimer's disease, supporting the amyloid beta hypothesis as a valid therapeutic target despite previous failures in amyloid-targeted treatments.

ALZ-801 is a promising oral drug that effectively penetrates the blood-brain barrier and inhibits the formation of toxic Aβ oligomers, with a phase 3 trial planned for patients with early Alzheimer's disease, specifically targeting those with the APOE4/4 genotype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis. Tolar, M., Abushakra, S., Sabbagh, M.[2021]

Akatinol memantine significantly improved cognitive function, behavior, and mood in patients with mild to moderate Alzheimer's disease, showing similar efficacy to donepezil over a 16-week treatment period with 100 participants.

The treatment was found to be safe, with only mild and transient adverse events reported in 6% of patients, indicating that akatinol memantine is a viable option for managing Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of akatinol memantine in treatment of mild to moderate Alzheimer disease: a donepezil-controlled, randomized trial]. Hu, HT., Zhang, ZX., Yao, JL., et al.[2018]

In a phase 1 trial involving 30 patients with mild-to-moderate Alzheimer's disease, bapineuzumab showed a manageable safety profile, although three patients experienced temporary MRI abnormalities related to vasogenic edema at the highest dose of 5.0 mg/kg.

The pharmacokinetics of bapineuzumab indicated a half-life of 21 to 26 days, suggesting that it could be administered every 13 weeks, which is important for planning future dosing schedules in larger efficacy trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Black, RS., Sperling, RA., Safirstein, B., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Untangling huge literature to disinter genetic underpinnings of Alzheimer's Disease: A systematic review and meta-analysis. [2021]

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

No association of dynamin binding protein (DNMBP) gene SNPs and Alzheimer's disease. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels. [2023]

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

Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. [2016]

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

AMPA potentiator treatment of cognitive deficits in Alzheimer disease. [2022]

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

The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis. [2021]

9. China pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of akatinol memantine in treatment of mild to moderate Alzheimer disease: a donepezil-controlled, randomized trial]. [2018]

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

A single ascending dose study of bapineuzumab in patients with Alzheimer disease. [2021]