GSK4527226 for Early Alzheimer's Disease

(PROGRESS-AD Trial)

Not currently recruiting at 126 trial locations

Overseen By US GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: GlaxoSmithKline

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

Disqualifiers: Stroke, CNS trauma, Alcohol use, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 76 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment, GSK4527226, to determine its effectiveness for people in the early stages of Alzheimer's Disease, including mild memory issues and mild dementia. Researchers aim to assess the treatment's effectiveness and safety by comparing it to a placebo (a harmless pill with no active ingredients). Participants will receive either one of two doses of GSK4527226 or a placebo. This trial suits those with mild memory problems due to Alzheimer's who have tested positive for certain brain changes linked to the disease. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that GSK4527226 is likely to be safe for humans?

Research has shown that GSK4527226, a new treatment tested for early Alzheimer's disease, has not raised any major safety concerns so far. Early results suggest most people tolerate it well. This treatment is a monoclonal antibody, designed to target specific proteins in the brain. Although this study phase does not fully confirm its safety, the absence of serious side effects is a positive sign for those considering joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

GSK4527226 is unique because it targets early Alzheimer's Disease with potentially different mechanisms than current treatments like cholinesterase inhibitors and NMDA receptor antagonists. Unlike these existing options, which mainly focus on managing symptoms, GSK4527226 might work by directly influencing the disease's progression. Researchers are excited about GSK4527226 because it could offer a more comprehensive approach to slowing down or altering the course of Alzheimer's, rather than just alleviating symptoms. This could lead to improved long-term outcomes for patients in the early stages of the disease.

What evidence suggests that GSK4527226 might be an effective treatment for early Alzheimer's Disease?

Research has shown that GSK4527226, also known as AL101, is being developed to treat early Alzheimer's Disease by boosting levels of a protein called progranulin. Progranulin may protect brain cells and enhance their function, potentially slowing the disease's progression. Early studies suggest that increasing this protein might improve brain cell health. While detailed information from human studies is still being gathered, the treatment's goal to support brain cells offers promise for those with early Alzheimer's. Participants in this trial will receive either GSK4527226 at different doses or a placebo to evaluate its effectiveness. ^{1 2 3 6 7}

Who Is on the Research Team?

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• GSK4527226

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.

How Is the Trial Designed?

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.

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4,834

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)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Alector Inc.

Industry Sponsor

Trials

11

Recruited

1,300+

Published Research Related to This Trial

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]

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]

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]

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 a study involving 144 subjects with amnestic mild cognitive impairment, AL-108 was found to be generally safe and well tolerated over 12 weeks of treatment.

While the overall efficacy analysis did not show a significant difference in cognitive memory scores between AL-108 and placebo, there were promising signals of potential efficacy in specific memory and attention tasks, suggesting further research is warranted.

NCBI (Pubmed)

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. Morimoto, BH., Schmechel, D., Hirman, J., et al.[2016]

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 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]

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]

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A new clinical trial is underway to assess the effectiveness and safety of GSK4527226, also known as AL101, in treating early Alzheimer's Disease. This study ...

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This study of the anti-sortilin antibody, GSK4527226, will comprehensively evaluate its efficacy, safety and effects on pathogenesis in early AD ...

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Press Release

Preliminary safety data have not highlighted any major safety concerns at present. ... early Alzheimer's disease (AD). Enrollment was completed in ...