ALN-APP for Alzheimer's Disease

Recruiting at 10 trial locations

Overseen By Alnylam Clinical Trial Information Line

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Alnylam Pharmaceuticals

Must not be taking: Amyloid antibodies

Disqualifiers: Non-Alzheimer's dementia, High ALT/AST, Low eGFR, others

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a treatment called ALN-APP for individuals with early-onset Alzheimer’s Disease. Researchers seek to determine the safety and tolerability of the treatment, as well as its movement and function in the body when administered through a spinal injection. The trial consists of two parts: one group will receive a single dose of either ALN-APP or a placebo (a harmless substance with no treatment effect), while another group will receive multiple doses of ALN-APP over a year. Individuals who notice mild memory issues or early dementia symptoms due to Alzheimer’s might be suitable candidates. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have recently received an investigational agent or treatment with an amyloid-targeting antibody, you may not be eligible to participate.

Is there any evidence suggesting that ALN-APP is likely to be safe for humans?

Research has shown that ALN-APP has been tested for safety in people with early-onset Alzheimer's disease. Early results from previous studies indicated that a single dose effectively targets and reduces the production of a protein called APP, which is linked to Alzheimer's. Participants tolerated the treatment well, with no serious side effects reported. Safety data over six months showed that the treatment's effects remained stable and continued without major issues. These results suggest that ALN-APP is generally safe for humans so far. ^{1 2 3 4 5}

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

ALN-APP is unique because it targets amyloid precursor protein (APP) in a novel way, which is different from standard Alzheimer's treatments that typically focus on reducing amyloid-beta plaques or tau tangles. Researchers are excited about ALN-APP because it employs RNA interference (RNAi) technology to silence the production of APP, potentially addressing the disease at an earlier stage in its pathway. This mechanism offers hope for a more targeted approach with the possibility of fewer side effects compared to existing options like cholinesterase inhibitors or NMDA receptor antagonists.

What evidence suggests that ALN-APP might be an effective treatment for early-onset Alzheimer's Disease?

Research shows that ALN-APP, which participants in this trial may receive, may help treat Alzheimer's disease. Studies have found that patients receiving ALN-APP experienced a reduction in certain proteins linked to Alzheimer's, such as soluble APPα (sAPPα). These proteins, found in the fluid around the brain and spine, are connected to the disease's progression. Additionally, the technology behind ALN-APP, called APP antisense oligonucleotides, has successfully reduced harmful protein build-up in human models. This suggests it might slow down or improve Alzheimer's symptoms. While these early results are promising, more research is needed to confirm these effects. ^{1 6 7 8 9}

Who Is on the Research Team?

Medical Director

Principal Investigator

Alnylam Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults with early-onset Alzheimer's Disease (EOAD) who have mild cognitive impairment or dementia. Participants should have a CDR score of 0.5 or 1.0 and an MMSE score over 20, indicating some memory issues but not severe dementia. People can't join if they have poor kidney function, recently took experimental drugs, suffer from non-Alzheimer's dementias, or have certain liver enzyme levels that are too high.

Inclusion Criteria

I have mild memory problems or mild dementia from early-onset Alzheimer's.

You have mild cognitive impairment with a specific score on two different memory tests.

Exclusion Criteria

Your ALT or AST levels are more than twice the normal limit.

My kidney function is reduced, with an eGFR below 45.

My condition is dementia, but not Alzheimer's disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Participants receive a single dose of ALN-APP or placebo administered by intrathecal injection

Single dose

Treatment Part B

Participants receive multiple doses of ALN-APP administered by intrathecal injection over 12 months

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ALN-APP
• Placebo

Trial Overview The study tests the safety and effects of ALN-APP given through spinal injection to EOAD patients compared to a placebo group receiving no active treatment. The drug's behavior in the body (pharmacokinetics) and its impact on disease processes (pharmacodynamics) will be monitored for up to one year.

How Is the Trial Designed?

Group I: Part B: Experimental Treatment 1 Intervention

Participants will be administered multiple doses of ALN-APP.

Group II: Part A: ALN-APP Experimental Treatment 1 Intervention

Participants will be administered a single dose of ALN-APP.

Group III: Part A: Placebo Placebo Group 1 Intervention

Participants will be administered a single dose of placebo.

Who Is Running the Clinical Trial?

Alnylam Pharmaceuticals

Lead Sponsor

Trials

81

Recruited

16,100+

Dr. Yvonne Greenstreet

Alnylam Pharmaceuticals

Chief Executive Officer since 2021

MD from the University of Leeds, MBA from INSEAD

Dr. Pushkal Garg

Alnylam Pharmaceuticals

Chief Medical Officer since 2016

MD from Columbia University

Published Research Related to This Trial

In a review of 23 randomized, placebo-controlled trials for Alzheimer's disease lasting 18 months, no trial demonstrated statistically significant benefits for the test drug, highlighting challenges in detecting modest drug efficacy in this timeframe.

The placebo groups showed a consistent decline in cognitive function (measured by the ADAS-cog) over 18 months, with variability in outcomes suggesting that many patients do not experience significant worsening, complicating the ability to identify effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Alzheimer's disease clinical trials: methods and placebo outcomes. Schneider, LS., Sano, M.[2022]

In a pooled analysis of eight Japanese Phase II and III studies, it was found that Alzheimer's patients in placebo groups showed a more significant decline in cognitive function at weeks 22 and 24 compared to week 12, indicating a rapid progression of symptoms over time.

The study revealed that patients with moderate Alzheimer's disease experienced a faster deterioration in cognitive scores (ADAS-cog) than those with mild Alzheimer's, which is crucial for clinicians in managing treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analyses of natural courses of Japanese patients with Alzheimer's disease using placebo data from placebo-controlled, randomized clinical trials: Japanese Study on the Estimation of Clinical course of Alzheimer's disease. Watanabe, M., Nakamura, Y., Yoshiyama, Y., et al.[2022]

In a multicenter trial involving 92 patients with Alzheimer's disease, idebenone treatment over 90 days showed effectiveness in improving memory, attention, and orientation, while also slowing disease progression.

The treatment was generally well-tolerated, with mild side effects such as insomnia and nausea, which did not require specific medical interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Bergamasco, B., Scarzella, L., La Commare, P.[2022]

In a 1-year study involving 431 patients with probable Alzheimer's disease, acetyl-L-carnitine hydrochloride (ALCAR) did not show a significant difference in cognitive decline compared to placebo for the overall group, indicating similar efficacy between the two treatments.

However, a subanalysis suggested that early-onset Alzheimer's patients (aged 65 or younger) may experience a slower decline with ALCAR compared to those on placebo, while late-onset patients may progress more rapidly on ALCAR, highlighting the need for further research in younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Thal, LJ., Carta, A., Clarke, WR., et al.[2019]

In a review of 69 Alzheimer's disease clinical trials, study duration was found to be the most consistent predictor of cognitive decline in placebo-treated subjects, indicating that longer trials may lead to more observable changes.

Factors such as the number of investigational sites, frequency of evaluations, and the severity of dementia at baseline were inversely related to cognitive decline, suggesting that these elements should be carefully considered in the design of future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study design factors and patient demographics and their effect on the decline of placebo-treated subjects in randomized clinical trials in Alzheimer's disease. Gold, M.[2022]

Citations

1. investors.alnylam.com investors.alnylam.com/press-release?id=27761

Alnylam Pharmaceuticals Press Release | Oct 25, 2023 Alnylam reports additional positive interim Phase 1 results for ALN-APP, in development for Alzheimer's disease and cerebral amyloid angiopathy.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05231785

A Study to Evaluate the Safety and Tolerability of ALN-APP ... The purpose of this study is to evaluate the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of a single dose and multiple doses of ALN- ...

3. investor.regeneron.com investor.regeneron.com/news-releases/news-release-details/regeneron-and-alnylam-report-positive-interim-phase-1-clinical

Regeneron and Alnylam Report Positive Interim Phase 1 ... Patients treated with ALN-APP experienced dose-dependent, rapid and sustained reduction in cerebrospinal fluid of both soluble APPα (sAPPα) and ...

4. molecularneurodegeneration.biomedcentral.com molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-024-00745-5

Therapeutic potential of APP antisense oligonucleotides for ... They found that APP ASOs are effective in reducing both intracellular and extracellular (secreted) Aβ-containing soluble aggregates in human ...

5. neurologylive.com neurologylive.com/view/overviewing-encouraging-early-stage-data-mivelsiran-rna-therapeutic-alzheimers-sharon-cohen

Overviewing Encouraging Early-Stage Data on Mivelsiran, ... An in-depth overview of results from an ongoing phase 1 study assessing mivelsiran as a treatment for patients with early-stage Alzheimer disease.

6. alnylam.com alnylam.com/sites/default/files/pdfs/mivelsiran-aln-app-fact-sheet.pdf

Mivelsiran (ALN-APP) Mivelsiran is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of ...

7. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.082650

Interim phase 1 part A results for ALN‐APP, the first ... This first clinical study of a CNS-administered RNAi therapeutic demonstrates target engagement of APP, with reductions in CSF sAPPα and sAPPβ.

8. capella.alnylam.com capella.alnylam.com/wp-content/uploads/2023/10/ALN-APP-Interim-Part-A_CTAD-2023-Oral_FINAL.pdf

ALN-APP-Interim-Part-A_CTAD-2023-Oral_FINAL.pdf - Capella Here, we present longer term safety and pharmacodynamic data of ALN-APP than previously reported plus novel data describing disease-related ...

9. alnylampharmaceuticalsinc.gcs-web.com alnylampharmaceuticalsinc.gcs-web.com/news-releases/news-release-details/alnylam-reports-updated-positive-interim-phase-1-results-aln-app

Alnylam Reports Updated Positive Interim Phase 1 Results for ... These Phase 1 results show that a single dose of ALN-APP can rapidly reduce APP production and that this effect is sustained at 6 months.