ALN-APP for Cerebral Amyloid Angiopathy

(cAPPricorn-1 Trial)

Recruiting at17 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Alnylam Pharmaceuticals

Must not be taking: Amyloid antibodies

Disqualifiers: Alzheimer's, Cognitive impairment, ICH, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of the study is to evaluate the effect of ALN-APP on measures of CAA disease progression and to characterize the safety, tolerability, and pharmacodynamics (PD) of ALN-APP in adult patients with sporadic CAA (sCAA) and Dutch-type CAA (D-CAA). The study will be conducted over 2 periods: a 24-month double-blind treatment period and an optional 18-month open-label extension (OLE) period. The estimated duration of study participation, inclusive of screening, treatment, and additional safety follow-up, is up to 50 months.

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 have been treated with an amyloid-targeting antibody, you may not be eligible to participate.

How is the drug ALN-APP different from other treatments for cerebral amyloid angiopathy?

ALN-APP is unique because it targets the underlying cause of cerebral amyloid angiopathy by potentially reducing the accumulation of amyloid-beta in the brain's blood vessels, whereas other treatments primarily address symptoms or complications like inflammation or bleeding. ^{1 2 3 4 5}

Research Team

Medical Director

Principal Investigator

Alnylam Pharmaceuticals

Eligibility Criteria

This trial is for adults aged 50 or older with probable Cerebral Amyloid Angiopathy (CAA) as per Boston Criteria, or those 30 and above with a known E693Q amyloid precursor protein gene mutation linked to Dutch-type CAA. It's not suitable for individuals who don't meet these specific conditions.

Inclusion Criteria

I have been diagnosed with cerebral amyloid angiopathy according to the Boston Criteria.

I am 50 years old or older.

I am 30 years old or older.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive multiple doses of ALN-APP or placebo during the double-blind treatment period

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-6 months

Open-label extension (optional)

Participants may opt into continuation of treatment with ALN-APP long-term

18 months

Treatment Details

Interventions

• ALN-APP (RNA-based Therapy)

Trial Overview The study tests the effects of ALN-APP on slowing down CAA disease progression compared to a placebo. Participants will be randomly assigned to receive either ALN-APP or placebo over a period of up to 50 months, including an optional extension phase.

Participant Groups

Group I: ALN-APP Experimental Treatment 1 Intervention

Participants will be administered multiple doses of ALN-APP during the double-blind treatment period and optional open-label extension period.

Group II: Placebo/ALN-APP Placebo Group 2 Interventions

Participants will be administered multiple doses of placebo during the double-blind treatment period. Participants who continue into the optional open-label extension period will be administered multiple doses of ALN-APP.

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

Findings from Research

Cerebral amyloid angiopathy associated with inflammation is a significant condition in older adults, often presenting with cognitive decline, seizures, and headaches, and is characterized by an inflammatory response to β-amyloid deposits in the brain.

A systematic review identified 213 pathologically proven cases, highlighting the need for improved diagnostic criteria and treatment strategies, as current management options are limited and the condition can be challenging to diagnose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebral amyloid angiopathy associated with inflammation: A systematic review of clinical and imaging features and outcome. Corovic, A., Kelly, S., Markus, HS.[2019]

Cerebral amyloid angiopathy (CAA) can lead to serious neurological issues like seizures and strokes due to inflammation caused by amyloid buildup in blood vessels, and its inflammatory subtypes (CAA-related inflammation and amyloid-beta-related angiitis) are part of a spectrum of central nervous system vasculopathies.

As treatments for Alzheimer's disease evolve towards anti-amyloid therapies, the recognition of inflammatory CAA is expected to rise, highlighting the importance of awareness and diagnosis, which may now be achieved without invasive procedures in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inflammatory Cerebral Amyloid Angiopathy: A Broad Clinical Spectrum. de Souza, A., Tasker, K.[2023]

In a study of 14 patients with cerebral amyloid angiopathy (CAA) related inflammation, MRI scans showed specific patterns of T2-hyperintense lesions that correlated with clinical symptoms, indicating the importance of imaging in diagnosis and monitoring.

The presence of the APOE epsilon4/epsilon4 genotype was found in 76.9% of patients with CAA-related inflammation, suggesting a strong genetic link that could influence treatment strategies and risk assessment for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Course of cerebral amyloid angiopathy-related inflammation. Kinnecom, C., Lev, MH., Wendell, L., et al.[2016]

Cerebral amyloid angiopathy (CAA) is linked to Alzheimer's disease and can lead to serious issues like intracerebral hemorrhage and cognitive impairment, particularly affecting elderly patients.

This case series highlights that CAA can present with atypical dementia syndromes, such as logopenic variant primary progressive aphasia and normal pressure hydrocephalus, complicating its diagnosis and emphasizing the need for careful evaluation in patients with dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atypical Clinical Manifestations of Cerebral Amyloid Angiopathy. Akers, C., Acosta, LMY., Considine, C., et al.[2020]

Cerebral amyloid angiopathy (CAA) is a significant cause of intracerebral hemorrhage and cognitive decline in older adults, characterized by specific brain lesions and diagnostic criteria that have led to increased detection of the disease.

At a biological level, CAA is linked to a failure in protein elimination, which exacerbates amyloid-β accumulation and vascular injury, highlighting the need for further research into potential treatments and interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging concepts in sporadic cerebral amyloid angiopathy. Charidimou, A., Boulouis, G., Gurol, ME., et al.[2022]

References

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

Cerebral amyloid angiopathy associated with inflammation: A systematic review of clinical and imaging features and outcome. [2019]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Inflammatory Cerebral Amyloid Angiopathy: A Broad Clinical Spectrum. [2023]

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

Course of cerebral amyloid angiopathy-related inflammation. [2016]

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

Atypical Clinical Manifestations of Cerebral Amyloid Angiopathy. [2020]

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

Emerging concepts in sporadic cerebral amyloid angiopathy. [2022]