A Study to Evaluate the Efficacy, Safety and Tolerability of ALN-APP in Patients with Cerebral Amyloid Angiopathy (CAA)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alnylam Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

9 Apr 2025 → ongoing

Decision date (initial)

2025-03-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Alnylam Pharmaceuticals Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Others, Pharmacodynamic

To evaluate the effect of ALN-APP on the incidence of new lobar Cerebral Microbleeds (CMBs)

Secondary objectives 5

1. To evaluate the effect of ALN-APP on the clinical severity of new cerebral hemorrhagic lesions
2. To evaluate the effect of ALN-APP on change in vascular reactivity.
3. To evaluate the effect of ALN-APP on the incidence of new cerebral hemorrhagic lesions and white matter hyperintensity.
4. To evaluate the effect of ALN-APP on the progression of small vessel abnormalities.
5. To evaluate the pharmacodynamic (PD) effect of ALN-APP.

Conditions and MedDRA coding

Cerebral Amyloid Angiopathy (CAA) is a neurological condition in which amyloid proteins build up in the walls of blood vessels in the brain, causing problems such as bleeding into the brain

Regulatory references

Plan to share IPD

Yes

IPD plan description

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the United States (US) and/or the European Union (EU). Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Inclusion Criteria for Sporadic Cerebral Amyloid Angiopathy (sCAA) patients. Male or female aged ≥50 years at the time of informed consent
2. Individuals with probable CAA per the Boston Criteria Version 2.0, characterized by the following history of clinical presentation and MRI findings at screening: a. Presentation with spontaneous intracerebral hemorrhage, convexity subarachnoid hemorrhage, transient focal neurological episodes, or cognitive impairment or dementia b. At least 2 strictly lobar hemorrhagic lesions on MRI, in any combination (ICH, CMB, or foci of cSS or cSAH), or c. At least 1 lobar hemorrhagic lesion plus 1 white matter feature (severe PVS in the CSO PVS or WMH in a multispot pattern), and d. Absence of any spontaneous deep hemorrhagic lesions (ie, intracerebral hemorrhage or microbleeds in basal ganglia, thalamus, or brainstem) on MRI, and e. Absence of other causes of the hemorrhagic lesions. Other causes of hemorrhagic lesions include antecedent head trauma, hemorrhagic transformation of an ischemic stroke, arteriovenous malformation, hemorrhagic tumor, CNS vasculitis. In addition, other causes of cSS and acute cSAH should also be excluded.
3. Individuals with probable CAA with supporting pathology per the Boston criteria version 2.0, with the following clinical data and pathological tissue (evacuated hematoma or cortical biopsy) at or prior to screening demonstrating: a. Presentation with spontaneous intracerebral hemorrhage, transient focal neurological episodes, convexity subarachnoid hemorrhage, or cognitive impairment or dementia. b. Some degree of CAA in specimen from evacuated hematoma or cortical biopsy. c. Absence of other diagnostic lesion.
4. Inclusion Criteria for Dutch-type Cerebral Amyloid Angiopathy (D-CAA) patients. Male or female aged ≥30 years at the time of informed consent
5. Individuals with a known E693Q APP gene mutation for Dutch-type CAA
6. Inclusion Criteria for both sCAA and D-CAA Patients. Corrected vision at 20/50 or better as measured per local procedures or sourced from documented medical history, for the subset of patients who will have BOLD-fMRI assessments. If otherwise eligible but without 20/50 or better corrected vision, omit BOLD-fMRI assessment.
7. Able and willing to meet all study requirements in the opinion of the Investigator, including travel to study center, procedures, measurements, and visits, including: a. Adequately supportive psychosocial circumstances. Must have a study partner who in the Investigator’s judgement is able to provide accurate information regarding the patient’s cognitive and functional abilities, who agrees to provide information at applicable study visits which require informant input for scale completion. Selection criteria of the study partner is included in the ICF and can differ by regional standards. If a study partner becomes unable to participate, a new study partner is required. b. Able to undergo MRI scans and able to tolerate them (eg, no metal implants including MRI incompatible intrauterine devices, myoclonus of a severity that precludes MRI scans or any condition that renders testing intolerable for the patient) c. Body Mass Index (BMI) ≥18 and ≤40 kg/m2 at Screening visit d. Able to tolerate LP
8. Evaluable brain MRI imaging at screening
9. Patient is able to understand, is willing, and able to comply with the study requirements and to provide written informed consent. at Screening visit. If the patient is unable to provide informed consent, legally authorised representative (LAR) (s) is (are) willing and able to comply with the study requirements and to provide written informed consent, provided that the patient also assents to participation. In countries where local laws, regulations, and customs do not permit patients who lack capacity to consent to participate in this study, they will not be enrolled. Ongoing participation in the trial will be contingent upon the patient maintaining mental capacity to provide informed consent, unless LARs are allowed per local regulations. During the study, a patient’s mental capacity will be assessed regularly, eg, prior to each treatment and after clinical events that may affect capacity (eg, stroke), by the Investigator and the study team members with relevant expertise who interact with the patient according to sites’ established processes. This comprehensive evaluation may include assessments already performed during the study and will incorporate the patient’s general understanding of the study and its procedures and input from study partner and possibly others including family members or care givers. If the Investigator determines a loss in mental capacity, the Investigator will document this change and will terminate patient's participation in the study if local regulations do not allow consent for continued participation by a LAR. Otherwise, the patient will be assigned a LAR as allowed per local law. In the Netherlands, patients who are not capable of consent will be excluded and, if deemed during the course of the study by the investigator to no longer have mental capacity to provide informed consent, their participation will be terminated.

Exclusion criteria 24

1. Moderate or Severe Stage AD (defined as global clinical dementia rating [CDR] 2.0 or 3.0, respectively) or significant CI (Mini Mental State Examination [MMSE] <22) at screening
2. History of previous clinical ICH with onset less than 90 days prior to anticipated randomization in the study
3. History of previous or contemporary diagnosis of CAA-related inflammation (CAA-ri) or amyloid beta related angiitis (ABRA) as defined by validated diagnostic criteria eg, [Auriel 2016] or on pathological examination.
4. Has any of the following laboratory parameter assessments at screening: a. Alanine aminotransferase or aspartate aminotransferase ≥ 3.0 x upper limit of normal (ULN) b. Total bilirubin ≥ 1.5 x ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN. c. International normalized ratio >1.4 d. Platelet count <100,000/microliter (μL) e. Estimated glomerular filtration (eGFR) of <30mL/min/1.73m2 (calculation will be based on the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine formula (2021) (refer to Section 10.1 of the protocol).
5. Treatment with another investigational drug, biological agent, or device within 6 months of Screening, or 5 half-lives of investigational agent, whichever is longer. Any agent that has received health agency authorization (including for emergency use) by local or regional regulatory authorities is not considered investigational.
6. Use of the following medications is prohibited unless the dose has been stable (prescribed dosing regimen is unchanged) for at least 12 weeks prior to Screening and the dosing regimen is not anticipated to change during the study: antidepressants, antipsychotics, anxiolytics, benzodiazepines (except when used for study imaging and procedures), acetylcholinesterase inhibitors, anticonvulsants, mood stabilizers, and memantine.
7. Antiplatelet or anticoagulant therapy within the 10 days prior to Screening or anticipated use during the study. This includes but is not limited to: clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban. Aspirin is allowed.
8. Treatment with amyloid-targeting antibody prior to Screening
9. Treatment with another IT administered medication within the last 1 year prior to Screening
10. Prior treatment with a CNS-targeted siRNA or antisense oligonucleotide (ASO)
11. Any history of gene therapy or cell transplantation or experimental brain surgery
12. Presence of an implanted shunt for the drainage of Cerebrospinal fluid (CSF) or an implanted CNS catheter
13. Clinically significant electrocardiogram (ECG) abnormalities at Screening, in the opinion of the Investigator, or a Fridericia-corrected QT interval (QTcF) >460 msec for males or >480 msec for females at Screening unless the QTcF measurement is not clinically significant in the judgement of the investigator in the presence of depolarization abnormalities (e.g., bundle branch blocks and ventricular paced rhythms).
14. Has systolic blood pressure >150 mmHg and/or a diastolic blood pressure >90 mmHg after 10 minutes of rest at screening.
15. Active fungal or bacterial systemic infection that will not be completely treated at least 7 days prior to the study drug dosing on Day 1
16. Attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to Screening. For patients with suicidal behaviors within the last 12 months, a risk assessment should be done by an appropriately qualified health professional to assess whether it is safe for the patient to participate in the study. In addition, patients deemed by the Investigator to be at significant risk of suicide, major depressive episode, psychosis, confusional state, or violent behavior should be excluded.
17. History of bleeding diathesis.
18. A medical history of brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment., Investigators should consider findings including but not limited to tumors or abnormalities visualized by MRI or computed tomography, suggestion of raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis, or curvature, Chiari malformation, hydrocephalus, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome.
19. History of uncontrolled seizures within the last 6 months prior to screening.
20. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening.
21. Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation; or, in the opinion of the Investigator, taking part in the study would jeopardize the safety of the patient.
22. Is not willing to comply with the contraceptive requirements during the study period, as described in Section 5.9.1 of the protocol.
23. Female patient is pregnant, planning a pregnancy, or breast-feeding.
24. History of alcohol abuse, within the last 12 months before Screening, in the opinion of the Investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Annualized rate of new lobar Cerebral Microbleeds as detected by MRI in patients with Cerebral Amyloid Angiopathy (sCAA)

Secondary endpoints 5

1. Global rank of patients based on clinical or MRI imaging outcomes by severity, count, presence of symptoms, and timing of: ­ New ICH ­ New cSS or cSAH ­ New lobar CMBs
2. Change from baseline over time in BOLD slope (amplitude over time-to-peak), amplitude, and time-to-peak detected, in a subset of enrolled patients, by visual-evoked fMRI
3. • Total number of new lobar CMBs over time detected by MRI • New ICH over time as detected by MRI or clinical diagnosis • Time to first ICH recurrence • New/extended cSS or new cSAH over time as detected by MRI or clinical diagnosis • Proportion of patients with hemorrhagic disease progression over time detected by MRI or clinical diagnosis where appropriate. • Total number of new symptomatic hemorrhages over time • Change from baseline over time in WMH volume
4. Change from baseline over time in total CAA SVD score as detected by MRI based on: ­ Lobar CMBs ­ CSO PVS ­ WMH ­ cSS
5. Change from baseline over time in sAPPα and in sAPPβ concentration in CSF

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alnylam Pharmaceuticals Inc.

Sponsor organisation

Alnylam Pharmaceuticals Inc.

Address

300 3rd Street

City

Cambridge

Postcode

02142-1103

Country

United States

Scientific contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Clinical Trials Information Line

Public contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Clinical Trials Information Line

Third parties 12

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 39 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications