Clinical Trials

Inclusion Criteria:

Age and Sex

• Male or female aged ≥ 50 years at the time of informed consent.

Patient and Disease Characteristics

• Individuals with probable CAA per the Boston Criteria Version 2.0, characterized by the following history of clinical presentation and MRI findings at screening:
  • Presentation with spontaneous intracerebral hemorrhage, transient focal neurological episodes or cognitive impairment or dementia.
  • At least 2 strictly lobar hemorrhagic lesions on MRI, in any combination (ICH, CMB, or foci of cSS or cSAH)
  • At least 1 lobar hemorrhagic lesion plus 1 white matter feature (severe PVS in the CSO-PVS or WMH in a multispot pattern)
  • Absence of any deep hemorrhagic lesions (ie, intracerebral hemorrhage or microbleeds in basal ganglia, thalamus, or brainstem) on MRI.
  • Absence of other cause of the hemorrhagic lesions. Other causes of hemorrhagic lesion: antecedent head trauma, hemorrhagic transformation of an ischaemic stroke, arteriovenous malformation, haemorrhagic tumour, CNS vasculitis. In addition, other causes of cSS and acute cSAH should also be excluded.
• A minimum of 4 lobar CMBs confirmed by MRI; or multifocal cSS (as defined in [Charidimou 2017] with 2 or more lobar CMBs confirmed by MRI; or multiple lobar ICH with 2 or more lobar CMBs confirmed by MRI.

Inclusion Criteria for D-CAA Patients

• Male or female aged ≥30 years at the time of informed consent.
• Individuals with a known E693Q APP gene mutation for Dutch-type CAA.

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.
• Able and willing to meet all study requirements in the opinion of the Investigator, including travel to study center, procedures, measurements, and visits, including:
  • 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.
  • 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)
  • Body Mass Index (BMI) ≥18 and ≤34 kg/m2 at Screening visit.
  • Able to tolerate LP.
• Evaluable brain MRI imaging at screening.
• Patient is able to understand, is willing and able to comply with the study requirements and to provide written informed consent.

Exclusion Criteria:

Disease-specific Conditions

• 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.
• History of previous clinical ICH with onset less than 90 days prior to anticipated randomization in the study.

Laboratory Assessments

• Has any of the following laboratory parameter assessments at screening:
  • Alanine aminotransferase or aspartate aminotransferase ≥ 3.0 x upper limit of normal (ULN)
  •  Total bilirubin ≥ 2.0 x ULN. c. International normalized ratio > 1.4
  • Platelet count < 100,000/microliter (μL)
  • 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).

Prior/Concomitant Therapy

• 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.
• 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, acetylcholinesterase inhibitors, anticonvulsants, mood stabilizers, and memantine.
• 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.
• Treatment with amyloid-targeting antibody prior to Screening.
• Treatment with another IT administered medication within the last 1 year prior to Screening.
• Prior treatment with a CNS-targeted siRNA or antisense oligonucleotide (ASO).
• Any history of gene therapy or cell transplantation or experimental brain surgery.
• Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.

Medical Conditions

• Clinically significant electrocardiogram (ECG) abnormalities at Screening, in the opinion of the Investigator, or a Fridericia-corrected QT interval (QTcF) > 450 msec for males or > 470 msec for females at Screening.
• Has systolic blood pressure > 150 mmHg and/or a diastolic blood pressure > 90 mmHg after 10 minutes of rest at screening.
• 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.
• 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.
• History of bleeding diathesis.
• A medical history of brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment, 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.
• History of uncontrolled seizures within the last 6 months prior to screening.
• Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening.
• 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. Contraception, Pregnancy, and Breastfeeding.
• Is not willing to comply with the contraceptive requirements during the study period, as described in Section 5.9.1.
• Female patient is pregnant, planning a pregnancy, or breast-feeding. Alcohol Use.
• History of alcohol abuse, within the last 12 months before Screening, in the opinion of the Investigator.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 4/12/2024. Questions regarding updates should be directed to the study team contact.