Clinical trial NCT04798989: A Study of the Effects of CY6463 in Participants With Alzheimer's Disease With Vascular Pathology
Official title: A Phase 2a Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CY6463 When Administered to Participants With Alzheimer's Disease and Vascular Pathology
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alzheimer's Disease With Vascular Pathology
Keywords: Alzheimer's disease
AD
ADv
CY6463
Subcortical small-vessel disease
Elderly
60 and older
Probable AD dementia
Vascular dementia
Mixed dementia
Lead sponsor: Tisento Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-03-16
Enrollment: 12
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is being conducted to test the safety, tolerability, and pharmacokinetics of the investigational drug CY6463 compared with placebo in individuals who are aged 60 years or older and have Alzheimer's disease (AD) along with common cardiovascular risk factors.

Detailed description: CY6463 is an investigational drug being developed as a symptomatic and potentially disease-modifying therapy for Alzheimer's disease (AD) and other serious central nervous system disorders. As a soluble guanylate cyclase (sGC) stimulator, CY6463 can cross the blood-brain barrier and boosts the activity of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway. This signaling pathway is important in many aspects of brain health, including in the control of blood flow in the brain, how brain cells use energy, and how those cells communicate with one another. Impairment of this pathway is a critical part of the origin of many neurodegenerative diseases that can cause a loss of brain function including memory and decision-making abilities. There are clear links between disrupted NO signaling and impaired brain function in patients with AD and vascular pathology (ADv). ("Vascular pathology" refers to abnormalities of the blood vessels that are more likely to occur when a person has cardiovascular risk factors like high blood pressure, diabetes, and/or obesity.) It is hypothesized that CY6463 may help patients with ADv maintain or recover some of their original cognitive function.

In this study, participants will be randomized to receive approximately 87 sequential days (\~3 months) of study drug (CY6463 or placebo) once daily (QD) and will complete 7 scheduled site visits over the course of the study, from Screening through Follow up.

Eligibility criteria: Inclusion Criteria:

1. Provide written informed consent prior to the performance of any protocol-specified procedure or, if unable to provide informed consent due to cognitive status, provides assent to participate, with a legally authorized representative (LAR) providing written informed consent on behalf of the participant.
2. 60 years of age or older
3. Meets core clinical criteria for probable AD dementia according to the 2011 National Institute on Aging-Alzheimer's Associated guidelines. Can be based on medical history.
4. Mini-Mental State Examination (MMSE) score of 20 to 26 (inclusive)
5. Confirmation of AD pathophysiology
6. At least 2 cardiovascular risk factors per protocol criteria
7. Magnetic resonance imaging (MRI) scan (existing MRI obtained ≤6 months before Screening is acceptable) findings of mild-to-moderate subcortical small-vessel disease
8. If receiving concomitant or chronic medication(s), has had no change for ≥4 weeks before study drug initiation and has no plans to alter the regimen(s) during the study
9. If male, agrees to refrain from donating sperm from the Screening visit through 90 days after taking the final study drug dose
10. If male, agrees to use protocol-specified, effective contraception methods from the signing of the informed consent form (ICF) until ≥90 days after taking the final study drug dose.
11. If female, is postmenopausal/not of reproductive potential defined per protocol
12. Agrees to the study procedures, including undergoing lumbar puncture for cerebrospinal fluid (CSF) samples

Exclusion Criteria:

1. Severe visual, auditory, social, or cognitive impairment
2. Dementia-related disorder other than AD or vascular dementia (eg, Parkinson's disease, Huntington's disease, frontotemporal dementia, schizophrenia, Lewy body dementia)
3. Symptomatic large-vessel disease, symptomatic carotid artery disease, large vessel infarcts, or strategic lacunar infarcts or infarcts\>15 mm
4. History of significant central nervous system (CNS) trauma that has affected brain function
5. Low blood pressure (BP), defined as systolic BP ≤90 mmHg or diastolic BP ≤60 mmHg.
6. Orthostatic hypotension.
7. Unable to undergo MRI
8. Unable to undergo lumbar puncture procedure
9. Unable to participate in electroencephalography (EEG) protocol due to hearing impairment or inability to tolerate EEG cap or headphones
10. Uncontrolled or unstable chronic disease
11. Kidney impairment requiring dialysis; history of renal transplant
12. Needs continuous direct medical care and nursing supervision.
13. Family history of short QT syndrome or long QT syndrome
14. Clinically significant cardiac involvement
15. History of cancer. Exceptions: localized cutaneous basal or squamous cell carcinoma in the last 5 years, low-grade localized prostate/cervical cancers, or previous localized prostate/cervical cancers that have a low likelihood of recurrence
16. Is not suited for study participation in the clinical judgment of the investigator

Additional inclusion and exclusion criteria apply, per protocol.

Primary outcomes:
measure: Incidence of Treatment-emergent Adverse Events (TEAEs) From Study Drug Initiation Through Follow-up
timeFrame: From first dose of study treatment through ~14 (±4) days after the final dose
Secondary outcomes:
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Clinical Endpoints
state: Arizona
city: Miami
country: United States
facility: Optimus U Corp
state: Florida
city: Honolulu
country: United States
facility: Hawaii Pacific Neurosciences, LLC
state: Hawaii
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Tisento Therapeutics
name: Study Director
role: STUDY_DIRECTOR
References: