Sirtuin-NAD Activator in Alzheimer's Disease

Dementia Clinical Trial

Official title:

A Proof of Concept Trial of a Sirtuin-NAD Activator in Alzheimer's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05040321
• Other study ID #: 2021P001366
• Secondary ID: MIB-AD
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 1, 2021
• Est. completion date: December 1, 2024

Study information

• Verified date: May 2023
• Source: Brigham and Women's Hospital
• Contact: Shalender Bhasin, MD
• Phone: 6175259150
• Email: sbhasin[@]bwh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objectives are to:

1. To determine whether MIB-626, after its daily oral administration, penetrates the blood-brain barrier in humans by measuring the cerebrospinal fluid (CSF) concentrations of MIB-626 and its key metabolites, nicotinamide (NAM), NR, 2-PY, and MeNAM at baseline and on day 90 at steady state.

2. To evaluate whether oral MIB-626 administration engages the sirtuin-NAD pathway by determining the abundance of NAD (a SIRT1 substrate) in the brain using ultra-high field 7T magnetic resonance spectroscopy and in peripheral blood mononuclear cells using a validated LC-MS/MS assay.

3. To determine whether MIB-626 alters the circulating biomarkers of aging that the geroscience experts have recommended (HbA1C, IGF1, T3, IL6, TNF, and urinary F2-isoprostane).

Description:

The sirtuin family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylase enzymes are important regulators of the aging process and mediate many of the beneficial effects of caloric restriction. The upregulation of the sirtuin-NAD pathway by increasing intracellular NAD through administration of NAD precursors, such as niacinamide β nicotinamide mononucleotide (βNMN) and nicotinamide riboside, has been shown to engage fundamental mechanisms of aging and prevent or attenuate Alzheimer's disease (AD) pathology in preclinical models. In contrast to many AD drugs in development that target one mechanism, NAD precursors may prevent AD pathology by multiple mechanisms: by improving mitochondrial energetics; inducing a switch to non-amyloidogenic processing of amyloid precursor protein (APP) due to increased α-secretase activity; reducing the synthesis of oligomerized Aβ peptides; preventing microglia-dependent Aβ toxicity; attenuating neuroinflammation; promoting neuronal regeneration; and improving insulin action.

In spite of the promising preclinical data, the human studies of the clinical pharmacology, physiologic effects, efficacy, and safety of NAD precursors have been few and constrained by several methodological barriers. First, βNMN and nicotinamide riboside (NR) are sold as dietary supplements and these over-the-counter products have suffered from variable manufacturing quality. Second, there is only limited information available on the pharmacokinetics (PK) and pharmacodynamics (PD) of βNMN and NR in humans, and the doses used in some initial studies were low. Third, NAD and many other metabolites of βNMN and NR are labile and susceptible to rapid degradation ex vivo. Furthermore, the assays for the measurement of intracellular NAD, βNMN, and its metabolites have been challenging. Although NR and βNMN have been shown to cross the blood-brain barrier, attenuate AD pathology, and improve cognitive function in preclinical models, no clinical trials have been conducted to determine whether βNMN crosses the blood-brain barrier or engages the target mechanisms in humans.

To overcome these methodological barriers, we have characterized the pharmacokinetics of MIB-626 in phase 1 studies, validated the methods for measuring intracellular NAD, and established the procedures for blood collection to ensure pre-analytical stability. These phase 1 studies have shown that a regimen of 1 g MIB-626 twice daily is safe and effective in substantially raising circulating NAD levels in healthy adults (preliminary data). These foundational methods and single and multiple-dose pharmacokinetic studies have paved the way for the proposed 90-day randomized trial in 24 mild AD dementia participants to determine whether MIB-626 crosses the blood-brain barrier, engages the hypothesized target mechanism, and whether it improves the biomarkers of aging. We hypothesize that MIB-626 administration at the proposed dose will cross the blood-brain barrier and be associated with an increase in brain NAD. Because of the important role of the sirtuin-NAD pathway in regulation of the mechanisms of aging, we will also assess whether MIB-626 is more efficacious than placebo in improving biomarkers of aging in participants with mild AD dementia.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 1, 2024
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years to 85 Years

Eligibility

Inclusion Criteria:

1. A man or a woman between the ages of 55 and 85 years (inclusive)

2. Meets National Institute on Aging-Alzheimer's Association (NIA-AA) clinical diagnostic criteria for AD dementia

3. Has evidence of AD pathological process by a positive amyloid assessment with cerebrospinal fluid (CSF) Aß42

4. Has a Clinical Dementia Rating (CDR) global score of 0.5 or 1

5. Has a Mini-Mental State Exam (MMSE) Score of 18 to 26 (inclusive)

6. Has a 15-item Geriatric Depression Scale (GDS) score of < 6

7. Impaired memory performance below education adjusted cut-off score on the Logical Memory II subscale delayed paragraph recall (LM-IIa) of the Wechsler Memory Scale-Revised (WMS-R) (=16 years: =8; 8-15 years: =4; 0-7 years: =2)

8. May take Food and Drug Administration (FDA) approved medications for the treatment of AD dementia (cholinesterase inhibitors and/or memantine), but if taking such medications, they must be stable for at least 8 weeks before screening

9. Has adequate visual and auditory acuity to participate in neuropsychological testing and other study assessments

10. Has the availability of an informant (study partner) who has regular contact with the participant and knows him/her well

11. Is willing and able to participate in all assessments in English

12. Is capable of providing written informed consent

Exclusion Criteria:

Subjects may not be enrolled if:

1. Neurologic diseases: Any significant neurologic disease other than AD that can lead to cognitive impairment, such as Parkinson's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, normal pressure hydrocephalus, corticobasal syndrome, brain tumor, seizure disorder, subdural hematoma (within the last 1 year), multiple sclerosis, or history of significant head trauma (e.g. loss of consciousness for 30 minutes or more) followed by persistent neurologic deficits or known structural brain abnormalities.

2. Neuroimaging: Baseline or prior magnetic resonance imaging (MRI) scans with evidence of cortical stroke or hemorrhage, strategically located lacunar stroke (ex: left thalamus), or severe small vessel ischemic disease.

3. History of alcohol or substance use disorder or dependence (DSM V criteria) within the last 2 years.

4. Psychiatric disorder: Major depressive disorder (within the last 1 year), bipolar disorder, schizophrenia (DSM V criteria), or current major psychotic symptoms or behavioral problems that could interfere with study procedures.

5. Any significant systemic illness or unstable medical condition, which could obfuscate cognitive aging or neurodegenerative trajectories or affect valid cognitive and self-report measurements.

6. Excluded medications: Niacin or dietary supplements containing nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR); antipsychotic medications, antidepressant medications with anticholinergic side effects. Washout from psychoactive medications for at least 8 weeks before screening.

7. Current use of anticoagulants; significant back or spine disease that would make a lumbar puncture difficult or unsafe as determined by a clinician.

8. Other laboratory abnormalities: Has AST or ALT > 3 times the upper limit of normal; serum creatinine > 2.0 mg/d; HbA1C > 8.5%

9. Participation in an investigational trial to evaluate pharmaceuticals or biologics within the past 3 months or 5 half-lives, whichever is shorter

10. Other medical conditions which, in the opinion of the investigator, would jeopardize safety or impact the validity of the study results.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease (Incl Subtypes)
• Dementia

Intervention

Drug:
• MIB-626
Participants will be randomized to either receive MIB-626 or matching placebo. The proposed intervention - targets multiple contributors to the pathology of AD; MIB-626 improves mitochondrial function, bioenergetics, and insulin sensitivity, inhibits A beta accumulation by reducing its synthesis and increasing its clearance, reduces neuroinflammation, exerts neuronal protective effects, and promotes neuronal regeneration and connectivity in preclinical models.
• Placebo
Subjects will be randomized to receive either the placebo or 500mg MIB-626 twice daily orally.

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Brigham and Women's Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	change in CSF concentrations of biomarkers of amyloid deposition (Aß-42, Aß-40), neuronal/axonal degeneration (t-tau, p-tau, NFL), synaptic function (neurogranin) and neuroinflammation (YKL40, GFAP)	change from baseline to day 90 in CSF concentrations of biomarkers of amyloid deposition (Aß-42, Aß-40).	90 days
Other	Change in circulating biomarkers of amyloid deposition (Aß-42, Aß-40), neuronal/axonal degeneration (t-tau, p-tau, NFL), synaptic function (neurogranin), and neuroinflammation (YKL40, GFAP)	Change from baseline to day 90 in circulating biomarkers of amyloid deposition (Aß-42, Aß-40), neuronal/axonal degeneration (t-tau, p-tau, NFL), synaptic function (neurogranin), and neuroinflammation (YKL40, GFAP)	90
Other	Change in cognition	Change from baseline to day 90 in cognition, assessed using the Alzheimer's Disease Assessment Scale cognitive subscale 13-item version (ADAS-Cog-13)	90
Other	Change in instrumental activities of daily living (IADL)	Change from baseline to day 90 in the Functional Activities Questionnaire (FAQ) score	90
Other	Change in neuropsychiatric symptoms	Change from baseline to day 90 in Neuropsychiatric Inventory (NPI) score and 15-item GDS scale score	90
Primary	change in CSF concentrations of MIB-626	change in CSF concentrations of MIB-626 at baseline and on day 90 at steady state	90 days
Secondary	change in CSF concentrations of MIB-626 metabolites, nicotinamide (NAM), NR, 2-PY, and MeNAM	change from baseline to day 90 in CSF concentrations of MIB-626 metabolites NAM, NR, 2-PY and MeNAM; The concentrations of MIB-626's metabolites NAM, NR, 2-PY, and MeNAM will be measured in the CSF	90 days
Secondary	change in the abundance of NAD in the brain using ultra-high field 7T magnetic resonance spectroscopy	change from baseline to day 90 in the abundance of NAD in the brain using ultra-high field 7T magnetic resonance spectroscopy	90 days
Secondary	change in NAD concentrations in peripheral blood mononuclear cells	change from baseline to day 90 in NAD concentrations in peripheral blood mononuclear cells using validated LC-MS/MS assay	90 days
Secondary	change in the concentration of biomarkers of aging recommended (HbA1C, IGF1, T3, IL6, TNF-alpha, and urinary F2-isoprostane)	change from baseline to day 90 in the concentration of biomarkers of aging recommended (HbA1C, IGF1, T3, IL6, TNF-alpha, and urinary F2-isoprostane)	90 days