Ignite Creation Date:
2024-05-06 @ 4:37 PM
Last Modification Date:
2024-10-26 @ 2:13 PM
Study NCT ID:
NCT05040321
Status:
RECRUITING
Last Update Posted:
2023-05-10
First Post:
2021-07-27
Brief Title:
Sirtuin-NAD Activator in Alzheimers Disease
Sponsor:
Brigham and Womens Hospital
Organization:
Brigham and Womens Hospital
Study Overview
Official Title:
A Proof of Concept Trial of a Sirtuin-NAD Activator in Alzheimers Disease
Status:
RECRUITING
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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-MSMS 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
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-MSMS 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
Detailed 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 Alzheimers 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
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| MIB-AD | OTHER | Metro International Biotech LLC | None |