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Clinical Trial Summary

The primary objectives are to: 1. To determine whether βNMN, after its daily oral administration, penetrates the blood-brain barrier in humans by measuring the cerebrospinal fluid (CSF) concentrations of βNMN 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 βNMN 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 βNMN alters the circulating biomarkers of aging that the geroscience experts have recommended (HbA1C, IGF1, T3, IL6, TNF, and urinary F2-isoprostane).

Clinical Trial Description

The sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase enzymes are important regulators of the aging process (1-5) and mediate many of the beneficial effects of caloric restriction (6-9). The upregulation of the sirtuin-NAD+ pathway by increasing intracellular NAD+ through administration of NAD precursors, such as β nicotinamide mononucleotide (βNMN), has been shown to engage fundamental mechanisms of aging (10-18) and prevent or attenuate Alzheimer's disease (AD) pathology in preclinical models (19-26). 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 (19-26). 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 (27-32). 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 a crystalline βNMN formulation 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 βNMN 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 NMN crosses the blood-brain barrier, engages the hypothesized target mechanism, and whether it improves the biomarkers of aging. We hypothesize that βNMN 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 βNMN is more efficacious than placebo in improving biomarkers of aging in participants with mild AD dementia. ;

Study Design

Related Conditions & MeSH terms

NCT number NCT05040321
Study type Interventional
Source Brigham and Women's Hospital
Contact Shalender Bhasin, MD
Phone 6175259150
Email [email protected]
Status Not yet recruiting
Phase Phase 1/Phase 2
Start date October 1, 2021
Completion date December 1, 2024

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