Research paper

MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults

Karol M. Pencina, Siva Lavu, Marcello dos Santos, Yusnie M. Beleva, Ming Cheng, David Livingston, Shalender Bhasin

The Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 2023 Volume 78, Issue 1, pages 90–96

Tier 2 · Single well-powered human RCT or comprehensive human reviewSafety and pharmacokinetics

Source identifiers

DOI 10.1093/gerona/glac049
PubMed PMID 35182418
Funding This project was funded by a research grant from Metro International Biotech.
Declared competing interests S.B. reports receiving research grants from National Institute on Aging, National Institute of Nursing Research, National Institute of Child Health and Human Development - National Center for Medical Rehabilitation Research, Alivegen, AbbVie, and Metro International Biotech and consultation fees from OPKO. These grants are managed by the Brigham and Women's Hospital. S.L. and D.L. are employees of Metro International Biotech.

Study snapshot

Design
Randomised, double-blind, placebo-controlled, multiple ascending dose trial
Population
Overweight or obese, medically stable adults (BMI 28–40 kg/m²) aged 55–80 years, without diabetes or significant cardiovascular, renal, or hepatic disease
Sample
n = 32 (16 men, 16 women; 3:1 randomisation to MIB-626 vs placebo within each dose cohort)
Intervention
MIB-626 tablets (500 mg microcrystalline β-NMN each) administered as 1,000 mg once daily, 1,000 mg twice daily, or matching placebo, for 14 days
Endpoints
Blood NMN pharmacokinetics (Cmax, Tmax, AUClast); Blood NAD+ concentrations (baseline, day 8, day 14); NAD metabolome (2-PY, NAM, 1-methyl NAM, NR); Urinary NMN and metabolites; Adverse events and safety laboratory analytes; Fasting glucose, insulin, HOMA-IR, lipids, uric acid

What the study found, in plain language

This trial tested whether a pharmaceutical-grade formulation of NMN — MIB-626, a microcrystalline polymorph milled to a specific particle size — could reliably raise blood NAD+ levels in middle-aged and older adults. Thirty-two overweight or obese adults aged 55 to 80 were randomised to receive either 1,000 mg MIB-626 once daily, 1,000 mg twice daily, or placebo for fourteen days. Blood samples were collected in a way designed to preserve NMN and NAD from the rapid degradation that has complicated earlier trials.

Both dosing regimens were safe and well tolerated, with adverse-event frequencies matching placebo. The key finding was pharmacodynamic: NAD+ rose substantially above placebo in both treatment groups, and the increase was dose-related. By day 8 the treated groups had reached the NAD+ levels they would maintain through day 14, suggesting steady-state was achieved within a week.

Circulating levels of the major downstream metabolites — 2-PY, nicotinamide, 1-methyl nicotinamide, and nicotinamide riboside — all rose alongside NAD+. Very little unchanged NMN appeared in urine, meaning almost all of the administered dose was absorbed and metabolised. The authors position 1,000 mg daily as the minimum regimen worth carrying forward into efficacy trials, based on earlier dose-finding work showing that doses below 1,000 mg did not consistently raise NAD+.

Key findings

  • Blood NAD+ rose substantially above placebo at day 14 in both MIB-626 groups (p < .001 for Cmax and AUClast).
  • Blood NMN concentrations on day 14 were 2.7-times and 4.5-times higher than placebo at Cmax in the once-daily and twice-daily groups, respectively.
  • NAD+ levels on day 8 were already near day-14 levels, suggesting steady-state within about a week of dosing.
  • All four measured NAD metabolites (2-PY, NAM, 1-methyl NAM, NR) rose from baseline; 2-PY was the most abundant.
  • Very little unchanged NMN appeared in the urine, indicating near-complete absorption and metabolism of the oral dose.
  • Adverse event frequency was similar to placebo. One participant on twice-daily dosing discontinued due to diarrhoea; two participants (one on 1,000 mg once daily, one on placebo) had mild AST/ALT elevations that resolved after discontinuation.
  • No significant changes in fasting glucose, insulin, HOMA-IR, lipids, or uric acid over 14 days.

What this study can and cannot tell us

  • Short duration (14 days) and small sample (n = 32) — not designed or powered to detect changes in metabolic outcomes such as insulin sensitivity or lipids.
  • Narrow BMI (28–40 kg/m²) and age (55–80 years) range; participants were overweight or obese and medically stable. Generalisability to leaner, younger, or medically complex populations is limited.
  • Findings are specific to the MIB-626 microcrystalline polymorph formulation. Pharmacokinetics of over-the-counter NMN products may differ, since manufacturing quality varies and NMN is prone to degradation.
  • NAD+ was measured in whole blood as a surrogate for tissue NAD+; direct tissue measurement was not performed.
  • Tier-2 evidence: establishes pharmacokinetics and short-term safety of a specific pharmaceutical-grade formulation. Efficacy in disease conditions requires dedicated trials.