Tier 2 — strong

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

Pencina KM, Lavu S, Dos Santos M, Beleva YM, Cheng M, Livingston D, Bhasin S
The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 2023 Volume 78, issue 1, pages 90–96

Bibliography

PubMed
PMID 35182418
DOI
10.1093/gerona/glac049
Funding
This project was funded by a research grant from Metro International Biotech.
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

DesignSingle-centre, randomised, double-blind, placebo-controlled, multiple-ascending-dose trial with two sequential cohorts and a shared placebo arm.
ModelCommunity-dwelling overweight or obese medically-stable middle-aged and older men and postmenopausal women (age 55–80 y, BMI 28–40 kg/m²), free of significant medical problems and not using other NAD+ precursors.
Samplen=32 randomised (16 men, 16 women) — 8 to placebo, 12 to MIB-626 1000 mg once daily, 12 to MIB-626 1000 mg twice daily. n=31 completed the study; 1 discontinued in the twice-daily arm due to diarrhoea.
InterventionMIB-626 tablets (500 mg microcrystalline β-NMN per tablet, cGMP pharmaceutical grade) taken as two tablets once daily (1000 mg/d) or two tablets twice daily (2000 mg/d), or matching placebo tablets, for 14 consecutive days.
Duration14 days of daily dosing; participants followed for 28 days after the last dose.
EndpointsBlood NMN pharmacokinetics (Cmax, Tmax, AUClast); Blood NAD concentration and PK; Blood NAD metabolome (NAM, 1-methyl NAM, N-methyl-2-pyridone-5-carboxamide, NR); Urinary NMN, NAM and 2-PY-NAM standardised to creatinine; Adverse events, safety labs, QTc; Fasting glucose, insulin, HOMA-IR, lipids, uric acid, free fatty acids

What the study showed, in plain terms

This is one of the first human trials to test a pharmaceutical-grade oral NMN — a specific microcrystalline form of β-NMN called MIB-626, made under cGMP manufacturing conditions and delivered as a 500 mg tablet — for its ability to raise blood NAD levels in older adults. The point of using a pharmaceutical-grade product is to sidestep the manufacturing-quality problems that have plagued NMN sold as an over-the-counter supplement, where actual content and purity often do not match the label.

Thirty-two overweight or obese adults aged 55 to 80 years were randomly assigned to take 1000 mg of MIB-626 once daily, 1000 mg twice daily (a total of 2000 mg per day), or a matching placebo, for 14 days. The trial was double-blind, so neither the participants nor the investigators knew who was on what. Blood was collected at multiple time points on day 1 and day 14 to track NMN, NAD and their downstream breakdown products with validated mass-spectrometry assays.

The once-daily 1000 mg regimen roughly doubled whole-blood NAD compared with placebo, and the twice-daily 2000 mg regimen roughly tripled it. Levels of NMN's downstream metabolites (nicotinamide, 1-methyl-nicotinamide, and N-methyl-2-pyridone-5-carboxamide) also rose in a dose-dependent way, showing that the NMN was being absorbed and processed rather than simply excreted intact. Only trace amounts of unchanged NMN appeared in the urine.

The product was well tolerated. There were no serious adverse events, and only one person dropped out because of diarrhoea. Fasting glucose, cholesterol, triglycerides, HOMA-IR, and other metabolic markers did not change over the 14 days in any group — this trial was not long enough or large enough to test metabolic outcomes, and the authors are explicit about that.

Key findings

  • At 1000 mg once daily, mean blood NMN concentration on day 14 rose 2.7-fold in Cmax and 1.7-fold in AUClast above baseline versus placebo (p=0.007 for Cmax, p=0.037 for AUClast).
  • At 1000 mg twice daily, blood NMN Cmax rose 4.5-fold and AUClast 3.7-fold above baseline versus placebo — significantly higher than the once-daily arm (geometric mean ratios: Cmax 1.98, 90% CI 1.12–3.48; AUClast 3.32, 90% CI 1.14–9.67).
  • Whole-blood NAD rose in a dose-dependent manner: the day-14 NAD Cmax and AUClast were both significantly higher in the 1000 mg once-daily and 1000 mg twice-daily arms than in placebo (p<0.001 for both).
  • Circulating NAD-metabolome markers (2-PY, NAM, 1-methyl-nicotinamide) rose on days 8 and 14 versus baseline in both MIB-626 arms; 2-PY was the most abundant circulating and urinary metabolite.
  • Very little unchanged NMN appeared in the urine, indicating that oral NMN is metabolised rather than excreted intact.
  • No clinically meaningful changes in fasting glucose, insulin, HOMA-IR, lipids, uric acid, or free fatty acids over the 14-day window in any arm.
  • No serious adverse events. Adverse-event frequency was similar between arms; one participant on the twice-daily regimen withdrew due to diarrhoea. Two participants (one on 1000 mg daily, one on placebo) had mild AST/ALT rises on day 14 that resolved after stopping study product. No clinically significant change in vital signs or QTc.
  • PK parameters were not significantly associated with sex, age, or BMI, though the age and BMI range was narrow.

What this study can and cannot tell us

This is a pharmacokinetic and pharmacodynamic trial, not an efficacy trial. It establishes that oral MIB-626 raises circulating NAD in a dose-dependent way and is well tolerated over two weeks — it does not establish that NAD elevation improves any health outcome. The authors say this directly and position the study as the necessary safety-and-PK foundation before larger efficacy trials.

The sample is small (n=32), the age and BMI range is narrow (55–80 y, BMI 28–40), and the duration is short (14 days of dosing with 28 days of follow-up). The trial is not powered to detect metabolic changes or to characterise longer-term safety, and it is not designed to answer whether people at younger ages, lower BMI, or with specific medical conditions would show the same response.

The study product is a pharmaceutical-grade microcrystalline formulation manufactured under cGMP by Metro International Biotech; results should not be extrapolated to over-the-counter NMN supplements, whose manufacturing quality, particle size, polymorph, and actual β-NMN content vary. The authors reference this variability explicitly as one reason for the trial's design.

Conflict-of-interest exposure is substantial. The trial was funded by Metro International Biotech, and two of the authors (S.L. and D.L.) are employees of that company. The corresponding author reports research grants and consulting income from several biotech and pharmaceutical entities including Metro. These conflicts are disclosed clearly and do not invalidate the PK data, but readers should weigh the framing of the paper accordingly.

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