The U.S. military says it is months away from launching clinical trials of a pill designed to block or reduce many degenerative effects of aging—an oral treatment that a leading researcher in the field says is better than nothing while questioning how effective it will ultimately prove.

U.S. Special Operations Command (SOCOM)—which develops and employs Special Operations Forces worldwide to advance U.S. policies and objectives—has “completed preclinical safety and dosing studies in anticipation of follow-on performance testing” of a first-in-class nicotinamide adenine dinucleotide, oxidized state (NAD+) enhancer, a small molecule drug being developed by Metro International Biotech (MetroBiotech), Navy Cmdr. Timothy A. Hawkins, a spokesperson for SOCOM, told GEN.

SOCOM and MetroBiotech are set to start clinical trials during the 2022 federal fiscal year, which starts October 1.

“If the preclinical studies and clinical trials bear out, the resulting benefits include improved human performance, such as increased endurance and faster recovery from injury,” Hawkins said.

“This effort in particular is about enhancing the mission readiness of our forces by improving performance characteristics that typically decline with age,” Hawkins explained. “These efforts are not about creating physical traits that don’t already exist naturally.”

The SOCOM testing is among studies being carried out to assess MetroBiotech’s lead candidate, David J. Livingston, PhD, MetroBiotech’s president and CSO, told GEN.

“I can confirm that we and our clinical partners have completed multiple Phase I human safety trials of a lead molecule,” Livingston said. “Metro has also initiated exploratory Phase II studies in several areas of therapeutic application, including the treatment of rare diseases, diseases of aging, and in collaboration with SOCOM, studies on the effects of our compounds on muscle energetics and human performance.”

Livingston said MetroBiotech won’t discuss details of its clinical trials in advance of future postings on or joint publications of clinical data.

Potential to “truly delay aging”

SOCOM has spent $2.8 million on its anti-aging effort since it began in 2018, Hawkins said.

Lisa R. Sanders, director of science and technology for Special Operations Forces, Acquisition, Technology, & Logistics, said during a virtual conference last month that SOCOM was able to fund its anti-aging testing through Other Transaction Authority (OTA) funds and Middle Tier Acquisition authority, created in 2015 to enable rapid acquisitions designed to deliver capabilities within 2–5 years.

“This small molecule has the potential, if it is successful, to truly delay aging [and] truly prevent onset of injury, which is just amazingly game-changing,” Sanders said, addressing “Assisting the Modern Warfighter,” a featured session held as part of the Defense One Defense Tech Summit, held June 21–25.

“We’ve stayed out of long-term genetic engineering—that makes people very, very uncomfortable—but there’s a huge commercial marketplace for things that can avoid injury, that can slow down aging, that can improve sleep,” Sanders added.

That marketplace is set to grow 55% over the next five years, according to a market study issued in January by 360 Market Updates, from $84.6 billion this year to $130.87 billion by 2026—a compound annual growth rate of 7.5%.

“Better than nothing, but…”

Can MetroBiotech’s treatment be the one that can tap into that potentially lucrative anti-aging marketplace?

“This is better than nothing, but not much better,” cautioned Aubrey D.N.J. de Grey, PhD, a biomedical gerontologist who is CSO and co-founder of SENS Research Foundation. De Grey is also editor-in-chief of Rejuvenation Research, a peer-reviewed journal published by GEN publisher Mary Ann Liebert, Inc., publishers.

Based in Mountain View, CA, SENS Research Foundation aims to prevent and reverse age-related ill-health by applying principles of regenerative medicine to repair the damage of aging at the level where it occurs. The foundation focuses on rejuvenation biotechnologies designed to restore the normal functioning of the body’s cells and essential biomolecules, returning aging tissues to health and bringing youthful vigor back to the human body.

According to de Grey, SENS’ approach to anti-aging contrasts with MetroBiotech’s, which he characterized as reflective of a consensus view within gerontology toward simply reducing the rate of cellular damage from aging.

“Unfortunately the field of gerontology went about it in another wrong way, which was to try to, in effect, clean up metabolism, to slow down the rate at which metabolism generates damage and thereby to postpone the age at which damage reaches this pathogenic threshold. That has been basically unsuccessful,” de Grey said. “The pill that MetroBiotech is looking at is probably going to fail, for that reason.”

Not so, insists MetroBiotech.

“Our company’s strategy is to design small molecule therapeutics that leverage our scientists’ detailed understanding of the biochemistry and genetics of human pathways of aging and stress response,” Livingston said. “Based on discoveries in these exciting areas of biology, Metro has created a library of novel NAD enhancers as therapeutics for the treatment of human disease and preservation of muscle and cognitive performance.”

Building NAD+ portfolio

Privately-owned MetroBiotech, based in Worcester, MA, states on its website that it has established “the most comprehensive portfolio of proprietary NAD+ precursors in the world.” The company reasons that increasing NAD+ to preserve health and normal metabolism has broad pharmaceutical potential since levels of NAD+ have been shown to decline as people age. Reduced levels of NAD+ are linked to aging and numerous diseases, including mitochondrial dysfunction, inflammation, and a variety of associated diseases.

NAD+ plays a key role in the function of all living cells, as a cofactor required for the enzymatic processes that generate energy within the cell through the adenosine triphosphate (ATP) cycle—both in traditional oxidoreductase reactions and as a signaling molecule for reactions catalyzed by sirtuins, which regulate cellular health, and poly-ADP ribose polymerases (PARPS), proteins that help cells repair themselves.

MetroBiotech’s lead pipeline candidate, MIB-626, is one of over 100 novel NAD+ enhancers the company says it has designed, synthesized, and screened for optimal therapeutic properties. MetroBiotech says its efforts have resulted in “robust” preclinical data that support the broad therapeutic potential of modulating NAD+.

Most recently, in a study published last year in the journal Experimental Neurology, researchers at Medical University of South Carolina and Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland studies two approaches to increasing NAD+ availability in mouse models of amyotrophic lateral sclerosis (ALS): Ablation of a NAD+-consuming enzyme (CD38), and supplementation with a bioavailable NAD+ precursor, nicotinamide riboside or NR.

While the ablation approach showed no effect on the survival of the mouse models, adding NR delayed motor neuron degeneration, decreased markers of neuroinflammation in the spinal cord, appeared to modify muscle metabolism and modestly increased the survival of the hybrid superoxide dismutase 1 G93A (hSOD1G93A) mouse model of ALS.

“The results indicate that the approach used to enhance NAD+ levels critically defines the biological outcome in ALS models, suggesting that boosting NAD+ levels with the use of bioavailable precursors would be the preferred therapeutic strategy for ALS,” researchers concluded in the study, whose corresponding author Marcelo R. Vargas, PhD, is now at University of Wisconsin-Madison.

“Get something that works”

While acknowledging that an oral treatment to reverse aging would be much easier for patients than a surgical approach, de Grey of SENS added; “The way I look at it is, first of all get something that works, even if it’s really nasty in terms of needing surgery, and then you can refine it and make it injectable and maybe even oral.”

He cited growing researcher interest in an anti-aging application for one already-marketed drug long in use by patients. The type 2 diabetes treatment Metformin is set to be the subject of the proposed Targeting Aging with Metformin (TAME) Trial. TAME, to be managed by the American Federation for Aging Research, will be a series of nationwide, six-year clinical trials at 14 top-tier research institutions across the United States that are designed to engage over 3,000 individuals between the ages of 65–79.

Another potential anti-aging treatment already under clinical study is rapamycin, a natural anti-fungal antibiotic that has shown antitumor and immunosuppressive activity. The University of California, Los Angeles, partnered with AgelessRx last year to launch the Phase II Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study (PEARL) trial (NCT04488601), designed to evaluate Rapamycin in an estimated 1,000 older adults.

“The researchers aim to establish a long-term safety profile, determine the long-term efficacy of Rapamycin in reducing clinical aging measures, and biochemical and physiological endpoints associated with declining health and aging in healthy older adults,” according to the trial’s page.

MetroBiotech has disclosed one clinical trial for its lead NAD+ candidate MIB-626 on The Phase II trial (NCT04817111) does not involve SOCOM, but is designed instead to assess MIB-626 in up to 10 adults with Friedreich’s Ataxia (FA) without overt heart failure and with a left ventricular ejection fraction ≥ 40%.

“A key secondary objective is to test the effects of MIB-626 on cardiac and skeletal muscle bioenergetics,” according to MetroBiotech.

The trial’s estimated primary completion date is April 10, 2022.

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