Editor’s note: This is part two of a two-part series of articles examining the applicability of the so-called drug preclusion clause in DSHEA (Dietary Supplement Health and Education Act of 1994) to an ingredient marketed in dietary supplements called β-NMN. Go here to read part one.

Metro International Biotech LLC, developer of a proprietary form of β-NMN (beta-nicotinamide mononucleotide) called MIB-626, has been devoted to pursuing a pharmaceutical development pathway since the company’s inception, according to its president and chief scientific officer, David Livingston, Ph.D.

The company’s investment, reflected in comments filed in December with FDA, raises a question for the natural products industry. Does the investigation of MIB-626 as a new drug preclude the use of β-NMN in dietary supplements in the U.S.?

The answer may be “yes” if three criteria are satisfied in section 201(ff)(3)(B) of the Federal Food, Drug & Cosmetic Act (FDCA), according to attorneys well versed in FDA matters. First, the “article” or ingredient must be authorized for investigation as a new drug. Second, substantial clinical investigations must have been instituted. Third, the clinical investigations must have been publicized.

Meeting the three criteria does not trigger the drug exclusion clause if the article was previously marketed as a dietary supplement or as a food prior to its authorization for investigation as a new drug.

Related:Pharma company raises questions over race to market between drugs, supplements

“After compiling significant information on the human safety and pharmacokinetics of MIB-626, independent clinical investigators initiated Phase 2 clinical studies of our NMN investigational drug under several INDs [investigational new drug applications] filed by our company,” Livingston said in an email to Natural Products Insider.

He suggested FDA’s Center for Drug Evaluation and Research (CDER) issued “Study May Proceed” letters in response to IND applications filed with FDA. FDA issues such a letter when notifying an IND applicant that a clinical investigation may proceed, an agency spokesperson confirmed.

It’s unclear, however, when β-NMN was authorized for investigation as a new drug. FDA does not typically disclose such information, Livingston didn’t respond to a follow-up question regarding when his company received “Study May Proceed” letters from FDA, and he said he could not grant requests for interviews due to his company’s size and stage of development.

Taking the drug preclusion provision ‘seriously’

In public comments filed in December with FDA, a representative of Metro International Biotech requested “FDA take the preclusion provision of section 201(ff) of the Federal Food, Drug and Cosmetic Act seriously.”

The comments were submitted to an FDA docket in response to a citizen petition filed by the Natural Products Association (NPA) regarding NAC (N-acetyl-L-cysteine) products marketed as dietary supplements. Although NAC is a different ingredient than β-NMN, both substances have been investigated and/or approved as a drug.

Michael A. Willis, Ph.D., corporate counsel to Metro International Biotech, asked FDA to “protect the right of companies that have spent significant time and research to develop drug products from competition from dietary supplements that are clearly new dietary ingredients that have never filed a new dietary ingredient notification prior to the institution of substantial clinical trials.”

The effective date of an IND is critical since FDA interprets it as the race-to-market date between supplements and drugs, according to attorneys who practice food and drug law. Those IND dates, however, are often a mystery to manufacturers of dietary ingredients and finished supplement products.

FDA doesn’t typically reveal information related to INDs if the information is deemed part of a pending application, and the IND is still considered pending once it takes effect, CDER confirmed in an email to Natural Products Insider. Several federal statutes and regulations preclude FDA from discussing details of an IND application, CDER said, including the Freedom of Information Act, Trade Secrets Act and FDCA.

The IND is not disclosable, CDER added, until approval of the new drug application (NDA) referencing the IND.

“Somebody’s effective date for an IND could be today, and you and I would have no idea about that,” Robert (“Bob”) Durkin, a former FDA official in the Office of Dietary Supplement Programs, who practices law at Arnall Golden Gregory LLP (AGG), said in an interview.

In a follow-up email, Durkin said, “Until there are publicly available documents, there’s no way for regulated industry, other than the IND holder, to know that an IND exists.”

Yet FDA officials “use the effective date of the IND as the race-to-market date,” he observed. “It sets up a situation where the other two elements of the exclusionary clause can be satisfied after a dietary ingredient legally goes to market and then, when the last two requirements of 201(ff)(3)(B) are subsequently met, exclusion is triggered and a dietary ingredient that was legally on the market is suddenly retroactively excluded from the definition of a dietary supplement. It’s hard to imagine that’s what Congress intended.”

According to FDA, an IND may take effect 30 days after the agency receives the application or on earlier notification from FDA that the clinical investigations in the IND may commence. There is an exception to the effective date of an IND if FDA notifies the sponsor that the investigations are subject to a clinical hold.

“SOMEBODY’S EFFECTIVE DATE FOR AN IND COULD BE TODAY, AND YOU AND I WOULD HAVE NO IDEA ABOUT THAT”

Complicating matters further, FDA appears to take the position that an “article” can be excluded from the definition of a dietary supplement if it was not “lawfully” on the market prior to an IND’s effective date.

In a 2013 warning letter to the CEO of Star Scientific Inc., FDA concluded that while two products containing anatabine “were labeled and promoted as dietary supplements, they were not legally marketed as dietary supplements” prior to an IND that took effect on June 8, 2021. FDA determined the supplements were adulterated due to the presence of a new dietary ingredient (anatabine) that did not meet the requirements of the law.

As it relates to β-NMN in supplements, five new dietary ingredient notifications have been filed with FDA since August 2020. However, FDA has objected to four of the notifications for various reasons, including over concerns that the evidence of safety provided in the submission was inadequate. The agency concluded the first notification for a product taken under the tongue did not meet the definition of a dietary supplement. 

MIB-626: Clinical studies focused on diseases

ClinicalTrials.gov reveals Metro International Biotech is sponsoring studies to examine the effects of MIB-626 on certain diseases.

For example, a Phase 2 study, which listed an estimated study completion date of September 2023, is focused on MIB-626 taken by adults with Friedreich's Ataxia, a rare degenerative disease. The information was posted March 25, 2021, and last updated May 5, 2022, 11 days before a company called SyncoZymes (Shanghai) Co. Ltd. received an acknowledgment letter from FDA for its β-NMN new dietary ingredient notification (NDIN). Neither the letter to SyncoZymes nor FDA's responses to four other NDINs for β-NMN (see timeline below) mentioned MIB-626 or drug preclusion.

Another Phase 2 study of 50 participants focuses on MIB-626 treatment relative to placebo in adults with Covid-19 infection and stage 1 acute kidney injury. The study was estimated to be completed in August 2022.

The information was posted on ClinicalTrials.gov on Sept. 9, 2021, and last updated Dec. 1, 2021, the same day Metro International Biotech submitted public comments to FDA regarding drug preclusion.

Both studies are sponsored by Metro International Biotech.

SEVERAL FEDERAL STATUTES AND REGULATIONS PRECLUDE FDA FROM DISCUSSING DETAILS OF AN IND APPLICATION, FDA'S CENTER FOR DRUG EVALUATION AND RESEARCH SAID, INCLUDING THE FREEDOM OF INFORMATION ACT, TRADE SECRETS ACT AND THE FEDERAL FOOD, DRUG & COSMETIC ACT

One of the objectives of a third study, which is sponsored by Brigham and Women’s Hospital, is to determine whether daily oral administration of MIB-626 penetrates the blood-brain barrier in humans. ClinicalTrials.gov indicates the drug is being studied in patients with Alzheimer’s disease, with an estimated study completion date of December 2024.

The latter research also was referenced by the Alzheimer’s Drug Discovery Foundation in August 2021.

“The objective of the first trial is to determine whether MIB-626, after daily oral administration for 90 days, penetrates the blood brain barrier,” according to a press release from the Alzheimer’s Drug Discovery Foundation. “If the primary outcome is met in the first trial, a second trial will be planned to determine whether MIB-626 dosed orally for 180 days improves indicators of disease, including amyloid biomarkers in cerebrospinal fluid, synaptic function and neuroinflammation. The compound will also be assessed for improvement of cognition and activities of daily living in the trial participants.”

There are likely various ways to publicize that clinical investigations have been instituted. For instance, in a 2016 warning letter concluding clinical investigations regarding CBD had been made public, FDA referenced announcements by GW Pharmaceuticals that it had commenced clinical trials of Sativex and Epidiolex.

It’s possible FDA would find disclosure (via ClinicalTrials.gov) of the clinical investigations into MIB-626 satisfies the third element in the drug preclusion clause since an FDA spokesperson acknowledged “a listing on ClinicalTrials.gov is public information.”

‘Nobody wins here'

But again, the drug preclusion clause in the law is not triggered if β-NMN was marketed as a supplement or as a food prior to the effective date of the INDs. And those IND dates have not been disclosed to the public.

Durkin, the lawyer and former deputy director and acting director of FDA's Office of Dietary Supplement Programs, said the regulatory process pitting drugs against dietary supplements isn’t fair to anybody, including the pharmaceutical industry. The only way pharma can provide notice that a drug has been authorized for investigation, he said, is to make an IND public, and a company may have business reasons for not wanting to do that.

“This situation is not equitable for either side,” he concluded. “Nobody wins here.”

He also raised concerns over how FDA “sets the identity of the ‘article’ that might be excluded,” such as whether a broad-spectrum hemp extract is excluded from dietary supplements since it is partly comprised of CBD. More to the point, would FDA determine MIB-626 is the same “article” as β-NMN in dietary supplements? 

“Another issue is that, for the most part, the agency seems to run unchecked when it comes to its interpretation and application of the race-to-market clause,” Durkin concluded. “Consider that after FDA applied it to NAC, it took a district court litigation brought by NPA to force the agency into any meaningful discussions on the matter.”

Durkin’s law firm, AGG, has represented the Natural Products Association in litigation against FDA regarding NAC. The latter ingredient was approved as a drug in 1963, but unlike β-NMN, NAC has been marketed in the U.S. in nutritional products for decades.

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β-NMN timeline

Aug. 25, 2020
New dietary ingredient notification (NDIN #1174) for β-NMN ingredient is filed with FDA on behalf of Willy Chemicals and that’s intended to be marketed in a supplement product called “Reju-Me.”

Dec. 3, 2020
NDIN 1189 is filed on behalf of Willy Chemicals.

Jan. 8, 2021
FDA publicizes letter to Willy Chemicals regarding NDIN 1174. FDA concludes product “taken under the tongue or in the buccal area” does not meet the definition of a dietary supplement because it is not intended for ingestion.

March 25, 2021
Information is posted on ClinicalTrials.gov revealing Phase 2 study that is focused on MIB-626 taken by adults with Friedreich’s Ataxia, a rare degenerative disease. ClinicalTrials.gov lists an estimated study completion date of September 2023.

April 9, 2021
FDA publicizes letter to Willy Chemicals regarding NDIN 1189, which raised “significant concerns about the evidence on which you rely to support your conclusion that your dietary supplement containing ‘NMN’ will reasonably be expected to be safe under the conditions of use described in your notification.”

April 2021
Study published in Food and Chemical Toxicology, disclosing safety evaluation of high purity nicotinamide mononucleotide (NMN-C) in Sprague-Dawley rats. Developer of NMN-C, Seneque SA, says on website that ingredient is “self-GRAS” [generally recognized as safe] based on FDA guidelines.

Sept. 9, 2021
Information is posted on ClinicalTrials.gov revealing Phase 2 study of 50 participants that is focused on MIB-626 treatment relative to placebo in adults with Covid-19 infection and stage 1 acute kidney injury. The study was estimated to be completed in August 2022.

Nov. 15, 2021
NDIN 1234 is filed on behalf of Willy Nutra Inc. for β-NMN intended to be marketed as a bulk dietary ingredient.

Dates not disclosed to public 
Effective dates of INDs for MIB-626

Dec. 1, 2021
Metro International Biotech requests in public comments that “FDA take the preclusion provision of section 201(ff) of the Federal Food, Drug and Cosmetic Act seriously.”

Dec. 27, 2021
NDIN 1240 is filed on behalf of SyncoZymes (Shanghai) Co. Ltd. for β-NMN that’s intended to be marketed as a bulk dietary ingredient.

March 21, 2022
NDIN 1247 is filed on behalf of SyncoZymes for β-NMN that’s intended to be marketed as a bulk dietary ingredient.

June 13, 2022
FDA publicizes letter to Willy Nutra regarding NDIN 1234, which raised “significant concerns” about evidence provided in NDIN to support its safety conclusion.

June 13, 2022
FDA publicizes letter to SyncoZymes regarding NDIN 1240, which concluded the agency was unable to determine safety of β-NMN based on history of use and other evidence provided in the notification.

July 29, 2022
FDA publicizes letter to SyncoZymes, which acknowledged NDIN 1247 without an objection.