Firms feud over purported age-fighting molecule

Take your vitamins. That advice isn’t just old fashioned these days; it’s downright controversial. Study after study shows that most people with a decent diet do not benefit from taking vitamins.

But plenty of people still take vitamins and other nutritional supplements. Serving those consumers is big business: Supplement sales reached $41 billion in 2016 worldwide, up 6% from 2015, according to Nutrition Business Journal.

With little regulation of the field in the U.S., it’s common for supplement makers’ fortunes to grow and shrink depending on headlines about new research, even though many such findings are based on weak evidence.

Amid the hum of controversy around supplements, the battle over nicotinamide riboside, called NR for short, stands out. A humble molecule found in milk, NR is the subject of a grueling patent dispute plus accusations of theft, stolen trade secrets, and employee poaching.

It’s also the promising subject of several upcoming human clinical trials. Most of the studies share the general hypothesis that NR can combat the metabolic stresses that come with aging. If the studies demonstrate benefits from NR, demand for the molecule could soar.

For the two firms involved in the dispute, the financial stakes couldn’t be higher. ChromaDex has an exclusive license to produce NR as a supplement. It has restructured its business to put a singular focus on the product, which it introduced in 2013 as Niagen. ChromaDex was founded in 1999 and is a publicly traded company. Pitted against ChromaDex is Elysium Health, a four-year-old start-up that has raised over $25 million from investors. Though Elysium claims to have a product pipeline, its only commercial product is Basis, a combination of NR and pterostilbene, an antioxidant found in blueberries.

Both companies sponsor preclinical and clinical research on their similar products. They both sell supplements to consumers online. ChromaDex also supplies brick-and-mortar retailers.

The two firms have neatly divvied up the world of academic and industrial scientists who study nutrients, metabolism, and aging or related aspects of biochemistry and recruited them for their science advisory boards. ChromaDex claims University of Iowa biochemistry professor and leading NR researcher Charles Brenner as its chief science adviser; he is also a director of the school’s obesity initiative. Elysium’s cofounder and chief scientist, Leonard Guarente, is also the director of the Paul F. Glenn Center for Biology of Aging Research at Massachusetts Institute of Technology.

Until mid-2016, ChromaDex sold Elysium all the NR and pterostilbene it needed to make Basis, according to ChromaDex. But then the business relationship went south. ChromaDex reached out to C&EN as part of a larger effort to defend its business.

Elysium declined to comment for this story, citing the ongoing litigation.

Scientists once thought NR was an obscure nutrient used mainly by the flu bacterium Haemophilus influenzae. But Brenner, then at Dartmouth College, discovered that NR is also taken up by fungi, yeast, and humans (Cell 2004, DOI: 10.1016/s0092-8674(04)00416-7). He found it in cows’ milk along with niacin and niacinamide, together more commonly known as vitamin B-3. Brenner proposed that NR is a third form of vitamin B-3.

If NR were an essential nutrient, like its cousin molecules that make up vitamin B-3, it would have been discovered during the vitamin discovery era of the early 20th century. That’s when researchers studied components of milk and other foods to find out why people and animals who consumed them didn’t suffer from various diseases of malnutrition.

In the 1920s, a public health researcher named Joseph Goldberger discovered that milk was one of the foods that prevented pellagra, an illness marked by diarrhea, dermatitis, and dementia. The findings were controversial at the time, as many scientists strongly believed pellagra was a communicable disease. Later research determined the antipellagra agent to be niacin.

Biochemists eventually learned that vitamin B-3 is an important precursor to the enzyme cofactor nicotinamide adenine dinucleotide. NAD is involved in important reduction-oxidation reactions, including the metabolism of glucose. It also aids the functioning of enzymes known as sirtuins, which have been implicated in aging.

Brenner first learned about NR and H. influenzae 15 years ago. At the time, the various biochemical routes to NAD were a hot area of study that involved some interesting enzymes. He was looking at NAD pathways in yeast.

“I was minding my own business working on an enzyme called glutamine-dependent NAD synthetase,” Brenner recalls. “I liked that enzyme. It is a biochemist’s delight because it has two active sites, and nobody knew how they worked together.”

The hotness of NAD was also due to its function in a sirtuin called Sir2 in yeast. Sir2 was made famous by discoveries showing its production ramps up under conditions of calorie restriction, which slows the rate of aging.

“Right around 2003–4, people were postulating that Sir2 responded to the level of glucose in cells in a way that would extend or shortenlife span,” Brenner says. “By knocking out or increasing NAD synthetase genes you could modulate Sir2 in yeast and, potentially, longevity.”

Brenner wanted to find out whether all routes to NAD require glutamine-dependent NAD synthetase. He suspected that the answer was no. He and his colleagues found that yeast, like H. influenzae, can use a shortcut to make NAD from NR via the enzyme nicotinamide riboside kinase (NRK). He searched human gene databases for the NRK gene and found two versions, called NRK1 and NRK2.

“That pretty much indicated that NR is a vitamin in people and has potential therapeutic uses such as in drugs or in nutritional, food, or personal care,” Brenner says. He worked with Dartmouth’s technology transfer office to obtain patents on the use of isolated NR in foods and supplements for the purposes of boosting NAD⁺, the reduced form of NAD.

Pharmacokinetic studies have shown that NR supplements do increase the amount of NAD⁺ circulating in the blood—by quite a lot in some people—with little to no side effects. Further trials are needed to show if supplements affect human health.

Some biochemists think NR could have positive health effects because the enzymes that use NAD⁺ have specific roles in aging: modulating life span, preventing neurodegeneration, and slowing metabolic decline. As people age, concentrations of NAD+ decline.

Intriguingly, yeast and worms that were given NR lived longer than control populations. In mice that were fed a high-fat diet, NR supplements protected against metabolic abnormalities normally caused by such a diet (Science 2015, DOI: 10.1126/science.aac4854).

The animal studies and human pharmacokinetic findings drew the attention of executives at ChromaDex. At the time, the company was purifying natural products for use in scientific studies and synthesizing larger quantities of a few substances to sell to supplement makers. It licensed the Dartmouth patents and started selling its Niagen-branded NR to customers in 2013.

ChromaDex conducted studies needed to apply to the U.S. Food & Drug Administration for “new dietary ingredient” and “generally recognized as safe” statuses, which it received. Obtaining the approvals made marketing Niagen easier because they add an indication of safety.

In the spring of 2016, ChromaDex says, Elysium requested a significant price discount for a very large order of NR and the antioxidant pterostilbene.

But when Elysium took possession of the discounted shipment it didn’t pay for it, ChromaDex alleges. ChromaDex sued Elysium for the nearly $3 million it says it is owed. Documents unearthed during litigation showed that Elysium got hold of a confidential spreadsheet listing prices and volumes of NR ordered by another ChromaDex customer.

After ChromaDex ended the supply agreement, Elysium found a different, undisclosed company to supply the ingredients for its Basis product.

In the summer of 2017, Elysium challenged both of Dartmouth’s NR patents. It argued that because early research by Goldberger and others showed that milk contains vitamins that cure pellagra, the use of naturally occurring nutrients from milk as a health supplement is too obvious to patent.

So far, one of the Dartmouth patents has survived the Elysium challenge. But the U.S. Patent & Trademark Office sided with Elysium in instituting a review of the second patent. That proceeding is ongoing and a final decision is not expected for several more months.

Key to the surviving patent claims is that Dartmouth described a composition of a supplement or nutritional food containing 25% by weight of isolated NR, says Kendrew H. Colton, a partner at the patent law firm Fitch, Even, Tabin & Flannery. That helps distinguish it from milk, which contains only trace amounts of NR, and tends to undermine the obviousness claim. Colton is a C&EN Advisory Board member who reviewed the claims for C&EN.

With appeals, the dispute could drag on for years. “Yes, litigation is costly, but there are big margins in the supplement market,” Colton says.

At the end of June, ChromaDex amended its suit against Elysium to include allegations of misappropriation of trade secrets. It claims that Elysium recruited Mark Morris, ChromaDex’s vice president of business development, to act as an inside agent to transmit confidential information to Elysium. Morris is now vice president for R&D at Elysium.

The suit further alleges that Morris’s recruitment and Elysium’s subsequent refusal to pay for its order was part of a “plot to cheat and steal” from ChromaDex and that Elysium wanted to weaken and harm its former supplier.

Brenner characterizes the alleged skulduggery as “a pretty shocking story of scientific theft and piracy.”

In the midst of the legal drama, Brenner says he is pleased to have ChromaDex as a commercial partner. He and Dartmouth turned down other prospects, he says, to choose one they felt was ethical and rigorous. To Brenner, that means a partner who pays for research proving that the substance is safe for people, follows up on potential health findings, and does not make unproven health claims.

“My advice for people with discoveries is to apply the same criteria for industrial partners as you would for academic collaborators,” he says. With some companies, he says, “you have to educate people involved in marketing a product to stay inside the lines.”

For its part, ChromaDex plans to keep defending its patents and pressing for Elysium to pay its bill. But CEO Rob Fried says ChromaDex doesn’t want the lawsuits to distract from the excitement forming around NR as researchers study its possibly salubrious effects in people.

“We will continue to develop the science around NR and NAD in general and continue to make the argument of why this is a special and unique molecule,” he says.