From Fish Oil to Snake Oil
Sirtris Scandal Aside, Drugs Face No Supplemental Threat
By Trista Morrison
BioWorld Insight Editor
The biotech industry was abuzz last week with the news that Christoph Westphal and Michelle Dipp – who sold resveratrol-based Sirtris Pharmaceuticals Inc. to GlaxoSmithKline plc for $720 million – were exposed for selling resveratrol online.
In a nutshell, resveratrol is a natural substance found in red wine that's thought to positively impact caloric intake, insulin sensitivity and other factors by activating the sirtuin SIRT1. It's widely sold as a nutritional supplement, but Sirtris had developed a formulation with improved bioavailability, known as SRT501, and moved it into clinical trials for diabetes and MELAS syndrome. The biotech also was developing a handful of more potent, small-molecule SIRT1 activators when it was acquired by GSK. (See BioWorld Today, April 24, 2008.)
After the acquisition, Sirtris CEO Westphal and senior director of corporate development Dipp joined the GSK ranks. The two later started a side project together: an anti-aging-focused nonprofit called the Healthy Lifespan Institute. GSK spokeswoman Louise Dunn told BioWorld Insight that the big pharma firm was aware of the nonprofit, but it wasn't aware until Xconomy broke the story earlier this month that the Healthy Lifespan Institute was selling resveratrol online.
The situation spotlights the sometimes-nebulous dividing line between the worlds of nutritional supplements and FDA-approved prescription drugs.
Competitive Considerations
According to the Food, Drug and Cosmetic Act, dietary supplements are labeled as such, intended for ingestion but not a conventional food, and contain a vitamin, mineral, herb/botanical, amino acid and/or other dietary substance, or some concentrate, metabolite, constituent, extract or combination thereof.
A supplement can be an experimental or approved new drug as long as it was marketed as a supplement first, according to the FDA. The only differences between the nutritional version and the drug version are that the latter has a rigorously identified and controlled composition, has been proven safe and effective in clinical trials, and has passed the FDA's regulatory process.
Hence resveratrol could be marketed as a nutritional supplement, while Sirtris's resveratrol formulation, SRT501, could conceivably be marketed as a drug.
But that was not GSK's intent. Dunn said the company is not initiating any additional trials of SRT501 and is instead focusing on its second-generation SIRT1 activators, which are chemically unrelated to resveratrol and said to be 1,000 times more potent than the original.
Even though GSK isn't advancing SRT501, the Healthy Lifespan Institute has stopped selling resveratrol online, and Westphal and Dipp have resigned their positions with the nonprofit at GSK's request.
Of course, that doesn't stop other nutritional supplement companies from selling resveratrol. But Dunn said GSK doesn't see the resveratrol supplement makers as any commercial threat to GSK's SIRT1 activators because the compounds are completely different.
"Prescription medicines and nutraceuticals don't compete," Dunn said.
GSK should know. A few years ago, the big pharma paid $1.65 billion to acquire Reliant Pharmaceuticals Inc., gaining the rights to several drugs including Lovaza (omega-3-acid ethyl esters), a fish oil-based treatment for high triglycerides. (See BioWorld Today, Nov. 26, 2007.)
Unlike the SIRT1 activators, Lovaza is not a synthetic chemical designed to mimic the activity of the natural product – it is actually FDA-approved fish oil. It costs, on average, $28.70 for insured patients and $180 for uninsured patients for a 30-day supply. And although patients could buy a variety of unapproved fish oil nutritional supplements online or from stores like GNC, Lovaza enjoys 83 percent coverage through managed care formularies and generated some $700 million in revenue for GSK last year.
Declan Doogan, chief medical officer of Amarin Corp. plc, explained that fish oil nutritional supplements are "fine as a general tonic," but once a patient has been diagnosed with a medical condition, like elevated triglycerides, both doctor and patient tend to want a drug.
"For high cholesterol, does your doctor tell you to go buy garlic oil? No, he tells you to change your diet and exercise, and if that doesn't work, he gives you statins," Doogan said.
Since the FDA does not regulate nutritional products, their consistency of dosing and quality of manufacture often cannot be verified. But there are other factors that deter nutritionals from competing with drugs as well.
Doogan explained that patients with high triglycerides need 2 g of the omega-3 EPA daily. Supplements usually contain much less than that. To fit such a high concentration into one pill, they would need increased purity, which Amarin holds patents on. Additionally, increasing the dosage and the manufacturing purity significantly increases the cost to make the pills. Once you head in that direction, "you need a system to support the cost of the product, and that system is reimbursement," Doogan said.
Additionally, the marketability of nutritional supplements and foods is limited by the fact that such products can't be promoted with medical claims. Last year, the FDA slammed General Mills for illegally marketing Cheerios as a drug, citing advertising claims that the cereal is clinically proven to lower cholesterol.
Amarin is in Phase III trials for hypertriglyceridemia and mixed dyslipidemia with AMR101, a prescription grade, ultra-pure ethyl-EPA. Doogan said Amarin expects the pure EPA to offer benefits over Lovaza's mixed omega-3 formulation, such as potentially decreased risk of elevated LDL cholesterol.
Safety? Or Just Sketchy?
Interestingly, while a product sold as a nutritional supplement can be purified, tested and approved as a drug, the process does not work in reverse. The FDA told BioWorld Insight that if a drug failed in clinical trials or failed to gain FDA approval, the sponsor could not try to salvage the compound by selling it as a supplement "if it has never been marketed as a dietary supplement and the [investigational new drug] information has been made public."
However, the FDA added that if the IND was never made public, the product could potentially be marketed as a dietary supplement.
That's the path Neurochem Inc. sought to take after Alzheimer's disease drug Alzhemed (tramiprosate) failed a Phase III trial. The company rebranded itself as Bellus Health Ltd. and said it would commercialize tramiprosate as a branded nutraceutical. (See BioWorld Today, Aug. 28, 2007.)
Tramiprosate, also known as homotaurine, is a naturally occurring amino acid found in certain types of seaweed, according to the Bellus Health website. Scientific literature describes it as a synthetic gamma-aminobutyric acid analogue similar to the sulfonic acid taurine. Bellus sells the product on its website as Vivimind, but has temporarily stopped marketing the nutraceutical in Canada after a government directive requested that pharmacists not sell natural health products without a Health Canada Natural Health Product Number.
Bellus reported C$37,000 (US$35,587) in net sales during the three months ended June 30, 2010.
So if drug makers don't necessarily view nutritional supplements as an economic threat, why was GSK concerned with Westphal and Dipp's extracurricular resveratrol activities?
There's the safety consideration. Clinical trials conducted in a limited number of people sometimes fail to detect adverse events. If a supplement were to become hugely popular and taken by a lot of people, new safety issues could crop up.
"Any kind of safety signal is going to be taken very seriously," GSK's Dunn said. But since GSK's SIRT1 activators are completely different compounds from resveratrol, Dunn said the pharma firm isn't terribly concerned that a safety issue with one would translate to the other.
Amarin's Doogan, whose AMR101 actually is EPA, was similarly unconcerned about safety issues with EPA supplements. "We are not entering into the unknown . . . omega-3s enjoy a long safety record," he said.
In the end, GSK's primary concern was not competition or safety, but conflict of interest, Dunn said. "The specific issue was the involvement of GSK employees . . . contributing to our work to generate sirtuin-based prescription medicines" while being affiliated with a company that sold resveratrol, she said.
It was that conflict of interest, especially involving two extremely seasoned biotech veterans, that caught everyone's attention and caused such a scandal.
Published: August 23, 2010
AI
