Star-Crossed: The Rise and Fall of AnatablocÂ®

In the past year, much has changed for Jonnie R. Williams Sr. and his dietary supplement company, Star Scientific, Inc. In December 2013, the US Food and Drug Administration (FDA) sent a warning letter to Williams notifying him that two of his company’s products — Anatabloc^® and CigRx^® — did not meet the legal definition of a dietary supplement and were therefore adulterated under the Federal Food, Drug, and Cosmetic Act.¹ Both products contain anatabine, a minor alkaloid present in small quantities in tobacco (Nicotiana tobacum) and certain other plants (see Table 1), which the company promotes for its anti-inflammatory properties and smoking cessation benefits.² Shortly thereafter, Williams stepped down as the CEO of Star Scientific, and by mid-2014 the company had rebranded itself as Rock Creek Pharmaceuticals, Inc. and moved its headquarters from Glen Allen, Virginia to Sarasota, Florida.³

In January 2014, less than a month after Williams resigned as CEO of the company he founded, Robert McDonnell, the former Republican governor of Virginia, and his wife, Maureen, were indicted on 14 criminal counts of corruption, filed in the US District Court for the Eastern District of Virginia.⁴ The McDonnells were charged with accepting more than $177,000 in loans and gifts from Williams in exchange for official acts performed by governor and his office to promote Star Scientific products such as Anatabloc.⁵ Williams — the prosecution’s key witness — agreed to testify “in exchange for an extraordinary, rarely granted form of immunity.”³

The McDonnells’ corruption trial began in late July 2014 and has been the focus of much media attention.⁵ On August 11, two weeks after the trial began, Rock Creek Pharmaceuticals announced in its quarterly report to the Securities and Exchange Commission (SEC) that it was voluntarily halting sales of Anatabloc and CigRx, citing changing priorities for the company.⁶

“This action was taken in connection with an ongoing review of the extent to which our dietary supplement business … will impact our primary focus of developing pharmaceutical products from our anatabine-based compounds,” Rock Creek stated in the report.⁶ “[W]e anticipate that this will bring the FDA warning letter matter to a close.”

The legal matters of Bob and Maureen McDonnell are ongoing. On September 4, 2014, the former governor was found guilty of 11 corruption-related charges — including conspiracy, bribery, and extortion — and his wife was convicted on nine counts. A judge has scheduled sentencing for January 6, 2015; the McDonnells’ legal team has vowed to appeal the jury’s decision.⁷

Williams, an entrepreneur and businessman, dabbled in a number of different ventures in the 1980s including car sales and optometry-related startups. In 1990, Williams founded Star Tobacco with the goal of making “safer” tobacco.⁸

“I don’t like tobacco,” Williams was quoted as saying in a Richmond Times-Dispatch article from 1988. “I am more interested in health care.”⁹

Star Scientific introduced smokeless tobacco products in the 1990s, and Williams eventually patented a tobacco-curing process involving microwave radiation, which greatly reduced the amount of tobacco-specific nitrosamines, a group of potent carcinogens, in the dried plant material. In the late ’90s, the company significantly reduced the scope of its cigarette manufacturing operations, and Williams was appointed CEO of the newly renamed Star Scientific in 1999.^9,10

“For most of its history as a maker of cigarettes, then smokeless tobacco, Star Scientific has presented itself as an innovator, seeking to bring change to an industry that for decades resisted it,” commented the author of a 2014 article in the Richmond Times-Dispatch.¹⁰

Table 1. Claimed Natural Sources of Anatabine*
	Reference
Anatabine exists in tobacco and certain foods [in the nightshade family, Solanaceae], including green tomatoes [Solanum lycopersicum], green potatoes [Solanum tuberosum], ripe red peppers [Capsicum annuum], tomatillos [Physalis philadelphica], and sundried tomatoes [Solanum lycopersicum].	12
As an alternative to preparing anatabine synthetically, anatabine can be obtained by extraction from tobacco or other plants, such as members of [Solanaceae], e.g., jimson weed [Datura spp.], mandrake [Mandragora officinalis], belladonna [Atropa belladonna], [chili peppers (Capsicum spp.)], potato, … eggplant [Solanum melongena], and petunia [Petunia spp.].	12
Although anatabine is present as an inherent constituent of foods such as cauliflower [Brassica oleraceae], eggplant, potatoes, and tomatoes, FDA is not aware of any information indicating that anatabine itself is an article used for food.	1
Corkwood (Duboisia myoporoides) Tobacco	13

*References 1 and 12 do not include primary scientific data supporting anatabine’s presence in the plants listed.

On August 5, 2010, Star Scientific launched CigRx, a dissolvable smoking cessation lozenge that contains anatabine and yerba maté (Ilex paraguariensis) as its active ingredients.¹⁴ One year later, the company introduced the dietary supplement Anatabloc, which retailed for $99.99 for a 30-day supply.²According to its online description, “Anatabloc^® leverages the body’s natural process for regulating its own inflammation using anatabine, a naturally-occurring compound found in some plants, combined with Vitamin A and D3.”² A $300-per-jar facial cream was added to the product line in 2012, promoted as being “infused with anatabine citrate, a rare ingredient that is exclusive to Anatabloc.”¹⁵

In December 2012, Star Scientific announced that it would focus on dietary supplements, officially severing ties with the tobacco industry. Despite Star Scientific’s revamped mission and new products, the company has reported 11 consecutive years of financial losses through 2013, according the most recent SEC report available.⁶

“Our future prospects,” Star Scientific notes in the report, “therefore are dependent on the expanded distribution and consumer acceptance of our dietary supplement products and cosmetic product.”⁶

McDonnells Indicted and Convicted of Corruption

Williams allegedly first became acquainted with Bob McDonnell during his 2009 gubernatorial race. According to the indictment filed in US District Court, McDonnell’s staff requested the use of Williams’ private jet for campaigning purposes. Shortly after McDonnell was elected Governor of Virginia in November 2009, Williams asked to meet with the McDonnells at a political event in New York City, and they remained in varying degrees of contact through March 2013.⁴

The federal indictment charges that over a period of roughly two years, the McDonnells schemed to provide “official actions … to legitimize, promote, and obtain research studies for Star Scientific’s products, including Anatabloc®” in exchange for loans and gifts from Williams, reportedly totaling more than $177,000.^4,5

McDonnell — whose campaign slogan was “Bob’s for Jobs” — maintains that any actions he took to support Williams and/or Star Scientific were consistent with his goal to promote Virginia businesses.¹⁶

The 43-page indictment provides numerous examples of such “official actions” performed by McDonnell, including the following:

“i. arranging meetings for [Williams] with Virginia government officials, who were subordinates of the Governor, to discuss and promote Anatabloc®;

“ii. hosting, and the defendants attending, events at the Governor's Mansion designed to encourage Virginia university researchers to initiate studies of anatabine and to promote Star Scientific's products to [medical] doctors for referral to their patients;

“iii. contacting other government officials in the OGV [Office of the Governor of Virginia] as part of an effort to encourage Virginia state research universities to initiate studies of anatabine;

“iv. promoting Star Scientific's products and facilitating its relationships with Virginia government officials by allowing [Williams] to invite individuals important to Star Scientific's business to exclusive events at the Governor's Mansion; and

“v. recommending that senior government officials in the OGV meet with Star Scientific executives to discuss ways that the company's products could lower healthcare costs.”^₄

Maureen McDonnell, who — according to her daughter’s court testimony — had a “mild obsession” with Williams, also was allegedly involved in promoting Anatabloc in return for luxury gifts, including designer clothes, shoes, and a $6,500 Rolex for her husband.⁴At a campaign event for Mitt Romney in 2012, Maureen — who was “particularly enthusiastic” about Anatabloc — reportedly suggested to Ann Romney that the supplement “could potentially cure [her] multiple sclerosis.”¹⁸

Legal and Regulatory Concerns

On December 20, 2013, anatabine became the latest dietary supplement ingredient with claimed botanical origins to receive a warning letter from the FDA. However, in contrast with recent FDA actions against supplements containing controversial ingredients claimed to be of plant origin — i.e., DMAA (1,3-dimethylamylamine) and dendrobium (Dendrobium nobile, Orchidaceae) extract — the FDA did not comment on the natural or synthetic source of anatabine in Star Scientific’s products. Instead, the agency focused on the product’s illegal therapeutic claims and brought up both anatabine’s New Dietary Ingredient (NDI) and Investigational New Drug (IND) status.¹
Therapeutic/Drug Claims

According to the FDA’s warning letter, Star Scientific’s website “promotes the product Anatabloc for conditions that cause the product to be a drug under section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act.”¹

In the “Health Research” section of its website — which has since been taken down — Star Scientific cited studies that suggest anatabine may be helpful in treating multiple sclerosis, mitigating “neuro-inflammatory conditions,” preventing ulcerative colitis, treating Alzheimer’s disease, and “alleviat[ing] the negative consequences of traumatic brain injury.”¹

At the time of this writing (August 2014), only two randomized, controlled human clinical trials have been published on anatabine. The first study, published in July 2013, found no benefit of anatabine over placebo in muscle damage indicators or strength recovery in 18 men after strenuous workouts.¹⁹ The second study, published a few months later, examined the effects of anatabine in 146 participants with Hashimoto’s disease,²⁰ a condition otherwise known as chronic lymphocytic thyroiditis.²¹ The authors found that anatabine had an impact on the levels of one thyroid antibody and recommended further study. (Both studies were funded by Rock Creek Pharmaceuticals and included company employees as authors.)

Star Scientific noted in its annual SEC filing dated March 17, 2014 that it was taking steps to address some of the concerns in the warning letter. "In light of our receipt of the FDA letter, we have substantially limited the marketing and advertising of our dietary supplements," the company noted.¹¹

Table 2. Relevant Sections of the US Federal Food, Drug, and Cosmetic Act^21*
*Section*	*Topic*	*Language*
201(g)(1)(B)	Definition of a drug	The term “drug” means… articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.
201(ff)(1)	Definition of a dietary supplement	The term “dietary supplement” … means a product (other than tobacco [emphasis added]) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin; (B) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E).
201(ff)(3)(B)(ii)	Dietary supplements and INDs	The term “dietary supplement”… does… not include… an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food unless the Secretary, in the Secretary's discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this chapter.
350b(d)	Definition of a new dietary ingredient	For purposes of this section, the term “new dietary ingredient” means a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994.
413(a)(1) and (2)	Dietary supplement adulteration	A dietary supplement which contains a new dietary ingredient shall be deemed adulterated under section 402(f) unless it meets one of the following requirements: (1) The dietary supplement contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered. (2) There is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe and, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement provides the Secretary with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.

*As amended by the Dietary Supplement Health and Education Act (DSHEA) of 1994.

INDs & NDIs

According to the FDA’s warning letter, anatabine was authorized as an investigational new drug (IND) on June 8, 2012.¹(One peer reviewer of this article familiar with the case, however, claims that the company did not submit an IND application in 2012. In its August 2014 quarterly SEC filing, Star Scientific writes: “We filed an IND application in June 2014, however, the FDA has issued a clinical hold on the application, pending clarification of data from 2010.”⁶)

As the FDA explains online, “the investigational new drug (IND) application is the result of a successful preclinical development program,” which is designed “to determine if the product is reasonably safe for initial use in humans.”²² Importantly, the FDA continues, an “IND is not an application for marketing approval. Rather, it is a request for an exemption from the Federal [statute] that prohibits an unapproved drug from being shipped in interstate commerce.”²²

Anatabine’s IND authorization, as detailed in the December 20 warning letter, thus complicates Anatabloc’s classification as a dietary supplement.

“Under section 201(ff)(3)(B)(ii) of the [Food, Drug and Cosmetic] Act,” the FDA writes, “a dietary supplement may not include an article authorized for investigation as a new drug for which substantial clinical investigations have been instituted and made public, unless the article was marketed as a dietary supplement or food before its investigation was authorized.”¹

Star Scientific began marketing Anatabloc one year before and CigRx two years before anatabine’s June 2012 authorization as an IND. According to FDA’s warning letter, however, because anatabine is considered a new dietary ingredient (NDI), and Star Scientific had failed to comply with legal requirements to provide the FDA notice within 75 days prior to introducing Anatabloc into the US market as an NDI, the marketing of anatabine prior to the IND authorization was not lawful. Therefore, anatabine was not “marketed” as a dietary supplement before it obtained status as a “drug” under the relevant provision of federal law (i.e., 21 USC§ 321(ff)(3)(B)(ii)). Therefore, according to the FDA, the company’s failure to file an NDI notification (NDIN) for the compound — before it sought to study anatabine as a new drug — disqualifies it from the definition of dietary supplement and precludes its marketing as a dietary supplement.¹

In June 2014, Star Scientific submitted an NDI notification for anatabine in an attempt to address this issue, qualifying its decision in the August SEC report: “Although the company does not believe that an NDIN is a prerequisite to the lawful marketing of the nutritional supplement,” the company explains, “the NDIN was voluntarily submitted to provide the FDA with preclinical and clinical data concerning the supplement.”⁶

Presence in Food & Origin of Anatabine

Unlike the above example of DMAA (1,3-dimethylamylamine), which has yet to be definitively proven to exist naturally in botanicals,²⁴ anatabine is known to be present in small quantities in certain plants such as tobacco, tomatoes, potatoes, and eggplant.^1,12,13 However, this evidence does not automatically qualify anatabine as a so-called old dietary ingredient, i.e., the term frequently used to refer to an ingredient marketed prior to October 15, 1994, when the Dietary Supplement Health and Education Act of 1994 was passed by Congress.

“[T]he mere presence of anatabine in such foods, without any evidence the foods were promoted for their anatabine content,” the FDA states in the warning letter, “does not constitute ‘marketing’ of anatabine as a food under section 201(ff)(3)(B).”¹

Although the FDA did not go into detail about the natural or synthetic derivation of anatabine in Star Scientific’s supplements, several publicly available documents suggest a possible synthetic origin. In the frequently asked questions section of archived version of www.anatabloc.com — under the question heading “Does Anatabloc® contain Tobacco?” — the company states “Although we first looked at the anatabine alkaloid in tobacco plants, the anatabine in Anatabloc is not derived from tobacco.”²⁵

On March 23, 2010, Rock Creek Pharmaceuticals — formerly the name of a subsidiary of Star Scientific, and, as of June 2, 2014, the company’s official new name — filed a patent titled “Methods of synthesizing anatabine.” According to the document, “The present invention relates to improved methods of synthesizing anatabine, especially methods that are useful in larger scale syntheses.”²²

McDonnell, who has claimed that his support of Anatabloc was part of his job as governor to promote Virginia businesses, apparently became aware of the compound’s synthetic origin. “It was only later that McDonnell learned, he said [in his court testimony on August 22, 2014], that Star synthesized anatabine out of state instead of drawing it from tobacco leaves.”²⁶

Tobacco Exclusion

Perhaps the most straightforward reason why FDA claims Anatabloc is not a legal dietary supplement is because anatabine is found in — and can be derived from — the tobacco plant. “[I]t appears that anatabine can be manufactured from tobacco,” the FDA observes in its warning letter.¹ “It is important to note that tobacco, including its constituents, is excluded from the definition of ‘dietary supplement’ under section 201(ff)(1) of the Act.” The FDA is referring to the fact that in the definition of “dietary supplement,” the Act states that it can be an “herb” or “botanical” product “other than tobacco” (see Table 2).

In his 23 years as the head of Star Scientific, Williams oversaw the company’s transition from a cigarette manufacturer to an innovative dietary supplement business. However, in just the past year, new legal, regulatory, and financial issues have put the company in a state of flux once again.

The tone of Rock Creek Pharmaceutical’s most recent SEC quarterly report is, at times, decidedly somber. “Since the introduction of Anatabloc^®, the Company’s revenues have been derived almost exclusively from the sale of this product. Future sales of the Company’s dietary supplements will be dependent on it resolving issues with the [FDA] relating to the status of its Anatabloc^® and CigRx^® products,” the report states.¹⁰ “In the long term, the Company expects that its revenues will shift to be more dependent on the ability to successfully implement its drug development program, but it has no drug products in advance development as of this date.”

After the McDonnell’s roughly six-week federal trial — “the biggest trial in Virginia political history”²⁷ — it took the jurors less than two days to render a verdict. Pending an appeal, Bob McDonnell could face up to 10 years in prison for his corrupt dealings with Williams.²⁸ It remains to be seen what impact, if any, the case will have on the future of Rock Creek Pharmaceuticals and Anatabloc.

1. Star Scientific, Inc. 12/30/13. Warning letter. US Food and Drug Administration website. Available here. Accessed August 29, 2014.

2. Anatabloc: 300ct original bottle. Anatabloc website. Available here. Accessed September 2, 2014.

3. Green F. Former Star Scientific CEO Williams lands immunity. July 12, 2014. Richmond Times-Dispatch. Available here. Accessed September 2, 2014.

4. United States of America v. Robert F. McDonnell (Counts 1-13) and Maureen G. McDonnell (Counts 1-11, 13-14), defendants. Indictment. January 21, 2014. Available here. Accessed August 26, 2014.

5. Zapotosky M, Weiner R. Judge sets July trial for former Va. governor McDonnell. January 24, 2014. Washington Post. Available here. Accessed September 2, 2014.

6. Rock Creek Pharmaceuticals, Inc. Quarterly report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 for the quarterly period ended June 30, 2014. Securities and Exchange Commission website. Available here. Accessed September 3, 2014.

7. Gabriel T. Virginians, surprised by ex-governor’s conviction, ponder the fallout. September 6, 2014. New York Times. Available here. Accessed September 6, 2014.

8. Helderman RS, Vozzella L. Jonnie R. Williams, key witness against McDonnells, has a complicated past. February 3, 2014. Washington Post. Available here. Accessed September 2, 2014.

9. Moomaw G. Star Scientific CEO has a long history of salesmanship. April 7, 2013. Richmond Times-Dispatch. Available here. Accessed September 2, 2014.

10. Blackwell JR. Star Scientific’s next controversy? Dietary aids. April 14, 2013. Richmond Times-Dispatch. Available here. Accessed September 2, 2014.

11. Rock Creek Pharmaceuticals, Inc. Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 for the quarterly period ended December 31, 2012. Securities and Exchange Commission website. Available here. Accessed September 3, 2014.

12. Rock Creek Pharmaceuticals, Inc. EP 2751091 A2: Products for anti-inflammation support. Filed July 12, 2012. Available here. Accessed August 26, 2014.

13. Anatabine. Dr. Duke’s Phytochemical and Ethnobotanical Databases. August 18, 2014. Available here. Accessed September 2, 2014.

15. Anatabloc Rare Cellular Facial Crème. Anatabloc website. Available here. Accessed September 2, 2014.

16. Glueck K. Bob McDonnell testifies on marriage woes. August 20, 2014. Politico. Available here. Accessed September 2, 2014.

17. Vasiliadis J. Defense rests in trial of former Virginia governor. August 27, 2014. USA Today. Available here. Accessed September 2, 2014.

18. The five weirdest revelations from the McDonell trial. August 21, 2014. Daily Beast. Available here. Accessed September 2, 2014.

19. Jenkins NDM, Housh TJ, Johnson GO, et al. The effects of anatabine on non-invasive indicators of muscle damage: a randomized, double-blind, placebo-controlled, crossover study [published online July 22, 2013]. Journal of the International Society of Sports Nutrition. 2013;10:33. Available here. Accessed September 8, 2014.

20. Schmeltz LR, Blevins TC, Aronoff SL, et al. Anatabine supplementation decreases thyroglobulin antibodies in patients with chronic lymphocytic autoimmune (Hashimoto’s) thyroiditis: a randomized controlled trial. Journal of Clinical Endocrinology and Metabolism. 2014;99(1). Available here. Accessed September 2, 2014.

21. Hashimoto’s disease. Mayo Clinic website. Available here. Accessed September 2, 2014.

22. Drug development and review definitions. US Food and Drug Administration website. Available here. Accessed September 2, 2014.

23. Federal Food, Drug, and Cosmetic Act. US Food and Drug Administration website. Available here. Accessed September 2, 2014.

24. Smith T. New research supports synthetic origin of DMAA in supplements. HerbalGram. 95;46-49. Available here. Accessed September 3, 2014.

25. Frequently asked questions about Anatabloc®. Anatabloc website. Available here. Accessed September 2, 2014.

26. Rock Creek Pharmaceuticals, Inc. US Patent 8,207346 B2: Methods of synthesizing anatabine. Filed March 23, 2010. Available here. Accessed August 26, 2014.

27. Fain T. McDonnell trial: Former governor sees coincidence, not conspiracy in government’s case. August 22, 2014. Daily Press. Available here. Accessed September 2, 2014.

HerbalEGram: Volume 11, Issue 9, September 2014

Star-Crossed: The Rise and Fall of Anatabloc