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Dr. John L. Faessel is a seasoned and respected Wall Street professional with industry-wide recognition for expertise in market strategy and analysis. He is widely recognized for his insights in public companies. For over 20-years Dr. Faessel’s ON THE MARKET reports have been widely distributed... More
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  • Breaking News For Star Scientific: Anatabine Is Effective In Models Of Inflammatory Bowel Disease

    Breaking News: Anatabine is Effective in Models of Inflammatory Bowel Disease

    Star Scientific (STSI) Nasdaq

    "Phenomenology is very different than pharmacology" - Dr. Phil Needleman, The Ten Commandments of Drug R&D

    Star Scientific recently announced that anatabine, the active ingredient in their flagship product Anatabloc was demonstrated to be effective in a mouse model of ulcerative colitis in research performed at the University of Virginia (link here). This adds to a growing list of autoimmune and inflammatory diseases for which anatabine has been shown to be effective in either a preclinical or clinical setting.

    First let's discuss this mouse model* of ulcerative colitis and the implications of the study, then let's talk about the above quote from Dr. Philip Needleman, inventor of Celebrex, professor emeritus at Washington University School of Medicine, and former Chief Scientist of Pharmacia, and see how it applies to Star Scientific's Anatabloc™ And let's not forget the numerous risks that loom large for Star's Anatabloc going forward.

    First the ulcerative colitis model: While I seldom focus on the precise details of the animal model and how the study designs are structured, in this case it will bring a fuller understanding of the relevancy in its ensuing use on patients in the clinic. In this model, mice are given a chemical called dextran sodium sulfate (NYSEMKT:DSS) in their drinking water. This chemical causes a disruption in the barrier of the colon that provides protection from bacteria that reside within the digestive tract of the mouse, as well as inside each and every one of us. With the protective mucosal barrier being ulcerated, these normally beneficial digestive tract bacteria are then able to penetrate inside the body, causing a major inflammatory response. This disruption and ulceration of the protective barrier combined with the infiltration of gut bacteria is an excellent model of what happens in patients with inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. What the researchers at University of Virginia did was test the ability of anatabine to prevent or reduce the severity of the disease in two manifolds: (NYSE:A) protection against disease development and (NYSE:B) treatment of existing disease.

    In the first manifold, the animals are given DSS and antabine concurrently at the beginning of the model, and these mice are compared to those given only DSS. In this case they saw that the animals given anatabine and DSS developed a less severe disease than those given DSS alone, demonstrating the protective effect of anatabine in development of the colitis. In the second mode, the animals were first given only DSS and the disease was allowed to develop. The diseased animals were then separated in two groups, and one group was given anatabine while the other was given nothing. Given the results of the first manifold, it would be expected that the mice treated with anatabine would also have a faster recovery from the DSS-induced colitis than those given no drug. However, this aspect of the experiment was inconclusive in this regard because the diseased animals did not drink sufficient anatabine-containing water during the course of treatment to provide proper dosing. Keep in mind that these are top-line results, and histological analysis and pathological scoring of colon tissue is generally part of this experiment; once the full results are in then a more complete conclusion can be drawn. However, the strength of these preliminary data clearly implicates that anatabine may be effective for the treatment of ulcerative colitis in humans, and suggest the possibility of piloting a clinical investigation.

    The implications are great in scope. Patients with inflammatory bowel disease (IBD) represent an enormous unmet medical need, and existing treatments are expensive, often ineffective, and come with major safety risks. Current gold-standard treatment options are biologic anti-TNF therapies such as J&J's Remicade and Abbott's Humira. These treatments are expensive (over $20K/year), require intravenous infusions in a clinical setting, and carry severe risks such as serious infection and malignancies (cancer). Imagine the potential of a safe, effective compound that could be taken as a pill and would be effective in both the prevention of disease and the treatment of existing occurrences. This type of treatment would be transformational for patients and have an enormous market advantage over the existing treatment paradigm. Also consider that the market for IBD was estimated to be $5.1 billion in 2012 alone, and is predicted to reach $6.2 billion by 2017. Link here.

    It should be noted that chronic inflammation of the colon is a major risk factor for colon cancer. Nearly 10% of patients with inflammatory bowel disease (IBD) eventually develop colon cancer, the second leading cause of cancer death in the United States. Link here. The treatments for IBD; Humira, Remicade, corticosteroids, also cause a much higher cancer risk. Link here.

    Now let's get back to the quote from the distinguished Dr. Needleman. (Link here). When he says that "phenomenology is very different than pharmacology", he is saying that seeing a drug work is very different than understanding how it works, and this understanding is critical to supporting the clinical development required to bring a medicine to market. In the context of anatabine, recent research from the Roskamp Institute has shown that anatabine effects important inflammatory pathways and biomarkers, and importantly that this effect comes from its ability to prevent the activation of STAT3. This suppression of STAT activity occurs concurrently with the reduction of numerous inflammatory factors such as TNF-αlpha, NF-kB, and pro-inflammatory interleukins. This is the "how" to which Dr. Needleman refers - and it is quite ironic that in these Roskamp studies anatabine was found to be even more effective than Celebrex, the drug invented by Dr. Needleman. Link here. Furthermore, Anatabine's proven ability to modulate the inflammatory JAK-STAT pathway places it broadly in the same pharmacological class as the JAK inhibitors such as Pfizer's recently approved Xeljanz. While certainly effective in the clinic, Xeljanz comes with serious safety risks and an FDA mandated "black box warning" that may limit its use and provide a barrier to market share. In contrast, anatabine has been clinically proven to be safe and well-tolerated, and is unlikely to carry any such safety limitations because it's STAT modulatory activity appears to result from nicotinic receptor agonism rather that JAK inhibition. Link here. This mechanistic distinction seems to allow anatabine to suppress STAT activation while circumventing the nasty safety concurs inherent to the JAK inhibitors.

    Now to the risks. Drug development is tricky business, and having solid science in place is no guarantee that a new medicine will be brought to the market. Let's take a look at some of the perils that Star will face going forward:

    · Effective corporate governance. Star is currently under investigation for actions relating to stock placements, and while these types of investigations often resolved without consequence, there is uncertainty and risk associated with this situation. This includes a litany of nuisance lawsuits that almost automatically follow such an investigation. Based on Star's stated level of cooperation with the regulatory officials, and vociferous response to the private-party suits, it is my belief that this situation will resolve sooner rather than later. Link here.

    · Ability to execute. Even the best ideas and most promising technologies can fail to reach the marketplace if the development and business plans are not painstakingly formulated and perfectly executed. This is especially true in the world of biotech; there are many ways to fail while the path to success can be very narrow and unforgiving.

    · Defense of intellectual property. If anatabine continues to encounter success in the clinic, there will no doubt be legal challenges regarding the validity of the patents. This is standard procedure in the pharma business, and as soon as you start making money it's assured that people will start suing you. For example, oftentimes companies file nuisance lawsuits that challenge intellectual property hoping for quick payoffs. Furthermore, potential competitors may look for holes in the patent protection, and try to devise their own competing intellectual property around any gaps.

    · There is inherent uncertainty that surrounds experimental medicines and clinical trials. Promising performance in preclinical models does not guarantee success in clinical trials, and success in early, biomarker-driven clinical trials does not ensure that clinically-relevant endpoints will be reached in later, outcome-driven trials.

    To summarize, these new results from the University of Virginia demonstrate anatabine's potential for preventing and treating inflammatory bowel disease. This is an important addition to the developing collection of clinical and preclinical science around anatabine that highlights it's potential to treat debilitating autoimmune and inflammatory conditions such as rheumatoid arthritis, thyroiditis, IBD, and well as neuroinflammatory diseases such as Alzheimer's and Parkinson's disease. In support of this, a stream of research emerging from the Roskamp Institute, as well as other academic institutions such as Johns Hopkins and University of Virginia, is elucidating the pharmacological basis of anatabine's anti-inflammatory actions at the molecular level, and providing an understanding of "how" that Dr. Needleman highlights as being critical to bringing a drug to market.

    Anecdotal, nonetheless worthy of note; a Big Pharma Ph.D. scientist who specializes in ulcerative colitis research and is out in front of the anatabine science emailed me commenting on the press release. He said. "If I had ulcerative colitis or Crohn's, I would be popping this stuff like M&M's." The "stuff" he mentions is Anatabloc.

    * Re studies on mice; we know in the hierarchy of scientific investigations that animal studies do not carry the weight of human studies, nonetheless there is an approximate 80% correlation. Remarkable for example is that 99% of mouse genes have an equivalent in humans making mice ideal for studying. Intriguing from the above link; "More so than any other genetically tractable organism, the mouse offers a close glimpse of humankind in terms of similarity in the underlying physiology, tissue structure and organization." The 2007 Nobel Prize in Physiology and Medicine was awarded to Mario Capecchi, Sir Martin Evans and Oliver Smithies for their pioneering work on gene targeting in the mouse.

    Disclosure: I am long STSI. I bought the stock in the open market and have no business relationship the company.

    Disclosure: I am long STSI. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

    Tags: RCPI, long-ideas
    Apr 03 2:21 PM | Link | 6 Comments
  • STSI - Star Scientific - Part II: What We Know - Scientific Publications, Patents, Deals, And Enormous R&D Investments In JAK-STAT Inhibition. The Latest Research Demonstrates Anatabine Affects The Same Biochemical Pathway Without Safety Concerns.

    Timeline / What We Know / and Beyond

    Star Scientific (STSI) Nasdaq

    Part II: What We Know - scientific publications, patents, deals, and enormous R&D investments in JAK-STAT inhibition. The latest research demonstrates anatabine affects the same biochemical pathway without safety concerns.

    This is the second installment of a three part series. For Part I ('Timeline') see here.

    Recently, venture capitalist and Forbes contributor Dr. Bruce Booth published an article entitled "Immunokinase Drug Candidates: $12B in Value Creation and Counting" with an in-depth analysis of drugs that inhibit the JAK family. The author states: "By my estimate, north of $10-12B in value has flowed to companies (and their shareholders) that possess hot immunokinase programs." Dr. Booth does a superb job of highlighting the scientific interest of those inhibitors of JAK and of fleshing out the extraordinary value creation that has resulted from the pursuit of this drug class.

    For those who are unfamiliar with the business and scientific landscape, a good scientific overview of the JAK/STAT pathway from the Journal of Immunology can be viewed here, and the Forbes article can be seen here. Additionally, the blog of Dr. Booth's (summa cum laude from Penn State and doctorate from Oxford University) can be seen here. As you may recall I spoke at some length on the subject last December in one of my own reports here.

    The Thomson Reuters database indicates that the pharmaceutical industry has at least 125 programs involving drugs that inhibit the JAK family. While it is beyond the scope of this communique to lay out the details of each of these programs, rest assured that pharma is following the rigorous Phase 1/2/3 guidelines of clinical trials regarding safety, toleration, dosing parameters, and efficacy. For the reader's edification, I will highlight below several key results from preclinical and clinical research programs with regards to the JAK-STAT pathway.

    So how does this all relate to Star Scientific?

    A peer reviewed research article from the Roskamp Institute published in November 2012 demonstrates that, like JAK inhibitors, anatabine also prevents STAT activation. To quote from the paper, "Our data show that anatabine prevents STAT3 and NF-kB phosphorylation induced by lipopolysaccharide [LPS] or TNF-alpha in SH-SY5Y, HEK293, human microglia and human blood mononuclear cells."

    This research from Roskamp convincingly demonstrates that antabine prevents STAT activation much as a JAK inhibitor does. However, anatabine is certainly not a JAK inhibitor and therefore likely modulates STAT activation through an entirely different mechanism. Recent research suggests that anatabine regulates STAT through nicotinic receptor agonism, and the fact that it modulates STAT independently of JAK suggests that it may have all the beneficial effects seen with the clinical JAK inhibitors for rheumatoid arthritis and inflammatory bowel disease, while circumventing the safety risks.

    The dilettante of the science will say, "So what! What's that all mean?" If one believes that money talks and that following the money is relevant in evaluating scientific as well as investing interest, take a deep dive into Dr. Booth's article and the referenced interactive dashboard here. What becomes apparent even to the scientific novice is the enormous amount of business and medical interest in this area, as reflected in the huge grant numbers, rapidly growing scientific and patent literature, and massive Big Pharma investments.

    It will do well-actually it's a must-to spend a few minutes perusing the just-mentioned interactive dashboard (here again) compiling trends and targets related to immunokinase science in order to grasp the import of the evolving JAK science and related inhibitors of inflammation,* and explore the range of other analyses including publications, patents, deals, and R&D pipelines over time.

    The dashboard platform vividly portrays the interest in the pharma targets that show promise:

    1. The relative output of research grants, scientific publications, and intellectual property in relation to each target.

    2. The targets in terms of which of them are "emerging," meaning not well known but steadily gaining a presence in research and patents, and which of them are "established," meaning well known and enjoying a steady, stable presence in research and patents.

    3. The pipeline of drugs, pre-clinical or clinical that target one of the conditions.

    The top five immunokinase programs demonstrated in the dashboard are; JAK2, JAK1/3, PI3K-delta, BTK, and Syk. Once again, the Thomson Reuters database indicates that pharma has at least 125 programs against those targets.

    The take away message from the dashboard and Roskamp's peer reviewed research here is as follows:

    1. The scientific and medical community has the subject on front burner as demonstrated by the significant increase in grants, publications, deals and R&D pipelines.

    2. Pharma is spending billions unreservedly working in the JAK family signaling pathway.

    3. Peer reviewed research on anatabine demonstrates that it acts in the same biochemical pathway, but is far safer.

    In Addition:

    Dr. Booth particularly focuses on Interleukin -1- Receptor Kinase 4 or [IRAK4] a critical signaling protein downstream of the interleukin family IL1R, IL18R, IL33R. The interluken's are of great pharma interest in autoimmune diseases or immune deficiency, where efficacy has been shown in lupus, psoriasis, irritable bowel syndrome, rheumatoid arthritis, and other debilitating diseases.

    Here again, Roskamp found that anatabine prevents Interleukin-1ß (IL-1ß) production induced by LPS using human whole blood in a dose-dependent manner. The Roskamp team also observed that anatabine reduces pro-inflammatory cytokine production (IL-6, IL-1, and TNF-α) in the plasma, kidney and spleen of the animals following the injection of LPS with concomitant suppression of STAT3 phosphorylation induced by LPS in the spleen and kidney. These results hold great promise for the control of inflammation in many human conditions, and research is ongoing at the Roskamp Institute to enable clinical studies that will test the ability of anatabine to regulate inflammatory diseases.

    Similarly, a PLOS ONE peer reviewed Roskamp paper published in January 2013 describes the positive effects of anatabine in a mouse model of multiple sclerosis (NYSE:MS). To quote the article "We found that orally administered anatabine markedly suppressed neurological deficits associated with Experimental Autoimmune Encephalomyelitis (EAE). Analyses of cytokine production in the periphery of the animals revealed that anatabine significantly reduced Th1 and Th17 cytokines known to contribute to the development of EAE. Anatabine appears to significantly suppress STAT3 and p65 NF-κB phosphorylation in the spleen and the brain of EAE mice. These two transcription factors regulate a large array of inflammatory genes including cytokines suggesting a mechanism by which anatabine antagonizes pro-inflammatory cytokine production."

    A key quote from the PLOS article "Other studies suggest that the plasma levels of anatabine that produce these effects in mice are attainable in humans without prohibitive side effects. Collectively, our data suggest that anatabine may be effective in the treatment of MS."

    Recap: Essential Points Regarding Anatabine:

    1. Anatabine is a nicotinic receptor agonist, and recent research shows that modulation of these receptors exerts an anti-inflammatory effect via the JAK-STAT pathway. This unique mechanism of action gives anatabine a potentially huge safety advantage over the JAK inhibitors that are being hotly pursued by so many pharma companies.

    2. Anatabine has been unequivocally demonstrated to prevent STAT activation much like the JAK inhibitors, and pharma is in the hunt in a big way here: Pfizer - link here, Lilly - link here, J&J - link here, Vertex - link here, YM Biosciences - link here and Galapagos - link here. For the science-heavy details see Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation, which illustrates how anatabine acts upon the JAK-STAT signaling pathway.

    3. Anatabine has been clinically proven to lower TNF-α levels in humans, and the anti-TNF drug market is at least $25 billion per year in the ulcerative colitis and rheumatoid arthritis arena. The top three are Johnson & Johnson's Remicade brings in around $8 billion per year and Abbott's biggest drug Humira has 2012 sales of $9.2 billion. Amgen / Pfizer's Enbrel's sales were $7.8 billion in 2011, despite the harmful side effects for which they carry FDA mandated Black Box warnings. Anatabine has the potential to be a much safer alternative to the dangerous and expensive biologic drugs.

    In Conclusion:

    Dr. Booth's article and the rich interactive dashboard displays linked above bring to the fore the steep rise of interest and massive funding that is being allocated to JAK-STAT pathway research. Anatabine's action seems to run parallel with the above programs with no side effects and it's already available to the public at GNC stores and available online. Thus, positive implications for Star Scientific's anatabine compound Anatabloc™ continue to compound. When we connect the dots regarding anatabine science, the mosaic that comes increasingly into focus takes on a most vibrant and compelling shape. Consider what a private company with this science would bring - in my opinion the deal would be in the billions.

    * IRAK4, NIK, Tyk2, ZAP-70

    Disclaimer: I bought shares of Star Scientific in the open market and have no relationship with the company.

    Disclosure: I am long STSI.

    Tags: RCPI
    Mar 28 11:42 AM | Link | 3 Comments
  • After 15 Years In Development This Disruptive And Breakthrough Technology Is Days Away From Launch.

    GlyEco (OTCQB:GLYE) OTCQB

    After 15 years in development this disruptive and breakthrough technology is days away from launch. The revenue and bottom-line earnings potential sets in place what looks to be an uncommon investment opportunity. Read more ».

    Watch a video that aired last week on FOX Business News of GlyEco CEO John Lorenz being interviewed on the RedChip Money Report here.

    The ultra-short version of the profit proposition; picture a company that acquires a throwaway toxic waste at a cost of nil, processes it, and then sell it for $5.60 a gallon - and there's over a billion gallons of it within easy reach.

    This is a remarkable story with extraordinary potential and one not to miss…

    Disclosure: I am long OTCQB:GLYE.

    Tags: GLYE
    Mar 27 9:20 AM | Link | 1 Comment
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