Rock Creek Pharmaceuticals Inc. (fka RCPIQ)

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RATIONALE FOR STUDY IN INFLAMMATORY DISEASE
The Roskamp Research Institute (Sarasota, FL) studied the sponsor’s product as part of their investigation into the nutritional and behavioral risk factors for (and possible treatments for) inflammatory neurological disorders. They conducted tests of anatabine relative to other nicotinic compounds, and discovered that both in vitro and in vivo (rodents) it had inhibitory effects on inflammatory modulators (e.g., NF-?B). Data from a series of experiments conducted by Roskamp researchers showed that anatabine inhibited amyloid beta (Aß) peptide production in vitro, and that similar doses of anatabine inhibited NF-?B activation in various cell lines, suggesting that anatabine may modulate excessive production of Aß peptide via inhibition of NF-?B. These researchers also found that treatment with anatabine significantly reduced brain Aß accumulation in an in vivo (mouse) transgenic model of Alzheimer’s disease, and that anatabine significantly lowered plasma levels of the inflammatory marker CRP in these animals (17).
In addition to their work in animal models of Alzheimer’s disease, Roskamp researchers have also investigated anatabine’s effects in a mouse model of multiple sclerosis. In this model, very high levels of inflammation are experimentally induced in the brain, leading to neuronal destruction and progressive paralysis. Mice treated with anatabine showed a dramatic reduction in paralysis that was accompanied by an attenuation of pro-inflammatory mediators such as interferon-gamma, interleukin-8 (IL-8), IL-6, and tumor necrosis factor-alpha. Further information is available online at: http://www.rfdn.org/ms_anatabine.html.
Based on these data, Roskamp has synthesized the single major isomer (S)-anatabine, and is proceeding with evaluation of that isomer. The preliminary data, including human epidemiological data, strongly suggest that nutritionally relevant amounts of either racemic anatabine (50% S-isomer) or pure S-isomer may support normal immune balance in the aging CNS.
In a similar fashion, researchers within the endocrinology department at Johns Hopkins University School of Medicine initiated pilot pre-clinical studies of experimental autoimmune thyroiditis. Those studies, though small, were sufficiently positive so as to lead them to a larger study as described in the next section.
PRELIMINARY DATA FROM ANIMAL STUDIES OF THYROIDITIS
Researchers from Johns Hopkins have investigated the effects of anatabine in two mouse models of autoimmune thyroiditis (18, 19). In one model female CBA mice were injected with either 50, 75, or 100 µg of thyroglobulin in complete Freund’s adjuvant on days 0 and 7 to experimentally induce autoimmune thyroiditis (EAT model) of differing severity (i.e. low, moderate, or high), and in the second model C57BL6 mice were genetically engineered to express the pro-inflammatory cytokine interferon-gamma in the thyroid gland resulting in thyroiditis (IFN-? model).
For the EAT model, control mice drank regular water and experimental mice drank water supplemented with anatabine (12.5 mg/kg/day). Results showed that anatabine significantly suppressed the incidence and severity of thyroiditis. As shown by histopathological examination, only 13 of 21 (62%) mice treated with anatabine developed lymphocytic infiltration of the thyroid gland compared to 22 of 23 (96%) of the control mice (relative risk 0.59, p=0.0174). The median thyroiditis severity was 0.5 and 2.0 in anatabine and controls, respectively (p=0.0007 by Wilcoxon rank sum test). Anatabine also reduced the development of antibodies in response to thyroglobulin on days 14 (p=0.029) and 21 (p=0.045) after injection, and improved the recovery of thyroid function on day 21 (p=0.049). Interestingly, relative to saline-treated controls, anatabine treatment significantly suppressed the thyroidal expression of IL-18 and IL-1R2, two important cytokines involved in the thyroid autoimmune response that may contribute to tissue destruction that is common in human autoimmune thyroiditis. Results from these studies have recently been published in a peer-reviewed manuscript in the journal Endocrinology (19).
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Rock Creek Pharmaceuticals, Inc. Investigator’s Information - CONFIDENTIAL
For the IFN-? model, IFN-? transgenic females and wild type C57BL6 males were mated, and pregnant mothers and their pups were treated with anatabine water (0.05 mg/mL) or regular water from preconception to day 30 after delivery. Results showed that anatabine administration significantly corrected the pathological growth retardation (as measured by body weight) of the pups typically seen in IFN-? transgenic mice, and improved thyroiditis severity (although non-significantly).
In addition to this in vivo work, the Johns Hopkins researchers have also conducted an in vitro study to investigate anatabine’s effects on the production of pro-inflammatory mediators by stimulated macrophages. Macrophages are known to infiltrate the thyroid gland in the EAT model, and produce a number of potent pro- inflammatory mediators. Results from this study have been published (19), and show that anatabine dose- dependently suppressed macrophage production of inducible nitric oxide synthase and cyclooxygenase (COX)-2, two enzymes that increase universally during inflammation.
Study in Alzheimer’s Disease
Rock Creek Pharmaceuticals in partnership with the Roskamp Institute has started a three month, randomized, double-blind, placebo-controlled, parallel group study of the safety and biological effects of nutritional modification with Anatabloc in subjects with mild to moderate Alzheimer’s disease, looking at amyloid levels, inflammatory markers, tolerance to the supplement and subjective effects.
Study in Autoimmune Thyroiditis
Rock Creek Pharmaceuticals is currently running a multi-site, five-visit, twelve-week, double-blind, randomized, placebo-controlled, parallel-group trial to evaluate the safety, tolerability, and potential effects of anatabine dietary supplementation on antithyroid autoantibodies, thyroid structure, and thyroid function in subjects with autoimmune (Hashimoto’s) thyroiditis.
Human Experience with Anatabine Self-Administration Other Than for Tobacco Craving
A 55 year-old, 56 kilogram female with active Hashimoto’s thyroiditis, self-supplemented with 15 mg a day of anatabine (0.267 mg/kg per day) in divided doses with the consent of her physician. Medical follow-up over 12 months has shown no progression of her disease, as well as sonographic, serological, and clinical evidence of possible reduction in active thyroid inflammation. This case, coupled with the epidemiological evidence and animal studies cited above led to interest in the potential for anatabine in supporting human thyroid health.
A 50 year-old, 82 kilogram female with autoimmune thyroiditis reported baseline antithyroid antibodies (AbTPO, normal range 0-60 IU/ml) of 2720 IU and 3655 IU taken six months apart. She started taking anatabine 10 mg/day (0.12 mg/kg per day) three months following the latter baseline measure, with follow-up antibodies of 300 IU/ml after 16 days of treatment. Follow-up is ongoing and shows continued reduction in anti-thyroid antibodies.
A 42 year-old, 63 kilogram, non-smoking female began taking an anatabine preparation for Hashimoto’s thyroiditis. She initiated treatment with many multiples of the recommended starting dose (6-8 times; 36 to 50 mg/day, or 0.6 to 0.8 mg/kg per day) and developed severe nausea and vomiting. Initial medical evaluation was negative, but she developed mild dehydration and transient mild transaminase elevations over the course of two days. Approximately 36 hours following her initial complaint of nausea her symptoms began to subside, and she recovered uneventfully.
A 75 kilogram male patient with Alzheimer’s disease self-supplemented with 30 mg a day of anatabine (0.4 mg/kg per day) in divided doses with the consent of his physician. His subjective experience, supported by his family was an improvement in memory and cognition. Clinical examination of his case is ongoing, showing possible improvement in serological markers, but the period of observation has been too brief (3-6 months) to
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Rock Creek Pharmaceuticals, Inc. Investigator’s Information - CONFIDENTIAL
reach a definite conclusion regarding disease progression or to document improvement on standardized tests.
A number of anecdo