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Hollis-Eden Pharmaceuticals Presents Positive Updated Data from Phase I/II Clinical Trial with TRIOLEX in Obese Insulin Resistant Subjects

SAN DIEGO--(BUSINESS WIRE)--Sep 25, 2008 - Hollis-Eden Pharmaceuticals, Inc. (NASDAQ:HEPH) today presented additional positive interim data from its on-going Phase I/II clinical trial with its investigational oral drug candidate TRIOLEX(TM) (HE3286) in obese insulin resistant subjects at the 6th World Congress on Insulin Resistance Syndrome, being held September 25th - 27th in Los Angeles, California. Dr. Jaime Flores-Riveros, Vice President, Endocrinology and Metabolism at Hollis-Eden Pharmaceuticals, presented the data.

The additional data extend findings previously reported in a corporate symposium held in conjunction with the 68th Scientific Sessions of the American Diabetes Association demonstrating that TRIOLEX is safe and well tolerated to date, and that it significantly improved insulin sensitivity and lowered fasting blood glucose and insulin levels in obese insulin resistant subjects treated orally with 5 or 10 milligrams of the compound administered twice daily for 28 days, as compared to placebo-treated subjects.

Dr. Flores-Riveros presented additional data showing that insulin resistant subjects (as defined by a physiological index of glucose disposal or M-value less than 5), displayed a significantly exacerbated inflammatory response characterized by higher levels of the pro-inflammatory cytokines MCP-1, TNF-alpha, IL-6 and IL-1beta produced in LPS stimulated peripheral blood mononuclear cells (PBMC) from these patients. In contrast to more insulin sensitive subjects (M greater than 5), treatment of these insulin resistant subjects (M less than 5) with TRIOLEX was associated with a positive trend towards lowering these inflammatory cytokines, which in turn was accompanied by signs of glucose lowering in the same subjects.

Dr. Flores-Riveros also presented new data showing that retinol-binding protein 4 (RBP4), a protein secreted by fat cells that is associated with insulin resistance, was markedly decreased in the insulin resistant subjects (M less than 5) treated with TRIOLEX compared to placebo-treated subjects. In addition, C-reactive protein (CRP) was significantly decreased in the insulin resistant subjects (M less than 5) compared to placebo-treated subjects (p = 0.018). CRP is a well-known serum marker of inflammation, which has been linked to cardiovascular risk.

"The findings to date from this on-going clinical trial suggesting that initial serum CRP and levels of MCP-1, TNF-alpha, IL-6 and IL-1beta secreted by PBMC are elevated in insulin resistant subjects provide further rationale for the belief that insulin resistance is closely linked with inflammation," stated William Cefalu, M.D., of Pennington Biomedical Research Center in Baton Rouge, Louisiana. "The trend observed to date in this on-going study that TRIOLEX appears to decrease these elevated inflammatory markers, as well as the previously reported interim data showing that TRIOLEX significantly improved insulin sensitivity in these subjects when compared to placebo-treated subjects, lend support for the continued clinical development of TRIOLEX. If successfully developed, TRIOLEX has the potential to be an anti-inflammatory pharmaceutical that may provide benefit in type 2 diabetes without the side effects associated with the current glitazone class of insulin sensitizing agents as well as potentially providing benefit for diabetes-associated cardiovascular events."

TRIOLEX may represent a novel, first-in-class insulin sensitizer that Hollis-Eden believes acts by modulating inflammatory pathways. Leading academic researchers have linked inflammation and type 2 diabetes, reporting that chronic, subclinical inflammation can result in impaired insulin signaling by a variety of mechanisms. The involvement of inflammation through this pathway in causing insulin resistance and type 2 diabetes is well described in the scientific literature. In addition, activation of NF-kappaB due to inflammatory mediators or oxidative stress leads to a feed forward cycle of increased production of inflammatory cytokines such as MCP-1, TNF-alpha, IL-6 and IL-1beta.

The therapeutic approach inherent in Hollis-Eden's drug candidate is to restore the biological activity of cellular signaling pathways disrupted by disease and aging. In the setting of type 2 diabetes, the Company believes that the mechanism of action for TRIOLEX may be the regulation of the NF-kappaB pathway and other proinflammatory pathways, particularly when these are stimulated through the TLR4 receptor. TLR4 is a receptor expressed on the cell surface of macrophages and other cells that is stimulated by certain pathogens such as bacteria and viruses or certain chemicals such as dietary fatty acids. Upon stimulation of the TLR4 receptor, a cascade of proinflammatory kinases that include IKK, JNK and p38 is activated, setting off a complex network of signaling pathways, which culminate with the activation of NF-kappaB and a number of genes involved in the inflammatory and cell stress response. Based on experiments conducted to date, TRIOLEX appears to act independently of the PPAR-gamma pathway and down regulates proinflammatory kinases JNK, IKK and p38, which have been associated with impairment of the insulin receptor substrate-1 protein (IRS-1) function, an important cellular mediator of insulin signaling, ultimately causing inappropriate insulin action. Since this mechanism for improving insulin sensitivity does not seem to occur primarily through the PPAR-gamma pathway, TRIOLEX may avoid the side effects associated with the current glitazone class of insulin sensitizing agents, such as Avandia(R) and Actos(R), which work through PPAR-gamma. Side effects reported to date with the glitazone class of drugs include weight gain, edema and increased cardiovascular events. To date, experiments in vitro have shown no evidence that TRIOLEX directly binds and/or transactivates the PPAR-gamma receptor. Unlike the glitazones, TRIOLEX does not cause body weight gain when administered to mice or rats.

Added Richard Hollis, Chairman and CEO of Hollis-Eden Pharmaceuticals, "Data presented today by Dr. Flores-Riveros at this World Congress on Insulin Resistance Syndrome is relevant to our goal of developing a novel, first-in-class insulin sensitizer addressing the role of inflammation in driving insulin resistance. We believe this data is exciting because it may reflect the inherent ability of TRIOLEX to down regulate specific inflammatory signaling pathways that are thought to impair insulin signaling when chronically stimulated. We are also examining several other parameters known to be dysregulated as part of the metabolic syndrome, which includes both triglycerides and cholesterol. If TRIOLEX is successfully developed, we believe that the ability to regulate both glucose homeostasis and inflammation may result in a better and safer insulin sensitizer and make a significant advancement in the treatment of type 2 diabetes as well as potentially be beneficial in mitigating the serious consequences associated with uncontrolled inflammation in cardiovascular disease. A new generation of novel steroid hormones that regulate inflammation without serious side-effects could have multiple medical uses and could offer medicine the ability to better manage immune-mediated diseases."

Type 2 Diabetes Market

There are approximately 20 million Americans and over 160 million people worldwide with type 2 diabetes. As a result of an aging population and a rise in obesity rates, a common risk factor in this disease, the prevalence of type 2 diabetes is increasing rapidly. Included among the therapeutic approaches to type 2 diabetes are drugs designed to increase insulin production by the pancreas, drugs to reduce glucose production by the liver, and drugs to increase the body's sensitivity to insulin, thereby improving glucose disposal by the blood stream. The global annual sales of oral anti-diabetic drugs exceed $11 billion annually. Of these insulin sensitizers, Avandia(R) and Actos(R) represent the largest class of oral anti-diabetic agents, currently garnering over $5 billion in worldwide sales annually. However, patient control of glucose levels remains a large unmet medical need as 64% of this patient population fails to achieve optimal glucose levels. Furthermore, now that it is increasingly understood that inflammation is at the root cause of insulin resistance, there is a need to address inflammation in type 2 diabetes.

About Hollis-Eden Pharmaceuticals, Inc.

Hollis-Eden Pharmaceuticals, Inc. is a world leader in the development of a proprietary class of adrenal steroid hormones as novel pharmaceuticals for human health. Through its Hormonal Signaling Technology Platform, Hollis-Eden is developing a new series of small molecule compounds that are metabolites or synthetic analogs of endogenous hormones derived by the adrenal glands from the body's most abundant circulating adrenal steroid. These steroid hormones, designed to restore the biological activity of cellular signaling pathways disrupted by disease and aging, have been demonstrated in humans to possess several properties with potential therapeutic benefit -- they regulate innate and adaptive immunity, reduce nonproductive inflammation and stimulate cell proliferation. The Company's clinical drug development candidates include TRIOLEX (HE3286), a next-generation compound currently in clinical trials for the treatment of type 2 diabetes and ulcerative colitis and being prepared for clinical trials in rheumatoid arthritis, and APOPTONE(TM) (HE3235), a next-generation compound selected for clinical development for cancer. In addition to these clinical development candidates, Hollis-Eden has an active research program that is generating additional new clinical leads that are being further evaluated in preclinical models of a number of different diseases. For more information on Hollis-Eden, visit the Company's website at

This press release contains forward-looking statements within the meaning of the federal securities laws concerning, among other things, the potential and prospects of the Company's drug discovery program and its drug candidates and the benefits to be derived therefrom including the potential advantages of TRIOLEX compared to other treatment approaches, how TRIOLEX is believed to work and its potential for use in the treatment of type 2 diabetes. The inclusion of forward-looking statements should not be regarded as a representation by the Company that any of its plans will be achieved. Any statement included in this press release that are not a description of historical facts are forward-looking statements that involve risks, uncertainties, assumptions and other factors which, if they do not materialize or prove correct, could cause the Company's actual results to differ materially from historical results or those expressed or implied by such forward-looking statements. Such statements are subject to certain risks and uncertainties inherent in the Company's business, including, but not limited to: the outcome of final analysis of data from the Company's phase I/II clinical trial of TRIOLEX once it is completed may vary from the Company's initial analysis and findings, and the FDA may not agree with the Company's interpretation of such results; the ability to complete preclinical and clinical trials successfully and within specified timelines, if at all; the risks and uncertainties inherent in clinical trials, and drug development and commercialization, including the uncertainty of whether results in clinical testing of TRIOLEX to date will be predictive of results in later stages of development; the ability to obtain regulatory approval for TRIOLEX (HE3286), APOPTONE (HE3235) or any other investigational drug candidate; the Company's future capital needs; the Company's ability to obtain additional funding; the ability of the Company to obtain and protect its intellectual property rights and to not infringe the intellectual property rights of others; the development of competitive products by other companies, the market potential for type 2 diabetes, and the Company's ability to compete; and other risks detailed from time to time in the Company's filings with the Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this press release. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All forward-looking statements are qualified in their entirety by this cautionary statement. Except as required by law, the Company undertakes no obligation to update or revise the information contained in this press release as a result of new information, future events or circumstances arising after the date of this press release. None of the Company's drug candidates has been approved for sale, significant additional animal and human testing is required in order to seek marketing approval for any of its drug candidates, and the Company cannot assure you that marketing approval can be obtained for any of its drug candidates or that, even if such marketing approval were received, such drug candidates would ultimately achieve commercial success. Furthermore, as is typically the case at this stage of the regulatory review process, the FDA has not yet performed an in-depth review of the Company's preclinical and clinical data, so its views remain subject to change.


Hollis-Eden Pharmaceuticals, Inc.
Scott Rieger, Vice President, Corporate Communications

Posted: September 2008