Start Of Phase II Clinical Trial With TRIOLEX™ (HE3286) In Type-2 Diabetes Patients; Sites Expanded To Accelerate Enrollment

Main Category: Diabetes
Also Included In: Clinical Trials / Drug Trials
Article Date: 19 Jul 2008 - 1:00 PDT

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Hollis-Eden Pharmaceuticals, Inc. (NASDAQ:HEPH), the world leader in the development of a new class of small molecule compounds based on endogenous adrenal steroid hormones, announced that it has commenced a Phase II clinical trial with its oral drug candidate TRIOLEX™ (HE3286) in type 2 diabetes patients, and that it is expanding the number of clinical sites to accelerate enrollment. The Phase II, double-blinded placebo controlled 12-week dosing trial will enroll approximately 90 patients who are stable on metformin treatment only, the current first-line therapy for type 2 diabetes, with a hemoglobin A1c (HbA1c) level in excess of 7.5 percent. The primary endpoints for the trial will be safety and a reduction in HbA1c. Hollis-Eden plans to release preliminary interim data from this trial in the fourth quarter of 2008, and to completely enroll by the end of the year.

TRIOLEX may represent a novel, first-in-class insulin sensitizer that Hollis-Eden believes acts by modulating inflammatory pathways. Recently announced interim data from the Company's on-going Phase I/II clinical trial with TRIOLEX demonstrate that the compound is safe and well tolerated to date, and that it significantly improved insulin sensitivity and lowered fasting blood glucose, insulin and triglyceride levels in obese insulin resistant subjects treated orally with the compound for 28 days when compared to placebo-treated subjects. As would be expected in a population of insulin resistant subjects, blood levels of the chemokine monocyte chemoattractant protein (MCP-1) were elevated at baseline, before initiating treatment. MCP-1 plays a central role in the evolution of insulin resistance because it causes increased migration of macrophages into adipose tissue (and other tissues), leading to low-grade chronic inflammation and gradual loss of insulin sensitivity. Subjects treated with TRIOLEX at the highest dose showed a significant drop in MCP-1 in blood and IL-6 production by peripheral blood mononuclear cells, compared to placebo-treated subjects. This finding is consistent with what the Company believes is the anti-inflammatory mechanism of action of TRIOLEX.

Leading academic researchers have linked inflammation and type-2 diabetes, reporting that the chronic stimulation of the inflammatory kinases JNK and IKK can impair insulin signaling by inhibiting the biological function of insulin receptor substrate-1 (IRS-1), a protein that acts as a major mediator of insulin action in target cells. 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 the impairment of IRS-1 function ultimately causing inappropriate insulin signaling. Since this mechanism for improving insulin sensitivity does not occur through the PPAR-gamma pathway, TRIOLEX may avoid the side effects associated with the current glitazone class of insulin sensitizing agents, such as Avandia® and Actos®, 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.

"Advancing TRIOLEX into a Phase II clinical trial for type-2 diabetes is a significant achievement for Hollis-Eden," stated Richard B. Hollis, Chairman and Chief Executive Officer. "Results to date from our 28-day trial with TRIOLEX in obese insulin resistant subjects bode well for us as we initiate our clinical trial in patients with frank type-2 diabetes. We plan to accelerate enrollment in this multicenter clinical trial with the goal of having preliminary interim data in the fourth quarter of this year, and the trial completely enrolled by the end of the year. Since TRIOLEX targets inflammation as an underlying cause of type-2 diabetes, the compound, if successfully developed, holds the promise to become a first-in-class treatment option with competitive advantages over existing therapies in the marketplace. In addition, since we believe TRIOLEX is acting as a novel anti-inflammatory, the compound may have benefit in other diseases as well. Accordingly, in this Phase II study we will be evaluating the ability of the compound to affect a number of other markers associated with low-grade inflammation. We believe, and many scientists have reported, that chronic low-grade inflammation is at the root cause of type 2 diabetes, cardiovascular disease, ulcerative colitis, rheumatoid arthritis as well as many other diseases associated with aging. If this hypothesis is correct and TRIOLEX is successfully developed to treat just one inflammatory condition, the clinical applications and eventual market potential for this compound could be substantial."

Type 2 Diabetes Market

There are approximately 22 million Americans and over 170 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 and Actos 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 entering clinical trials in rheumatoid arthritis, and APOPTONE™ (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 http://www.holliseden.com.

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 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.