Hollis-Eden Pharmaceuticals Presents Data Demonstrating Discovery of an Endogenous Hormone Potentially Central to Glucose Metabolism
These findings represent years of scientific discoveries, research and development by Hollis-Eden scientists in a pharmaceutical development program targeting metabolism. Studies in rats fed with a diet containing the parent hormone of HE3286 showed a reduction in the expression levels of certain genes encoding key enzymes involved in glucose and cortisol metabolism (e.g. PEPCK or 11beta-HSD1), an effect which should lessen the severity or impact of type 2 diabetes or insulin resistance. This indicates that this hormone is potentially central to glucose metabolism. Through the application of medicinal chemistry, the Company has extended the innate properties of that hormone into a more pharmaceutically suitable compound, HE3286, for the treatment of type 2 diabetes. Data presented include:
-- When administered orally to genetically obese mice prone to diabetes (db/db model), HE3286, after 10 days, significantly (p less than 0.02) suppressed the progression of hyperglycemia typically observed in these animals.
-- In an animal model of diet-induced insulin resistance produced by feeding mice with a fat-enriched diet, HE3286 significantly (p less than 0.01) improved glucose handling in an oral glucose tolerance test (OGTT) when compared to the control group and at the end of the study was superior (p less than 0.003) to the active control (rosiglitazone). In addition, HE3286 demonstrated a statistically significant (p less than 0.006) reduction in fasting glucose values when compared to controls at days 14 and 29 of the study, and the activity was similar to the active control (rosiglitazone) (p less than 0.05).
-- Additional evidence of improvement in glucose disposal by HE3286 comes from a hyperinsulinemic/euglycemic clamp study, widely acknowledged as the "gold standard" model to measure insulin sensitivity in vivo. In this study, administration of HE3286 to diabetic db/db mice for 14 days markedly increased the glucose infusion rate (GIR) required to maintain normal levels of blood glucose following an intravenous infusion of a high dose of insulin. The GIR is a key parameter used to determine the degree of insulin sensitivity in vivo, and its increase following treatment with HE3286 indicates that this compound acts physiologically as an insulin sensitizer in the diabetic state.
In parallel experiments designed to understand the possible mechanism of action of HE3286 to produce these metabolic effects, it was found that HE3286 regulates the pro-inflammatory NF-kappaB pathway in cultured mouse macrophages or human monocytes. The Company believes this is an important finding because over the last several years reports in the scientific literature suggest that chronic activation of inflammatory pathways such as NF-kappaB can also lead to insulin resistance and may play a role in the progression towards type 2 diabetes. The January 2007 issue of Diabetologia includes a new study regarding this pathway, which concludes that moderate inhibition of NF-kappaB improves glucose tolerance in animals and is a suitable therapeutic target for the treatment of type 2 diabetes.
Diabetes is a disease in which the body does not produce adequate quantities of, or properly use, insulin. Insulin is a hormone needed to carry glucose from the blood into cells, where it is converted to energy the cells need to perform properly. When insulin is not present in sufficient quantity or does not function correctly, the result is high levels of glucose in the blood. Over time, chronically elevated blood glucose can lead to a host of severe medical conditions.
There are several pharmaceutical approaches to treating type 2 diabetes. These include drugs designed to increase insulin production by the pancreas, drugs designed to reduce glucose production by the liver and drugs designed to increase the body's sensitivity to insulin, thereby improving glucose disposal from the bloodstream. Frequently clinicians will combine drugs from these different approaches in an effort to achieve appropriate glucose control.
The only currently approved anti-diabetic agents that are known to act as insulin sensitizers are the glitazone class of drugs, which collectively represent 48% of the annual sales in the $12 billion per year global oral anti-diabetic market. Glitazones appear to act primarily through the activation of nuclear hormone receptor, PPARgamma. While these agents can lower blood glucose, they have been associated with undesirable side effects such as weight gain.. In contrast, preclinical studies with HE3286 indicate that it does not act on the PPARgamma receptor and does not have the undesirable effect of weight gain seen with the glitazone class. Therefore, these preclinical studies suggest that HE3286 may represent the first of a new class of insulin sensitizing agents that can be used in controlling type 2 diabetes.
The need for new classes of agents such as HE3286 to treat type 2 diabetes is clear. There are approximately 20 million Americans with type 2 diabetes and over 160 million type 2 diabetics worldwide. These figures are increasing rapidly as a result of the aging population and the rising incidence of obesity, which is a common risk factor for the disease. Clinical data indicates only 36% of type 2 diabetics are currently able to achieve the American Diabetes Association maximum recommended HbA1c glucose level of 7.0. Large clinical studies have shown that failure to achieve these glucose targets can progressively lead to severe health consequences including neuropathy, blindness, amputation, heart attack, stroke and death.
"The results presented at this meeting build on an impressive body of data indicating HE3286 may bring type 2 diabetes back under hormonal control, thereby playing an important role in treating and managing type 2 diabetes," stated Jaime Flores-Riveros, Ph.D., Vice President, Endocrinology and Metabolism at Hollis-Eden Pharmaceuticals, Inc. "Given the dire consequences associated with lack of glucose control and the limited benefit of existing agents, clinicians we have spoken with are eager to begin testing HE3286. The combination of a potentially new mechanism of action and an attractive safety profile makes this compound potentially useful either alone or in combination with existing alternatives."
HE3286 is a synthetic derivative of an endogenous hormone that produces numerous physiological actions. These include effects on immune function, bone metabolism, the cardiovascular system and metabolic function. The basic features of the biosynthesis, biotransformation and disposition of this parent hormone have only recently been described in the scientific literature. The recent body of knowledge developed around this parent hormone provides a rich opportunity for further understanding that could lead to the introduction of a new class of pharmaceutical candidates, such as HE3286. As with other hormones in the androstene series, their pharmacological actions reflect extensions of their physiological activities. To date, observations from preclinical studies suggest potential therapeutic benefit from HE3286 in rheumatoid arthritis, inflammatory diseases of the lung and type 2 diabetes.
HE3286 has demonstrated good oral bioavailability in primates. In addition, preliminary results of GLP toxicology studies indicate the compound is well tolerated. Based on these findings, Hollis-Eden plans to file an Investigational New Drug application (IND) for HE3286 for the treatment of type 2 diabetes with the U.S. Food & Drug Administration (FDA) in the first quarter of 2007.
"It is well documented in the scientific literature that hormones play a key role in metabolism, especially as we age," stated Richard Hollis, Chairman and CEO of Hollis-Eden Pharmaceuticals, Inc. "The challenge has always been in discovering the key hormones involved in the regulation of these metabolic pathways and then designing safe and effective stable synthetic hormones that can be used as therapies to regulate those pathways to treat a disease or condition. This data with HE3286 is exciting because it demonstrates that we have made those discoveries leading to a potential breakthrough treatment with a new class of hormones to control glucose metabolism in type 2 diabetes. Having garnered such positive results in a variety of the traditional preclinical models for type 2 diabetes, combined with a good safety profile of the compound to date, gives us confidence as we enter HE3286 into clinical trials this year.
"Furthermore, we have discovered and designed several other drug candidates from our hormonal signaling technology platform that we believe are analogs of hormones that are fundamental to our human hormonal network necessary to maintain optimal health. We are rapidly closing in on defining their natural signaling pathways and their chemical and biological functions in maintaining human health. Our class of steroid hormones has been associated, since their first discovery in the body back in the 1930s, with several diseases related to hormonal imbalances and the aging process itself. However, scientists never fully understood their role in the body or their metabolic profiles. We believe, as the world leaders in developing these adrenal steroids, that our discoveries will for the first time allow these compounds to be converted into pharmaceuticals. These products would represent a renaissance in the use of steroid hormones as biochemical signaling molecules to regulate inflammation, immunity and cellular function in the body lost to disease and in the aging process itself."
Hollis-Eden Pharmaceuticals, Inc. is developing a proprietary new class of small molecule compounds that are metabolites or synthetic analogs of adrenal steroid hormones. These compounds, 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 lead product candidate, NEUMUNE(R) (HE2100), is entering late-stage development for the treatment of Acute Radiation Syndrome (ARS), a life-threatening condition resulting from exposure to high levels of radiation following a nuclear or radiological incident, and is being explored for use in combating healthcare-associated infections. Hollis-Eden also is profiling optimized second-generation compounds for potential clinical development in a broad spectrum of therapeutic categories including hematology, metabolic disorders, autoimmune disorders, pulmonary diseases, oncology and infectious diseases. Certain patents related to NEUMUNE are licensed to Hollis-Eden by Roger Loria Ph.D., a professor of microbiology and immunology at Virginia Commonwealth University. For more information on Hollis-Eden, visit the Company's website at 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. 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 ability to complete preclinical and clinical trials successfully and within specified timelines, if at all; the ability to obtain regulatory approval for NEUMUNE under the U.S. Food and Drug Administration Animal Efficacy Rule, even if shown to be effective in preclinical studies; the ability to receive any stockpiling orders for NEUMUNE from the U.S. federal, state and foreign governments or agencies, even if approved by regulatory authorities; the Company's future capital needs; the Company's ability to obtain additional funding; the ability of the Company to protect its intellectual property rights and to not infringe the intellectual property rights of others; the development of competitive products by other companies; 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. 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.
Dan Burgess, Chief Operating Officer and CFO
Scott Rieger, Director, Corporate Communications
Posted: January 2007