Hollis-Eden Pharmaceuticals Inc. Reports Positive Preliminary Data from Ongoing Phase I/II Clinical Trial with TRIOLEX(TM) in Obese Insulin Resistant Subjects
“These preliminary data from the proof of concept clinical trial with TRIOLEX are extremely encouraging,” stated Dr. Flores-Riveros. “The clamp method of analysis is the gold standard for determining if an investigational compound is acting to improve insulin sensitivity. We are very pleased to see positive preliminary data from this clinical trial even at some of our lowest doses tested and with only 28 days of dosing. Furthermore, to see a drop in the inflammatory mediators from the peripheral blood mononuclear cells is exciting because this population contains the subset of cells associated with fatty acid induced inflammation that leads to insulin resistance.”
Overview of Data Presented
The double-blind placebo controlled Phase I/II clinical trial is designed to study the safety, tolerability, pharmacokinetics and potential activity of TRIOLEX at three dosing levels orally administered (5mg once daily, 5mg twice daily and 10mg twice daily) in obese insulin resistant subjects. Dr. Flores-Riveros presented data on the initial 19 subjects who have completed the study, 7 of whom were evaluated for insulin sensitivity by the “clamp” method. In addition, 15 subjects were evaluated for changes in inflammatory mediators. To date, the Company reported no serious adverse events at any of the dosing levels tested. In addition, when comparing the mean value of changes in fasting glucose levels and insulin sensitivity under clamp conditions, TRIOLEX-treated subjects exhibited both a reduction in fasting hyperglycemia and improved insulin sensitivity, as compared to placebo-treated subjects. Moreover, consistent with the apparent anti-inflammatory mechanism of action of TRIOLEX, subjects treated with the compound showed a drop in the inflammatory cytokine production of TNF-alpha, IL-6, IL-1beta and MCP-1 measured in LPS-stimulated peripheral blood mononuclear cells, as compared to placebo-treated subjects.
The Company plans to present additional data from this on-going Phase I/II clinical trial in a corporate symposium at the 68th American Diabetes Association annual meeting being held June 6 – 10, 2008 in San Francisco California. Based on the positive preliminary data reported today, the Company plans to commence a Phase II, 90-day clinical trial in patients with type 2 diabetes in the second quarter of 2008. The clinical endpoint for this Phase II study will be changes in hemoglobin A1c (Hb-A1c) as well as key biomarkers of insulin sensitivity and glucose disposal in these patients.
Dr. Flores continued, “We are on track to completing our enrollment with the remaining dosing groups, which will be evaluated by changes in clamp measurements, and we look forward to presenting at our symposium during the ADA meeting in June a more comprehensive dataset on additional clinical trial subjects. These data also bode well for our upcoming 90-day Phase II study, which will be evaluating the effect of TRIOLEX on HbA1c as its primary endpoint. It is well understood in this industry that improving insulin sensitivity in a clamp study is a good indicator of having a positive effect at lowering HbA1c.”
Richard Hollis, Chairman and CEO of Hollis-Eden added, “We are extremely gratified to see positive preliminary data of both safety and activity with TRIOLEX from our on-going 28 day clinical study. We look forward to reporting on a larger number of subjects treated from this clinical trial at the ADA meeting in June. We believe that TRIOLEX may represent a new and potentially safer approach to improving insulin sensitivity in patients with type 2 diabetes. The fact that TRIOLEX is an analog of a natural occurring hormone whose role in the body we believe is to restore immunological and metabolic homeostasis by regulating unproductive inflammation offers hope for our drug candidate to become a new first-in-class insulin sensitizer that may avoid the side effects of current insulin sensitizers. Moreover, this preliminary data indicating TRIOLEX is down regulating key inflammatory mediators in these subjects is very exciting given our clinical development programs for TRIOLEX in diseases of inflammation such as ulcerative colitis and rheumatoid arthritis.”
Possible Mechanism of Action for TRIOLEX in Type 2 Diabetes
TRIOLEX is an analog of a natural occurring hormone found in the body that has been associated with the regulation of unproductive inflammation and glucose metabolism. 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 TLR-4 receptor. TLR-4 is a receptor expressed in 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 TLR-4 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. Stimulation of the inflammatory kinases JNK, p38 and IKK can also impair insulin signaling by inhibiting the biological function of IRS-1, a protein that acts as a major mediator of insulin action in target cells. This inflammatory pathway that leads to insulin resistance is well characterized in the scientific literature (“TLR4 Links Immunity and Fatty Acid-Induced Insulin Resistance,” The Journal of Clinical Investigation, Volume 116, Number 11, pp 3015-25). 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 TNF-alpha, IL-6, IL-1beta and MCP-1. In experiments with macrophages in vitro, TRIOLEX appears to act upstream of NF-kappaB, attenuating the response of IKK, JNK and p38 to endotoxin (LPS) or fatty acid stimulation.
TRIOLEX also appears to act independently of the PPAR-gamma pathway and thereby may avoid the side effects associated with the current glitazone class of insulin sensitizing agents, such as Avandia® and Actos®, which work through the PPAR-gamma pathway. Side effects reported to date with the glitazone class of drugs include weight gain, edema and increased cardiovascular events. Experiments in vitro have shown no evidence that TRIOLEX directly binds and/or activates (transactivates) the PPAR-gamma receptor. Unlike the glitazones, TRIOLEX does not cause body weight gain when administered to mice or rats. These and other observations are consistent with the notion that TRIOLEX works through a different pathway than the PPAR-gamma receptor. The Company believes that TRIOLEX is a pharmaceutically optimized version of one of the body’s natural occurring ligands whose key function is to restore immunological and metabolic homeostasis.
Type 2 Diabetes Market
There are approximately 20 million Americans and over 190 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 $11B annually. Of these insulin sensitizers, Avandia and Actos represent the largest class of oral anti-diabetic agents, currently garnering over $5B in worldwide sales annually.
Conference Call: Hollis-Eden will conduct a conference call and live webcast on March 19, 2008 at 2:00 p.m. Eastern (11:00 a.m. Pacific) to update its drug development programs in the areas of metabolic disorders, inflammatory conditions and cancer and to discuss fourth quarter financial results. The conference call can be accessed by dialing 866-383-8008 (domestic) or 617-597-5341 (international) and requesting the Hollis-Eden conference call. A live webcast of the conference call will be available under “Event Calendar” on the Investors section of Hollis-Eden’s website at www.holliseden.com. The webcast will be archived at the Company’s website for 30 days, and a replay of the call will be available by phone for 24 hours beginning approximately one hour after the call is completed, and can be accessed at 888-286-8010 (domestic) or 617-801-6888 (international), passcode 73945303.
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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, ulcerative colitis and being prepared for 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 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 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 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.
Contact: Hollis-Eden Pharmaceuticals, Inc. Scott Rieger, Director, Corporate Communications 858-587-9333
Source: Hollis-Eden Pharmaceuticals, Inc.