PRNewswire - Monday December 18, 2000

Background

HE2000 is the lead investigational compound in a new class of immune regulating hormones and hormone analogs being developed by Hollis-Eden. Rather than acting as antivirals, these compounds appear from preclinical models to correct immune dysregulation that has been associated with pathology in many infectious diseases, certain types of cancer and a variety of autoimmune conditions. In the setting of HIV, Hollis-Eden's goal for HE2000 is to keep patients from progressing to AIDS or opportunistic infections by correcting a dysregulation in cell-mediated immunity, as opposed to the traditional approach of developing antiretrovirals which act directly on the virus.

Researchers have described a loss in cell-mediated immunity as potentially a key determinant in disease progression from HIV to AIDS. Those patients who are able to continue to mount a strong cell-mediated response tend to become long-term non-progressors. Cell-mediated immunity (Th1) is the portion of the immune system, which fights intracellular pathogens such as viruses, whereas humoral immunity (Th2) is the portion of the immune system generally responsible for attacking extracellular pathogens such as bacteria. As HIV progresses to AIDS, the immune system becomes increasingly dysregulated in favor of Th2 immunity rather than the desired Th1 immunity. A number of papers in the medical literature indicate that hormones that regulate immunity are heavily involved in controlling the magnitude of the immune response and balancing the Th1/ Th2 ratio. Investigators have previously reported that immune regulating hormones are depleted as HIV progresses to AIDS. This suggests that a hormone replacement therapeutic approach may prove valuable in arresting disease progression.

Clinical Findings

The Phase I/II clinical trial in South Africa is a dose escalation study evaluating the effect of HE2000 in three dosing groups (50 mg, 100 mg or 200 mg). Patients initially receive a single intramuscular injection followed one to two weeks later by a daily injection for five consecutive days. After a four to six week observation period, patients demonstrating benefit are allowed to receive additional courses of therapy (5 consecutive daily injections followed by a 6 week observation period). The study is now fully enrolled and the interim data being presented includes results through three treatment courses over a five-month period. At the discretion of the investigator, patients may continue receiving treatment beyond this period and some patients have now been on study for over 18 months.

The primary endpoint of the study is safety, and to date HE2000 has been generally well tolerated, with injection site irritation in 3 patients being the only drug related serious adverse event reported in this study. Other infrequent adverse events judged by the investigator as mild or moderate and possibly or probably related to HE2000 treatment included pain at the injection site, fatigue, dizziness, nausea, headache and anxiety. Many of these types of events are also seen in untreated patients infected with HIV. In addition to safety information, an extensive panel of key immune system markers is being analyzed.

As previously reported, significant increases relative to baseline were seen in a wide variety of immune cell subsets associated with cell-mediated immunity at different points during the study. The data presented at this meeting highlighted a number of these cell subsets that were statistically significantly elevated relative to baseline in an area-under-the-curve (AUC) analysis for all patients for the five-month treatment period. Included were statistically significant increases in total dendritic cells (p=0.001), CD11c+ dendritic cells (p=0.012), CD123+ dendritic cells (p=0.044) and activated cytotoxic T-cells (p=0.046). These long-lasting increases were seen despite the fact that HE2000 was only administered in intermittent treatment courses.

Dendritic cells are specialized antigen processing and presenting cells that are critical in regulating immune responses. The CD11c+ dendritic cell subset that was increased in this study is a primary driver in initiating adaptive cell-mediated immunity. The adaptive portion of cell-mediated immunity is important for controlling HIV replication and combating opportunistic infections to which the immune system has previously been exposed. A recent paper described the finding that the CD11c+ dendritic cell subset is dramatically depleted in HIV-infected patients and that this dysregulation persists even in patients on successful Highly Active Antiretroviral Therapy (HAART) with undetectable viral load.

It also has been reported recently in the medical literature that CD123+ dendritic cells can drive cell-mediated immunity. These cells are now believed to be a key source of stimulation of the innate portion of the cell- mediated immune system. This part of the immune system is particularly effective against pathogens, which are newly exposed to the immune system, including a variety of opportunistic infections seen in HIV/AIDS patients. In 1999 the CD123+ cell was identified as the immune system's primary source of the cytokine interferon alpha. It has also been reported in the literature that those patients with high levels of interferon alpha tend to remain clinically stable and avoid opportunistic infections irrespective of levels of the traditional markers of viral load and CD4.

Activated CD8 T-cells are part of the adaptive portion of Th1 immunity and are primed to recognize and destroy cells infected with a particular virus or opportunistic infection.

While not an antiviral, patients overall in South Africa receiving HE2000 as an intermittent monotherapy did not experience a progression in viral load during the five months on study and, as previously reported, a number of these patients experienced a significant transient drop in viral load that in some cases exceeded 1 log. Further improvements in viral load for a greater duration may be obtainable with improved formulation, dosing schedule and route of administration. Additional clinical studies are now being initiated in South Africa to test these possibilities. There was also a small decline in circulating CD4 and CD8 cells during the study, possibly reflecting increased cellular activation and trafficking of these cells to the tissues where they are needed to fight infection.

HE2000 also had a significant effect on the hematopoetic system in this study. Administration of HE2000 led to increases (versus baseline) in a number of cell types that were quite pronounced immediately after dosing. These increases were durable enough to be statistically significant in an area under the curve analysis during the entire five-month treatment period. Included in these cells types are neutrophils (p=0.025), basophils (p=0.003), monocytes (p=0.035) and platelets (p<0.001).

These findings are particularly interesting in light of recent preclinical studies (including a series of studies published in the current issue of the Annals of the New York Academy of Sciences) indicating that Hollis-Eden's second generation immune regulating hormones HE2100 and HE2200 provided a significant survival advantage in models of radiation-induced immunosuppression. The authors of these studies attribute the protection seen in these models to an increase in production of neutrophils and platelets stimulated by administration of these compounds. Thus, there may be a role for HE2000 and other immune regulating hormones in reversing radiation- and chemotherapy-induced immunosuppression in cancer patients.

"These results imply that HE2000 may be able to significantly reconstitute the immune system to overcome the immunosuppression of HIV-infected patients in a way that is useful in delaying or preventing opportunistic infections and cancers," stated Dr. Merigan. "Compounds with a new mechanism of action are desperately needed in the treatment of HIV and I am eager to see the results of further clinical trials that will assess the clinical benefits of these findings."

Hollis-Eden is now conducting a Phase II study in late-stage HIV patients in South Africa to test the ability of HE2000 to delay or prevent opportunistic infections. Phase II studies are also in the process of being initiated with the compound in the treatment of malaria, and additional studies are planned in other conditions of immune dysregulation including Hepatitis B and Hepatitis C.

"We are very excited about the continuing progress we are making in developing HE2000 and other compounds in this series," stated Richard Hollis, Chairman and CEO of Hollis-Eden. "These results build on an already impressive body of preclinical data and medical literature indicating that this class of compounds has the potential to play a very important role in medicine. Given that HE2000 appears to date to be generally well tolerated, is unlikely to produce resistance and is cost-effective to manufacture and administer, we believe the compound has the potential to be a global therapeutic that is useful in the treatment of a number of infectious diseases and immune system disorders."

Hollis-Eden Pharmaceuticals, Inc., a development-stage pharmaceutical company based in San Diego, California, is engaged in the development of a class of adrenal hormones and hormone analogs for a broad array of potential indications.

The Company's initial development efforts with this class of compounds are in the area of infectious diseases and immune system disorders. For more information on Hollis-Eden visit the Company's website at http://www.holliseden.com.

Statements made in this press release may constitute forward-looking statements and are subject to numerous risks and uncertainties, including the failure to successfully develop or commercialize the Company's products, the Company's future capital needs, the Company's ability to obtain additional funding and required regulatory approvals, 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. The actual results and timing of these results may differ materially from those contained in this press release.

SOURCE: Hollis-Eden Pharmaceuticals, Inc.

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