Hollis-Eden Pharmaceuticals Announces Positive Results in Models of Radiation and Chemotherapy-Induced Neutropenia with Investigational Immune Regulating Hormones.

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SAN DIEGO--(BUSINESS WIRE)--Dec. 8, 2003

Results Presented at American Society of Hematology Meeting

Hollis-Eden Pharmaceuticals, Inc. (NASDAQ: HEPH) today announced results from an oral presentation given at the American Society of Hematology (ASH) meeting demonstrating positive results with investigational immune regulating hormones (IRHs) in models of radiation and chemotherapy-induced neutropenia. These results included a second study in non-human primates showing beneficial effects with HE2100 (NEUMUNE(TM)) in a model of radiation injury, as well as positive results from separate studies in non-human primates with both NEUMUNE and a new IRH in carboplatin-induced neutropenia. Neutropenia, a significant loss of neutrophils (white blood cells) that are important in combating infection, is a primary toxicity of both radiation injury and of chemotherapy drugs like carboplatin that can be life threatening. In addition to these results, new data relating to the mechanism of action of NEUMUNE was also presented which showed that the compound acts directly on a number of important stem cell components. The ASH meeting is one of the premier meetings in the field of hematology and attracts an international audience of nearly 20,000 researchers each year. The meeting is taking place December 6-9, 2003 in San Diego, California.

RADIATION STUDY RESULTS

The Company has previously reported results from an initial pilot study in rhesus macaques showing that 8 days of dosing with a high dose of NEUMUNE could, on average, almost eliminate severe neutropenia (less than 500 neutrophils/uL) after exposure to 400 rads of whole body radiation and could significantly reduce the number of days of severe neutropenia in animals given a lower dose of NEUMUNE for 10 days. The results presented at the ASH meeting were from a second pilot study being conducted as part of a program to determine the optimum formulation, dose and dose schedule.

The focus of the current study was to test several different formulations of NEUMUNE versus a vehicle placebo. The new radiation results presented were from a total of 16 rhesus macaques that received 400 rads of whole body radiation and then two to four hours after exposure to radiation received 5 once-daily injections of either a vehicle placebo, a high dose of NEUMUNE, or one of 3 different formulations of a lower dose of NEUMUNE. In the placebo group, animals experienced an average of 12.5 days of severe (grade 4) neutropenia (less than 500/uL neutrophils) through the 36-day follow-up period. In contrast, those animals treated with NEUMUNE in the three lower dose groups experienced an average of 5-6 days of severe neutropenia (50-60% reduction), and in the high dose group, severe neutropenia was not observed in any animal at any time. The reduction in the number of days of severe neutropenia in each of the three lower dose groups and the high dose group were statistically significant (all p less than 0.03) compared with the placebo group.

As seen in previous studies, NEUMUNE also had an effect on preserving platelets in this experiment. While animals in the placebo group experienced on average of 3 days of grade 3 or 4 thrombocytopenia (less than 50,000/uL), those in the groups treated with lower doses of NEUMUNE experienced an average of only 1.3 to 2 days of thrombocytopenia (33-60% reduction) and those in the high dose group on average did not encounter grade 3 or 4 thrombocytopenia. NEUMUNE was generally well tolerated in this study, with injection site irritation and transient swelling being the only drug-related adverse events reported.

"These findings are very encouraging," stated Dr. Dwight Stickney, VP Medical Affairs for Hollis-Eden Pharmaceuticals, Inc. "Results from this follow-on study confirm results seen in the initial pilot study and show generally comparable or superior effects despite the fact that only 5 doses of NEUMUNE were given compared to 8-10 doses in the initial pilot study. We are moving aggressively to complete this dose optimization program to identify the schedule that maximizes the beneficial activity and minimizes the injection volume required."

Damage to the bone marrow is the primary cause of mortality and morbidity in the setting of acute radiation injury. Depletion of neutrophils can cause the body to become unable to respond to opportunistic infections, and the stress of such an event can lead to even further immune suppression. In addition, depletion of platelets can leave victims susceptible to severe bleeding episodes that can also be life threatening. Currently there are no approved drugs that can be practically stockpiled for treating millions of people for bone marrow damage after acute radiation injury.

Hollis-Eden is collaborating on the development of NEUMUNE with The Henry M. Jackson Foundation for the Advancement of Military Medicine and the Armed Forces Radiobiology Research Institute (AFRRI), an agency within the U.S. Department of Defense specializing in research on and development of countermeasures to radiation injury. NEUMUNE is being developed pursuant to a new rule implemented by the U.S. Food and Drug Administration (FDA) in 2002 for medical countermeasures to weapons of mass destruction. Under this new rule, in situations where it is deemed unethical to conduct efficacy studies in humans, a compound can be reviewed for approval on the basis of efficacy in the most relevant animal species and safety data in humans. The FDA has indicated to Hollis-Eden and AFRRI that NEUMUNE would be eligible for review under this new rule for the indication of protection from radiation injury.

"These results confirm our initial excitement about NEUMUNE as a compound to protect against radiation injury," stated Dr. Terry Pellmar, AFRRI's Scientific Director. "Given the urgent need for new drugs to add to our national stockpile in the area of radiation protection and the impressive results seen to date, we are committed to collaborating with Hollis-Eden in moving NEUMUNE forward in development."

CHEMOTHERAPY PROTECTION RESULTS

Hollis-Eden also presented data at the ASH meeting on recent findings with immune regulating hormones in a non-human primate model of chemotherapy-induced neutropenia. As with radiation injury, many chemotherapy agents can cause significant bone marrow toxicity that leads to depletion of neutrophils and platelets that can be life threatening. The Company has previously reported on the effect of NEUMUNE in a preclinical model of carboplatin-induced neutropenia which showed significant protection from neutropenia when NEUMUNE was given once daily for 10 days after administration of a therapeutically equivalent human dose of carboplatin. Carboplatin is a front-line chemotherapy agent used in the treatment of a number of cancer types including lung, breast and testicular cancer.

In the new data reported at the ASH meeting, a total of nine cynomolgus macaques were given carboplatin followed by once daily doses for five days of a vehicle placebo, NEUMUNE or a new IRH designed specifically for use in chemotherapy. In this study, placebo treated animals experienced an average of 5.3 days of grade 4 neutropenia (less than 500/uL), whereas those receiving NEUMUNE encountered an average of only 0.7 days of grade 4 neutropenia (88% reduction), and animals receiving the new IRH, which was given at only 1/20th the dose of NEUMUNE, did not experience any days of grade 4 neutropenia (p=0.03). As in radiation experiments and in previous studies in chemotherapy-induced bone marrow toxicity, immune regulating hormones also appeared to have a beneficial effect on platelets in this study.

"These results are important for several reasons," stated James Frincke, PhD, Chief Scientific Officer of Hollis-Eden. "First, they confirm our previous chemotherapy results and demonstrate that immune regulating hormones have significant potential in protecting the bone marrow from a number of different insults. We have now seen striking results repeated in two different species of monkey from two different types of damage to the bone marrow -- radiation injury and chemotherapy-induced myelosuppression. As with the studies in radiation injury, we have now also been able to show that these beneficial effects can be seen with just 5 days of dosing rather than the 8-10 days of dosing used in previous studies. Perhaps most importantly, we are also starting to see the fruits of the knowledge we are gaining about the structure-activity relationships of these compounds. This is well demonstrated by the fact that one of the first compounds to come out of our new chemistry program produced comparable or better results in this chemotherapy model to what has been seen with NEUMUNE, even when this new IRH was administered at a small fraction of the most active NEUMUNE dose. We are continuing to compare additional compounds in this series and are now actively discussing clinical trial protocols in chemotherapy-induced neutropenia with thought leaders in this area."

MECHANISM OF ACTION STUDIES

An important part of any potential future regulatory submission for approval of NEUMUNE will be a description of the mechanism of action by which NEUMUNE can protect the bone marrow. AFRRI has previously reported on the ability of NEUMUNE to improve the recovery of neutrophils, monocytes, natural killer cells and platelets after radiation injury. They have demonstrated that there are not only an increased number of neutrophils, but also that those neutrophils that remain are more effective at destroying pathogens (phagocytosis) than untreated cells. Similarly, monocytes in these studies also have an increased ability to kill foreign cells by increasing oxidative burst.

In the new data presented at ASH, Hollis-Eden described results from a series of different experiments designed to assess where in the hematopoietic cascade NEUMUNE was acting to provide protection. There are essentially two primary ways in which a drug could cause protective increases in neutrophil numbers after a bone marrow insult: increase the proliferative potential of residual bone marrow neutrophil precursor cells or increase the rate at which these progenitor cells are regenerated. In the results presented at ASH, NEUMUNE stimulated these two pathways in vitro using both murine and human bone marrow cells.

In addition, NEUMUNE appeared to act on very early upstream progenitor cells. This was associated with multilineage recovery as indicated by increased neutrophil precursors and megakaryocytes in the marrow, and stimulation of neutrophil and platelet generation in myelosuppressed macaques. Additionally, NEUMUNE stimulated mesenchymal progenitor cell colony development in vitro. These cells are believed to be involved in both bone marrow recovery as well as repair in other tissues. Lastly, NEUMUNE was able to increase progenitor cell self renewal in human bone marrow cells, indicating that NEUMUNE is not merely exhausting the existing bone marrow reserve in response to the initial insult, but is also speeding up the recovery of the marrow to be able to respond to future challenges.

"These results imply that immune regulating hormones like NEUMUNE are working through several pathways to protect the bone marrow from injury," stated Christopher Reading, PhD, Executive Vice President of Scientific Development for Hollis-Eden. "Existing drugs designed to treat bone marrow injury generally work late in the hematopoietic cascade, whereas NEUMUNE appears to be acting both early and late in the process, potentially providing broader protection for neutrophils as well as other important lineages such as platelets."

Commenting on the overall results, Richard Hollis, Chairman and CEO of Hollis-Eden stated, "These findings, taken together, show we are making excellent progress in advancing immune regulating hormones as a new class of small molecule hematopoietic growth factors that protect against bone marrow damage. In the radiation setting, results indicate that NEUMUNE may provide a safe, practical and very effective countermeasure to acute radiation injury, which is urgently needed to protect our population as a whole from a variety of potential threats. Working with our military, this program is on an accelerated development path and remains our top priority.

"Results from both our mechanistic studies as well as the studies in chemotherapy protection also indicate there is a significant opportunity in this area as well for immune regulating hormones. The results indicate that these compounds have the ability to provide dramatic protection of both neutrophils and platelets in this setting, with compounds that have an attractive safety profile to date and that are small molecules that are relatively cost-effective to manufacture. We are further encouraged by the fact that other therapeutic approaches to treating bone marrow damage that have shown efficacy in non-human primates have historically translated very well to results in humans. While the market for existing drugs in this area already exceeds $2.5 billion annually, our discussions with clinicians indicate that the high cost of existing therapies to protect neutrophils significantly limits their usage and that the need for a practical drug to protect platelets remains essentially unfilled."

Hollis-Eden Pharmaceuticals, Inc. is a development-stage pharmaceutical company based in San Diego, California, working to become the world leader in the development of a new class of investigational drugs known as Immune Regulating Hormones (IRHs). The goal of IRH therapy is to direct, through controlling gene expression, the production of key cytokines and enzymes that re-regulate immune and metabolic functions toward homeostasis, a profile that could be useful in a wide variety of diseases. The Company has a number of investigational IRHs under development, including HE2100, which the Company is co-developing with the U.S. military for use in protection from radiation injury, and HE2000, which is currently being studied in a number of infectious diseases. Hollis-Eden is also continuing to study HE2200 for improving vaccine responses in the elderly. For more information on Hollis-Eden, contact the Company's website at http://www.holliseden.com.

This press release contains forward-looking statements concerning the potential and prospects of the Company's drug discovery program and its drug candidates. Any statement describing a goal, expectation, intention or belief of the Company is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including the failure to successfully complete clinical trials, the Company's future capital needs, the Company's ability to obtain additional funding and required regulatory approvals, 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. The actual results may differ materially from those contained in this press release.