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Ampligen(R) Blocks Critical Ebola Viral Disease (EVD) Protein Which is Linked to High Mortality in Man

PHILADELPHIA, Nov. 17, 2014 (GLOBE NEWSWIRE) -- Hemispherx Biopharma, Inc. (NYSE MKT:HEB) (the "Company" or "Hemispherx"), announced today that it had received a new research report from Professor Tramontano in the Department of Life and Environmental Sciences, University of Cagliari, Italy. The biochemical study demonstrates Ampligen® can successfully bind to the lethal EVD viral protein designated VP35. VP35 protein normally inactivates a patient's immune/antiviral system by binding to viral dsRNA thereby sequestering a critical antiviral/immune activator of the body which leads to high morbidity and death rates. Ampligen® competes with viral dsRNA for VP35 binding and is consistent with recent studies at USAMRIID demonstrating that Ampligen® inhibits Ebola virus infectivity in vitro. The inhibitory concentration of 4 µg/ ml at 50% viral protection is similar to the VP35 binding result showing Ampligen® binds to VP35 and displaces the viral dsRNA with a 50% inhibition at 1.1 µg/ml. These experiments establish the scientific foundation for Ampligen®, an experimental drug, as a potential preventive and early onset therapeutic for Ebola.

The Cagliari University laboratory director, Professor E. Tramontano, is a recognized expert on the dsRNA interaction with Zaire Ebola virus (EBOV) VP35 (Antiviral Research 93:354-363, 2012). VP35 is a multifunctional protein that is indispensable for EBOV replication and, among the VP35 functions, dsRNA binding is most important in the context of EBOV pathogenesis. For example, mutations in its dsRNA binding domain cause greatly attenuated virus growth rates and loss of Ebola virulence (J Virology 84:3004-3015, 2010).

It is believed that one potentially suitable EBOV medical countermeasure may be to impair viral replication in such a manner to allow innate and adaptive immune responses to clear the Ebola infection. This strategy could thus be advanced by targeting the VP35 dsRNA interaction by use of Ampligen®, an experimental therapeutic, which has already been used in over 1,000 non-Ebola patients and has been generally well-tolerated clinically on repeat dosing schedules as would likely be required in life-threatening clinical situations.

The experimental outcome achieved by the Cagliari University is consistent with recent predictions published in the Nature group Emerging Microbes and Infections (3, e77; doi:10.1038/emi.2014.77; published online 29 October 2014) by affiliates of Hemispherx.

Another recent US government research report observed that the inhibiting concentration (EC50) of Ampligen® for Ebola was very low relative to the Ampligen® serum levels achievable in humans (Hemispherx Biopharma and United States Army Medical Research Institute of Infectious Diseases (USAMRIID) Collaborate on Alferon® and Ampligen® Against the Ebola Virus… Initial Ebola Studies of Alferon® and Ampligen® at USAMRIID Show Protective Activity of Both Compounds at Low Concentrations http://www.hemispherx.net/content/investor/default.asp?goto=805). Together, the two recent reports set the stage for accelerated clinical development of Ampligen® for prevention and treatment of EVD.

The Cagliari University's in vitro study was supported by a research grant to the University by Hemispherx Biopharma. The University designed, executed and analyzed the experimentation independent of any Hemispherx suggestions regarding the conduct of experiments.

Critical Role of VP35 in High Death Rates

VP35 is a multifunctional major virulence protein that is indispensable for EBOV replication. Double-stranded RNA (dsRNA) is a necessary component of Ebola viral replication, which initiates systemic signaling cascades that normally activate interferon (IFN) regulatory factors leading to the production of IFN-α/β (type I IFNs). VP35 inhibition of dsRNA effectively disarms essential components of the innate immune response. VP35 binds to dsRNA in a sequence-independent manner, resulting in the suppression of multiple steps in the IFN signaling cascade, which otherwise would provide a broad antiviral state by activation of both the innate and adaptive arms of the immune response. Multiple investigators have demonstrated that VP35 binds dsRNA (Antiviral Res 93:354-363, 2012) and molecular crystallographic analysis has demonstrated that binding in part is achieved by non-covalent bonding with the dsRNA phosphodiester backbone and thus shielding the viral produced dsRNA from host antiviral signaling pathways (Nat Struct Mol Biol 17:165-173, 2010). The inavailability of viral produced dsRNA during replication results in an increased virus load and its consequences. Thus, the VP35 dsRNA interaction is an ideal target for antiviral interruption of EBOV, potentially ameliorating the pathogenesis of EVD.

Therapeutic dsRNA May Be Able to Overcome the Lethal dsRNA Sequestration Action of VP35 and Reverse the "dsRNA Deficiency" Associated with Ebola

Various forms of dsRNA have been studied as inducers of type I IFNs. Although the original dsRNA studied for efficacy in humans, poly I:poly C, was found to induce serious adverse events in humans that limited pharmaceutical development, several derivatives have survived the rigors of animal and clinical testing. Poly I:Poly C12U (rintatolimod, Ampligen®) was designed as an IFN inducer with a markedly reduced incidence of adverse events compared to the parent compound poly I:poly C and has demonstrated antiviral activity against a wide variety of DNA and RNA viruses in pre-clinical testing, including SARS (Severe Acute Respiratory Syndrome). Multiple mechanisms may be involved in the antiviral activity of rintatolimod in its predicted EBOV utility. These include direct induction of innate immunity as a TLR3 agonist, competition for VP35 binding with dsRNA (the conclusion of the Cagliari study reported above) allowing activation of innate immune responses, and/or serving as a required dsRNA cofactor for IFN induced enzymes that function in the innate immune cascades triggered by viral infections. In contrast to drugs under intensive development to help contain this global crisis, sequestration of dsRNA by VP35 is non-sequence dependent. Since EBOV has been demonstrated to be mutating rapidly in this epidemic (Science 345:1369-1372, 2014), anti-EBOLA agents that depend on sequence maintenance (vaccines, monoclonal antibodies, active site viral enzyme inhibitors) may be at risk following clinical development even with crisis activated reductions in regulatory requirements.

Evidence Based Experimental Therapeutics and Global Ethical Standards for Clinical Research

The use of experimental pharmaceuticals such as Alferon® N and Ampligen® developed well beyond phase I in FDA-sanctioned clinical trials and with established safety profiles, could be advanced quickly for open-label clinical testing and analysis of efficacy. The use of potential drugs already in clinical trials also helps ensure a reliable immediate supply of clinical- grade drugs, which removes the ethical dilemma of patient selection for treatment (New England J Med 371:1086-1089, 2014). In third world countries, with limited facilities for medical intervention, protecting the individual from exposure to Ebola containing bodily fluids may also be achieved by heightening immunity on the majority of mucosal surfaces, as by the potential use of intranasal sprays of Ampligen® or Alferon® N delivered orally (Alferon® LDO). Hemispherx is working with regulatory authorities in both the U.S. and West Africa to advance testing of these options and to potentially inhibit further escalation of this global crisis.

On September 29, 2014, Hemispherx announced a series of collaborations designed to determine the potential effectiveness of Alferon® N and Ampligen® as potential preventative and/or therapeutic treatments for Ebola related disorders (http://www.hemispherx.net/content/investor/default.asp?goto=800). Laboratory experiments do not necessarily indicate clinical benefit. Some of the bioterror research both past and present has been, and may in the future be, sponsored in part by contracts or grants from Hemispherx Biopharma to various independent research entities.

Hemispherx's Anti-Ebola Drug Platform

The two platform drugs of Hemispherx, Alferon® N and Ampligen®, have certain unique structural attributes and developmental histories which suggest potential incremental value with respect to inclusion in various Ebola therapeutic cocktails under development. First, both drugs have mechanisms of action which are multifaceted by working thru cellular "molecular cascades" (i.e. multiple mediators which protect cells from viral pathogenesis) rather than target viral targets whose specificity is vulnerable to mutational change. Cellular antiviral pathways of innate immunity are not subject to the mutational pressures of rapidly dividing viruses, which suggests that - even in the face of viral mutation - products activating innate immunity may continue to show biological activity. For example, work at the Japanese National Institutes of Health (Journal of Infectious Diseases 196:1313-1320,2007) indicated that Ampligen® affords wider cross-clade protection apparently through epitope expansion when added to existing influenza vaccines, an observation which has recently been extended clinically at the University of Alabama Clinical Research Center (Vaccine 32:5490-5495, 2014) http://dx.doi.org/10.1016/j.vaccine.2014.07.078). Secondly, both drugs are unusually effective in vitro against highly virulent viruses such as SARS, as noted by Singapore investigators (Emerging Infectious Disease 10(4):581-586, 2004) and independent US health researchers (Virology 395:210-222, 2009). Alferon® N has also demonstrated superior in vitro potency to that shown by recombinant alpha interferons (AIDS Research and Human Retroviruses 9:1115-1122, 1993) and ability to afford apparent clinical benefit in the presence of antibodies against recombinant interferons (Journal of Interferon and Cytokine Research 32:95-102, 2012). Ampligen® is also active in vitro against the Respiratory Syncytial Virus (RSV) which is organized in a pattern very similar to EBOV genome and both the viruses are "negative sense" RNA viruses.

Comparison with Medical Countermeasures Presuming Genetically Stable Pandemic Viruses as Drug Targets

The Wall Street Journal (WSJ) (September 20-21, 2014), proposed that based on new cases multiplying in Liberia, Guinea, Sierra Leone, Nigeria and Senegal, the Ebola epidemic "foreshadows threats that will strike the US". This prediction proved correct. As of November 5, 2014, some 4,818 people have died, according to the World Health Organization (WHO). The WSJ article summarizes certain US readiness improvements since the year 2004 passage of Project Bioshield, including a large basic and translational research portfolio built by NIH and the Pentagon. Moreover, the majority of the specialized countermeasures within the existing portfolio implicitly assume that the viral targets will be immutable or stationary in their molecular configurations, thus providing relatively stable viral targets for drug development. However, similar assumptions made several years ago on the cusp of global preparation for a possible influenza pandemic proved to be largely incorrect; the ongoing genomic surveillance of Ebola in the year 2014 outbreak appears to be following a similar course by demonstrating genetic mutation/instability which may make many "designer" drugs (monoclonal antibodies, short interfering RNAs) largely ineffective despite promising preclinical results to date.

About Alferon® N and Alferon® LDO

Alferon® N is the only natural source, multi-species alpha interferon currently approved for sale in the U.S. Alferon® N is approved in the U.S. only for the treatment of refractory or recurring external genital warts caused by human papilloma virus in patients 18 years of age or older.

Clinical trial data will be necessary to establish the human efficacy of Alferon® N for EVD. Alferon® LDO is an experimental low dose form of Alferon® which can be delivered orally; Alferon® LDO was recently shown to be able to prevent viral induced lung pathology in primates exposed to pandemic influenza H5N1 (Antiviral Research 110:175–180, 2014).

About Ampligen®

Ampligen®, an experimental therapeutic, is a new class of specifically-configured ribonucleic acid (RNA) compounds targeted as potential treatment of diseases with immunologic defects and/or viral causation.

Ebola virus specifically inhibits the dsRNA within cells via a sequestration process. Such RNA would otherwise cause a robust antiviral response to be mounted. Ampligen® may be able to overcome this deficiency in host response. Clinical trial data will be necessary to establish the human efficacy of Ampligen® for Ebola virus.

About USAMRIID

Since 1969, USAMRIID has served as the Department of Defense's (DoD) lead laboratory for medical biological defense research. While its core mission is to protect the warfighter from biological threats, it also investigates disease outbreaks and threats to public health. Research conducted at USAMRIID leads to medical solutions—therapeutics, vaccines, diagnostics, and information—that benefit both military personnel and civilians. USAMRIID is a subordinate laboratory of the U.S. Army Medical Research and Materiel Command.

About The University of Cagliari and its history

The University of Cagliari is a public state University and has about 31,102 enrolled students, over 1,000 teaching staff and more than 1,000 professionals at the technical-administrative staff.

At the moment the University of Cagliari is one of the largest enterprises in the Region of Sardinia, thanks to its international policy, studies and its numerous agreements with prestigious universities in Europe and around the world.

The Studium Generalis Kalaritanum was founded in 1606 along the lines of the old Spanish Universities of Salamanca, Valladolid and Lérida. It originally offered Law, Latin, Greek and Hebrew Literature, the Liberal Arts, Medicine, Surgery, Philosophy and Science. The 19th and 20th centuries saw more and more emphasis placed on research activities, with the achievement of important, internationally acclaimed results, especially in the fields of Medicine, Physics, Chemistry, Biology and Archaeology. The largest campus is situated in Monserrato, on an area of 73 hectares. It hosts the science faculties, many departments with their respective faculties, and one of the University general hospitals, appropriately integrated with other medical institutions. The Department of Life and Environmental Science groups together more than 80 professors of the Biological and Chemical areas. In particular, the Biomedical Section, where the Laboratory of Prof. Tramontano is located, is composed by professors of Biochemistry and Microbiology.

About Hemispherx Biopharma

Hemispherx Biopharma, Inc. is an advanced specialty pharmaceutical company engaged in the manufacture and clinical development of new drug entities for treatment of seriously debilitating disorders. Hemispherx's flagship products include Alferon N Injection® and the experimental therapeutics Ampligen® and Alferon® LDO. Ampligen® is an experimental RNA nucleic acid being developed for globally important debilitating diseases and disorders of the immune system, including Chronic Fatigue Syndrome. Hemispherx's platform technology includes components for potential treatment of various severely debilitating and life threatening diseases. Because both Ampligen® and Alferon® LDO are experimental in nature, they are not designated safe and effective by a regulatory authority for general use and are legally available only through clinical trials. Hemispherx has patents comprising its core intellectual property estate and a fully commercialized product (Alferon N Injection®), approved for sale in the U.S. and Argentina. The Company's Alferon® N approval in Argentina includes the use of Alferon N Injection® (under the brand name "Naturaferon") for use in any patients who fail, or become intolerant to recombinant interferon, including patients with chronic active hepatitis C infection. The Company wholly owns and exclusively operates a GMP certified manufacturing facility in the United States for commercial products. For more information please visit www.hemispherx.net.

Disclosure Notice

Information contained in this news release, other than historical information, should be considered forward-looking and is subject to various risk factors and uncertainties. For instance, the strategies and operations of Hemispherx involve risk of competition, changing market conditions, changes in laws and regulations affecting these industries and numerous other factors discussed in this release and in the Company's filings with the Securities and Exchange Commission. The final results of these efforts and/or any other activities could vary materially from Hemispherx's expectations. In vitro experiments are not necessarily predictive of clinical outcome and no representations are made that any products described in this release will be ultimately determined safe and effective in the prevention and/or treatment of the Ebola virus. Moreover, it would take time, testing and funds to obtain approval of any such product and there are no assurances that a commercial approval for treatment of the Ebola virus can be obtained.

Forward-Looking Statements

To the extent that statements in this press release are not strictly historical, all such statements are forward-looking, and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as "potential," "potentially," "possible," and similar expressions are intended to identify forward-looking statements. The inclusion of forward-looking statements should not be regarded as a representation by Hemispherx that any of its plans will be achieved. These forward-looking statements are neither promises nor guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond Hemispherx's control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. Examples of such risks and uncertainties include those set forth in the Disclosure Notice, above, as well as the risks described in Hemispherx's filings with the Securities and Exchange Commission, including the most recent reports on Forms 10-K, 10-Q and 8-K. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Hemispherx undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise revise or update this release to reflect events or circumstances after the date hereof.

CONTACT: Company/Investor Contact Charles Jones CJones & Associates Public Relations Office: 888-557-6480 Cell: 305-987-7418 Email: cjones@cjonespr.comSource:Hemispherx Biopharma, Inc.