PHILADELPHIA, Oct. 30, 2014 (GLOBE NEWSWIRE) -- Hemispherx Biopharma, Inc. (NYSE MKT:HEB) (the "Company" or "Hemispherx"), reported today a new peer reviewed publication entitled, "The Quest for Effective Ebola Treatment; Ebola VP35 is an Evidence-Based Target for dsRNA Drugs" in the Nature Group's current issue of Emerging Microbes and Infections (October 29, 2014). This publication was authored by affiliates of Hemispherx. The publication provides an illustration of the crystallographic coordinates of a truncated VP35 complex with dsRNA.
Death from Ebola virus (EBOV) infection is associated with markedly impaired coagulation and innate immunity cascades, increased production of pro-inflammatory cytokines, profound immune suppression resulting in peripheral T lymphocyte apoptosis, and a lack of adaptive immunity (Fields Virology 923-956, 2013). By contrast, survivors of infection by EBOV develop an effective immune response with the production of EBOV neutralizing antibodies. Early events in EBOV infection influence the patient's ability to develop an effective immune response. The success of EBOV replication is dependent on viral inhibition of initial innate immune responses to infection. Disarming innate immune responses is a common mechanism employed by highly pathogenic human viruses, including those of the influenza and coronavirus families (Antiviral Res 100:615, 2013). EBOV is one of the more successful of the emerging highly pathogenic viruses in evasion of innate immune mechanisms.
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 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 sequence-independent dsRNA, 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 Res93:354, 2012) and molecular crystallographic analysis has demonstrated that binding is achieved by non-covalent bonding with the dsRNA phosphodiester backbone and thus shielding of viral produced dsRNA from host antiviral signaling pathways (Nat Struct Mol Biol 17:165, 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 evidence-based target for antiviral interruption of EBOV, potentially ameliorating the pathogenesis of EVD.
Therapeutic dsRNA May 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 allowing activation of innate immune responses, and/or serve 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 is non-sequence dependent with the phosphodiester backbone freely available for VP35 binding. Since EBOV has been demonstrated to be mutating rapidly in this epidemic (Science 345:1369, 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.
A Secondary Efficacy Mechanism
In animal studies, Ampligen® was also efficacious by a second mechanism as an adjuvant for highly pathogenic avian influenza virus vaccines, and this drug is now being evaluated as an adjuvant in a variety of cancer vaccine trials. Epitope expansion has also been observed with Ampligen® applied intranasally in man (Vaccine 32(42):5490, 2014) and this property may also result in antibody levels to accelerate recovery from Ebola and evade mutational inhibitory properties.
Evidence Based Experimental Therapeutics
The use of experimental pharmaceuticals beyond phase I in FDA-sanctioned clinical trials helps ensure the availability of products with established safety profiles sufficient for open-label clinical testing and analysis of efficacy. The use of potential drugs already in clinical trials also helps ensure a reliable supply of clinical- grade drugs, which removes the ethical dilemma of patient selection for treatment (New England J Med 371:1066, 2014). In third world countries, with limited facilities for medical intervention, protecting the individual from exposure to Ebola containing bodily fluids may be achieved by heightening immunity on the majority of mucosal surfaces, as by the potential use of intranasal sprays of Ampligen®. Hemispherx is working with regulatory authorities 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 ).
About Alferon® N
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 or Alferon® LDO for Ebola viruses. Positive results against Ebola in vitro have been reported to the Company by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). Clinical trial data will be necessary to establish human efficacy of Alferon® N for Ebola virus.
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 human efficacy of Ampligen® for Ebola viruses.
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.
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 will take time, testing and substantial 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.
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.
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