Hemispherx Biopharma expands Ebola research collaborations

Two experimental therapeutics may provide benefit despite recently observed Ebola viral mutations

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PHILADELPHIA—Hemispherx Biopharma, Inc., via its CEO Dr. William A. Carter, announced today a widened set of research collaborations designed to develop therapeutic cocktails against Ebola which may potentially overcome the emergence of drug resistance due to Ebola virus mutation.

In a lengthy explication of the current situation, Dr. Carter provided details and references concerning his company's collaborative efforts to develop effective therapies. The rapid acquisition of Ebola virus (EBOV) sequence variation has been recently demonstrated during genomic surveillance of the current Ebola virus disease (EVD). This observed genomic sequence variation suggests drugs that target specific viral non-variant protein sequences are at risk of mutation-mediated activity failure (Science (2014) 345:1369). This complicates significantly the development of EBOV inhibitors in the drug development pipeline, some of which have been highly effective in treating advanced EVD in non-human primates (Nature 2014, doc10.1038 (Nature137777), Epub Ahead of Print).
Similar concerns also apply to candidate Ebola vaccines. Historically, mutational drift has compromised the ability of candidate vaccines for other pandemic viruses, which undergo mutational change, as in the case of U.S. Health and Human Services-sponsored pandemic influenza vaccines for H5N1 influenza. Vaccines developed against Vietnamese strains were ineffective against H5N1 influenza strains with differing genomic sequences in neighboring geographic areas, such as Hong Kong and China. The current Ebola crisis situation in West Africa may be analogous (New England Journal of Medicine August 20, 2014 Epub Ahead of Print) in that EVD arose from sporadic self-limited clusters of EVD in Central Africa to epidemic status with evolving genomic sequence variation. Currently there are no proven efficacious drugs or vaccines available to contain the epidemic and EVD in West Africa is presently considered by the World Health Organization (WHO) to be a Public Health Emergency of International Concern.

The five integrated Ebola-based collaborations announced today by Hemispherx are with: 1) National Institutes of Allergy and Infectious Disease (NIAID), a branch of the National Institutes of Health (NIH); 2) the United States Army Research Institute in Infectious Disease (USAMRIID); 3) the Swiss Department of Defense (Spiez Lab); 4) research being conducted at Howard University, Washington, DC; and 5) a US-based facility with biosafety level 4 (BSL-4) capabilities with whom a Sponsor Research Agreement is currently being negotiated. Earlier in September, Ebola research collaborations were announced with USAMRIID and the Swiss Department of Defense
Previous collaborations with the NIAID, announced on May 5, 2014 and University of Texas Medical Branch, announced on June 3, 2014 identified Alferon® N, the only FDA approved natural alpha-interferon product, as a potent inhibitor in-vitro of Middle East Respiratory Syndrome (MERS) virus; both facilities have BSL-4 capabilities. 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 through cellular "molecular cascades" (i.e., multiple mediators which protect cells from viral pathogenesis) rather than targeting 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 (2007) 196:1313) 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 (2014).
Secondly, both drugs are unusually effective against highly virulent viruses such as SARS, as noted by Singapore investigators (Emerging Infectious Disease (2004) 10(4):581) and independent U.S. health researchers (Virology (2009) 395:210). Alferon N has also demonstrated superior potency to that shown by recombinant alpha interferons (AIDS Research Human Retroviruses.1993; 9:1115-111) and ability to afford apparent clinical benefit in the presence of antibodies against recombinant interferons (Journal of Interferon and Cytokine Research.2012; 32:95-9).  Ampligen is also active 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.

In a recent issue of the Wall Street Journal (WSJ) (September 20-21, 2014), the authors propose that based on new cases multiplying in Liberia, Guinea, Sierra Leone, Nigeria and Senegal, the Ebola epidemic "foreshadows threats that will strike the US." As of September 18, 2014, some 2,622 people have died since March 2014, according to the WHO. The WSJ article summarizes certain U.S. readiness improvements since the year 2004 passage of Project Bioshield, including a large basic and translational research portfolio built by NIH and the Pentagon. However, 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.

In the projected integrated body of experiments, it is expected that Hemispherx and its collaborators will study Ebola viral isolates in various experimental systems with various other drug candidates.

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.

Ampligen, an experimental therapeutic, is a new class of specifically configured RNA compounds targeted as potential treatment of diseases with immunologic defects and/or viral causation. Ebola virus specifically inhibits the RNA which 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 viruses.

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 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
Source: Hemispherix Biopharma

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