By Javier Hasse, Editor
Hemispherx Biopharma, Inc. is a specialty biotech with unique technology platforms for the treatment of seriously debilitating disorders. Hemispherx Biopharma is seeking commercial partners to advance drugs for immuno-oncology, infectious disease and immune dysfunction.
Drug discovery today is based on understanding the power of unique technologies combined with an enhanced understanding of the human response systems. Hemispherx Biopharma is set for today’s biotech bounce back as the pharma industry aims at effective therapies tailored specifically to the populations who will respond best to them while avoiding unnecessary exposure to other potentially toxic therapies.
The company’s flagship products include the experimental therapeutics Ampligen® and Alferon® LDO, as well as the commercially approved product, Alferon N Injection®. These drug platforms are designed to modulate the immune system, functioning as activators of the immune response with pluripotent activity. They have the potential to target large unmet medical needs in infectious disease, immune dysfunction and cancer.
The Advantages of a Selective TLR
The experimental drug Ampligen (rintatolimod) is a synthetic double-stranded RNA (dsRNA), a selective TLR3 agonist that stimulates adaptive and innate immune responses that minimize systemic cytokine responses. Ampligen is a new class of specifically configured dsRNA. TLR3 is a specific intracellular signalling system that responds to dsRNA produced during viral infections.
Humans possess ten Toll-like Receptors (TLRs), which provide initial inhibitory responses for invading micro-organisms (innate immunity). TLRs recognize structural patterns within microbes and respond by transiently activating hundreds of genes, producing a variety of biological responses. Over the last decade, toxicities associated with TLR technology have been seen as a barrier in drug development. TLR3, however, has a unique cytoplasmic signalling system that provides it with specific drug development advantages.
All other TLRs utilize a pro-inflammatory signalling system that utilizes the MyD88 cytoplasmic signalling mediator. TLR3 uses the TRIF mediated pathway. The TRIF pathway, moreover, has acute toxicity responses that are species-specific, with primates demonstrating the lowest toxicity.
Ampligen (rintatolimod) is a specifically configured TLR3 agonist, which minimizes systemic inflammatory cytokine induction. Crucially, unlike more promiscuous TLR3 agonists, Ampligen is a selective TLR3 agonist, which does not activate the pro-inflammatory cytosolic dsRNA helicases (RIG-l and MDA5). Ampligen has been generally well tolerated in controlled human clinical trials; this is believed to be, at least in part, due to the selectivity of TLR3 activation.
One of the largest growing arenas in cancer treatment today are PD-1 inhibitors. Although highly effective in a minority of cancer patients, the majority are not benefitted by this new drug class, which is associated with significant treatment toxicities. There is a race to find drug combinations to improve the effectiveness of these PD-1 inhibitors. In initial studies, TLR3 activation in combination with checkpoint inhibitors (anti-PD-1 / PD-L1), has shown synergy in mouse models. In fact, Ampligen has demonstrated synergistic ability to improve reduction in cancer tumour size in mouse models.
Pawel Kalinski, MD at the University of Pittsburgh has demonstrated, in humans, apparent effects of Ampligen to model the tumour microenvironment that favours immune attack, which is currently a focus of scientific attention in immune-oncology. In addition to its apparent remodelling of the tumour microenvironment, Ampligen activates immature dendritic cells essential to an effective immune response and can be considered an “immune driver”. The market growth of checkpoint inhibitors is expected to exceed $16 billion.
Early studies in cancer treatment have demonstrated that Ampligen has significant clinical activity against renal cell carcinoma and melanoma. According to CEO Thomas Equels, M.S., J.D., “We believe Ampligen is especially well-positioned for possible use in combination with other drugs in the immuno-oncology space due to its activity as a driver of the immune response and has been generally well-tolerated, even in long-term human administration. Ampligen has been granted orphan drug status by the FDA in both renal cell carcinoma and melanoma.”
Mr. Equels previously served as General Counsel and Chief Financial Officer at Hemispherx Biopharma in addition to serving as a Director since 2008. After becoming President, Mr. Equels was named Chief Executive Officer in February 2016, bringing to the table extensive experience in international business, contracts, intellectual property, trade secrets, sales and distribution of goods, and collaborative counsel.
Product Launch with Right Commercial Partner
Ampligen is currently being developed for the treatment of Myalgic Encephalomyelitis/
Chronic Fatigue Syndrome (ME/CFS), a serious chronic disease. Hemispherx’s focus is on the severe and disabling form of ME/CFS. Hemispherx has completed Phase II/III trials with Ampligen and is currently in discussions with the Food and Drug Administration (FDA), regarding the design of a confirmatory phase III study. Ampligen is the only drug targeted specifically for ME/CFS, and Hemispherx believes it is the only late stage drug in the pipeline.
Ampligen has been granted orphan drug status for the CFS indication. Equels noted, “We are very interested in finding a commercial partner who has the expertise to commercialize this product. Because no other drug targeted for CFS has advanced as far as Ampligen, once approved for commercial sales, we believe that there may be no competitive therapies.”
Having secured patent protection for Ampligen (rintatolimod) through 2029, Hemispherx announced in August 2016 that it had received approval of its New Drug Application (NDA) from the Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica (ANMAT), for commercial sale of the drug in the Argentine Republic, where it is poised to make a significant impact in the treatment of severe CFS. In addition, Hemispherx is working to expand the approval of rintatolimod to other countries, with a focus on Latin America. The company counts on the marketing assistance of its commercial partner in the region, GP Pharm.
This approval for commercial sale in Argentina provides Hemispherx with a major platform from which to launch future potential commercial sales in certain countries within the European Union, under regulations that support cross-border pharmaceutical sales of licensed drugs. In Europe, approval in a country with a stringent regulatory process in place, such as Argentina, adds further validation for the product as the Early Access Program (EAP) is launched in Europe. The Company believes that rintatolimod, a new class of macromolecular dsRNA drug, is the first drug to receive approval for this indication anywhere in the world.
Tackling Dangerous Infectious Diseases
In an experiment using Ampligen, conducted by the independent US Government facility, USAMRID, rodents were challenged with the Ebola virus and showed potential efficacy as an early-onset therapeutic or potential prophylactic. In this experiment, all of the rodents infected with Ebola virus, but not treated with Ampligen, died. However, in the low dose Ampligen group, there was 100% survival with no Ebola related weight loss. These results indicate a high level of bioactivity in this experimental setting. Similar bioactivity has been seen in a number of other animal model experiments with other viruses that are highly lethal, such as Venezuelan equine encephalitis and the SARS virus. Hemispherx believes that Ampligen may have utility against a variety of emerging viruses with lethal pandemic potential.
Another component of the Ampligen portfolio is as an immune driver for viral vaccines, such as influenza. Extensive studies on influenza conducted at the Japanese National Institute of Infectious Diseases by Dr. Hideki Hasegawa on seasonal and highly pathogenic (birds and humans) avian H5N1 influenza virus demonstrated sterilizing immunity in mucosal vaccine models. These studies provided protection against death against viral challenge with H5N1 including animals vaccinated with the routine seasonal influenza vaccine. These studies provided significant evidence for the phenomenon of epitope spreading since the experimental mice had never been exposed to H5N1. More recent experiments in humans using a seasonal influenza vaccine and Ampligen in a mucosal application induced antibodies against H5N1 and H7N9 influenza viruses (both highly pathogenic in humans with pandemic potential) extending apparent Ampligen-induced epitope spreading to humans. Based on Professor Hasegawa’s experimental work, Hemispherx has designed a formulation of Ampligen for nasal administration, as a potential immune driver for vaccines.
Based on these important results in influenza, Hemispherx believes that similar results might be achievable as a vaccine enhancer for other human viruses, in which clade variation may pose universal protection barriers such as Ebola and Zika.
Natural Interferon
Alferon N is a multi-species, highly purified natural interferon derived from pooled units of human leukocytes. Similar to recombinant interferons, it has potent immunomodulatory, as well as direct antiviral effects, enhancing various components of the immune response and activating cytotoxic cells. Unlike recombinant interferon, natural interferon does not generate neutralizing antibodies, and has greater specific activity – potency, and fewer adverse events.
The recombinant interferons (r-IFN) are limited in their clinical activity by the occurrence of neutralizing antibodies during treatment. These inactivate their pharmaceutical activity in a large variety of approved indications. In a recent review of the field, natural interferon (n-IFN) was not associated with the generation of neutralizing IFN antibodies. The Journal of Interferon and Cytokine Research reported that patients who became refractory to r-IFN, when switched to a natural interferon, were restored to approximately 82% clinical effectiveness. Re-examining the efficacy of natural interferon in recombinant IFN treatment failures opens a wide range of therapeutic targets. Alferon N is approved in Argentina for patients failing r-IFN.
Hemispherx’s product Alferon N is an approved FDA product for adults with reoccurring/refractory HPV (genital warts), which is the most common sexually transmitted disease. The pivotal study showed that 54% of Alferon N treated patients had a complete response of all treated warts. Genital warts are a source of physical discomfort, including pain, bleeding and itching, and a source of psychosocial distress. The high recurrence rate contributes to higher medical costs. Hemispherx is seeking a manufacturing partner for this $92 million opportunity.
Hemispherx owns and operates a 43,000-square-foot GMP facility in New Brunswick, New Jersey, which was recently enhanced with an $8 million upgrade, including installation of a state-of-the-art bioreactor process. Having recently been completed, the facility is in its final stages to start validation, and is being readied for an FDA Pre-Approval Inspection.
Talking With Management
For strategic objectives for 2016, what do you mean by looking for licensing opportunities, and can you talk about any changes to your business model?
Mr. Equels: “Hemispherx’s new management team is seeking partners to help commercialize its assets. We believe the best way for Hemispherx to bring these technologies to market is to create partnerships and collaborations accessing value added science, regulatory and commercial experience. Already, Hemispherx has entered into an agreement with Avrio Biopharmaceuticals as an additional CMO for the manufacture of Ampligen.”
What do you want a potential investor in Hemispherx Biopharma to know as it makes a Biotech Bounce Back?
Mr. Equels: “Our products range from late stage in the pipeline, to the growing immune-oncology space and addressing global threats. Both of our products are unique drug platforms that augment the body’s natural defenses used to protect us against cancers and viral diseases. We are going to accelerate the process, in part, by acquiring partners to accomplish these goals.”
Contact:
Company: Hemispherx Biopharma, Inc.
Name: Thomas K. Equels, CEO
Email: [email protected]
Web Address: www.hemispherx.net
Address: 617 JFK Blvd., Suite 500, Philadelphia PA 19103
Telephone: +1 215-988-0080