Pipeline

Biodefense and Emerging Diseases

Since 2001, a new sense of vulnerability to radiation, infectious diseases, toxins and chemical agents has generated significant research and development efforts to identify and produce innovative therapies and means to protect against threats that could be used as biological weapons. There is a growing need for products that protect the population against such agents of bioterrorism, as well as against emerging infectious diseases that could arise through natural epidemics. With very few exceptions, such products do not exist, and those that are available for current deployment are based on outdated and sometimes ineffective technologies. Many of these products will only be used in the event of an emergency.

Products to combat biological warfare or bioterrorism will be supplied to the population from medicines stored in the US Strategic National Stockpile (SNS). The federal government has established a special fund to acquire biological warfare countermeasures (termed Project Bioshield), which allocates $5.6 billion over a 10-year period to acquire products for the SNS. Realizing that many of these countermeasures do not exist, the US government has recently established Biomedical Advanced Research and Development Authority (BARDA). The existence of BARDA creates a situation in which products arising from research, primarily sponsored by the National Institutes of Health (NIH) and the Department of Defense (DoD), can be prioritized and then developed for large-scale manufacturing and clinical evaluation, and ultimately acquisition of the product for the SNS.

Soligenix, Inc. is addressing the development of products and technologies that can be used to protect against several biological threats considered agents of bioterrorism, consistent with biological warfare threats and emerging diseases that the National Institute of Allergy and Infectious Diseases (NIAID), a division of the NIH, has identified as high priorities. Soligenix is developing several potential products to prevent morbidity and mortality due to the threat of biological toxins for which preventive vaccination is the most feasible means to protect a susceptible population. This approach is being taken because the known mechanism of protection against toxin exposure is mediated through antibodies in the serum or present on mucosal surfaces that can be elicited by vaccination with subunit immunogens.

Soligenix was recently awarded a $9.4 million grant from NIAID, which will fund, over a five-year period, the development of formulation and manufacturing processes for vaccines, including RiVaxTM, that are stable at elevated temperatures. The grant will also fund the development of improved thermostable adjuvants expected to result in rapidly acting vaccines that can be given with fewer injections over shorter intervals. In addition, Soligenix is expanding the range of applicability of its lead product, oral beclomethasone dipropionate (BDP), for radiation injury following exposure to environmental radiation.

RiVax™ Ricin Toxin Vaccine

RiVax™ is Soligenix's proprietary vaccine developed to protect against exposure to ricin toxin and is the most advanced vaccine product in the company's portfolio. With RiVax™, Soligenix is the world leader in ricin toxin vaccine research. The immunogen in RiVax™ induces a protective immune response in animal models of ricin exposure and functionally active antibodies in humans. The immunogen consists of a genetically inactivated subunit ricin A chain that is enzymatically inactive and lacks residual toxicity of the holotoxin. One Phase 1 human clinical trial was completed, and a second trial is currently being conducted. The development of RiVax™ has been sponsored through a series of overlapping challenge grants (UC1) and cooperative grants (U01) from the NIH, granted to Soligenix and to the University of Texas Southwestern Medical Center (UTSW) where the vaccine originated. The second clinical trial is being supported by a grant from the FDA's Office of Orphan Products to UTSW. Soligenix and UTSW have collectively received approximately $15 million in grant funding from the NIH for RiVax™. Results of the first Phase 1 human trial of RiVax™ established that the immunogen was safe and induced antibodies anticipated to protect humans from ricin exposure. The antibodies generated from vaccination, concentrated and purified, were capable of conferring immunity passively to recipient animals, indicating that the vaccine was capable of inducing functionally active antibodies in humans. The outcome of the study was published in the Proceedings of the National Academy of Sciences (Vitetta et al., 2006, PNAS, 105:2268-2273). The second trial, sponsored by the UTSW, is currently evaluating a more potent formulation of RiVax™ that contains a conventional adjuvant (salts of aluminum), anticipated to result in higher antibody titers of longer duration in human subjects. Soligenix has adapted the original manufacturing process for the immunogen contained in RiVax™ for large scale manufacturing and is further establishing correlates of the human immune response in non-human primates.

Ricin as a Biological Weapon

The Centers for Disease Control (CDC) has classified ricin as a Category B biological agent. Currently, there is neither a therapeutic nor a vaccine that can be used to protect against ricin exposure or reverse the effects once exposed. The potential use of ricin toxin as a biological weapon of mass destruction has been highlighted in a FBI Bioterror report released in November 2007, entitled Terrorism 2002-2005, which states that "Ricin and the bacterial agent anthrax are emerging as the most prevalent agents involved in WMD investigations." Ricin has a long history of use in espionage and warfare. Recent economic surveys have shown that there are over 1 million tons of castor beans produced in the world annually. The global commercial production has the potential to yield approximately 50,000 tons of pure ricin. The fate of much of this ricin in countries outside of the US is unknown. Ricin toxin can constitute up to 5 percent of the total protein of the bean. Ricin is highly stable at room temperature and difficult to inactivate by conventional methods. Because of the high content of ricin in castor beans, ricin toxin can be extracted from the mash produced as a by-product of castor oil production by several simple enrichment steps and, therefore, easy to stockpile. While ricin is second in toxicity only to botulinum toxin, it is far easier to obtain, prepare, and use. Before the 1990 war, the Iraqi military had attempted to devise ways to disseminate ricin as an explosive bomb, attempts which were forestalled by the war and ensuing events. Ricin has also been detected in a powder form sent in a letter addressed to Senator Bill Frist in 2004, and several other similar but less publicized incidents. More recently, there have been sporadic reports of ricin stockpiles and attempted use of ricin in the US and Europe.

Once exposed to lethal doses of ricin, the effects are essentially irreversible and symptoms appear more rapidly than symptoms of botulinum intoxication (in a dose-dependent manner). Since its lethality is irreversible after four hours and takes three to five days to kill an individual, immunization after ricin exposure is impractical on a large scale. Since ricin is cleared rapidly from the blood and the symptoms of ricin intoxication mimic the symptoms of other diseases, it is not practical to carry out post-exposure immunization via infusion of neutralizing antibodies in a reliable manner. The current expectation that drives vaccine development is that ricin is most likely to be distributed as an aerosol form, since it is highly lethal by this route.

RiVax™ Development

A robust process for the purification of the modified ricin A chain immunogen in recombinant E. coli host cells has been developed. This process has been carried out under current Good Manufacturing Practices (cGMPs) with supporting engineering runs, for the production of vaccine for future Phase 1 and 2 studies and concurrent animal studies. Yields are consistent with the prospect of producing millions of vaccine doses at the current scale. Long-term stability studies are being conducted on the soluble protein immunogen (Bulk Drug Substance) and an aluminum adjuvant formulation (adsorbed RiVax™). All products that are destined to be in the SNS or used as military vaccines will be licensed by the FDA based on animal efficacy studies that are conducted in addition to human safety studies. In the case of RiVax™, human studies also include determination of immune response to the immunogen and critical correlation of the levels and types of antibodies with efficacy outcomes in an animal species that is thought to develop similar immune response as humans. In some circumstances, products will be used under Emergency Use Authorization, in which full licensure by the FDA has not taken place at the time of the required use of the product. In the case of RiVax™, there is no human burden of disease caused by ricin and the only means to assess vaccine efficacy is based on assessment of correlates of immunity in vaccinated animals. Soligenix is developing non-human primate animal models of efficacy through studies being conducted at the Tulane National Primate Research Center (TNPRC). The FDA has instituted specific rules of licensure for animal efficacy for products that cannot be evaluated in humans for efficacy. These studies entail pivotal efficacy studies conducted in well characterized animal models.

Government Funding

Soligenix's process for product development of biodefense products is highly cooperative with government funding, since the government itself will be the final supplier of the products. Soligenix has received three cooperative grants for development of RiVax™, with respect to development of large-scale manufacturing processes, the development of stabilized formulations and for the development of animal models of efficacy that can be used to support product licensure. The most recent award was a $9.4 million grant from NIAID funding Soligenix and its consortium over a five-year period for the development of formulation and manufacturing processes for vaccines, including RiVax™, that are stable at elevated temperatures. The grant will also fund the development of improved thermostable adjuvants expected to result in rapidly acting vaccines that can be given with fewer injections over shorter intervals.

Cooperative grants to UTSW have supported development of basic animal models of aerosol exposure and the establishment of antibody correlates of immunity. Soligenix has also collaborated with other academic and industrial, and not-for profit institutions for different facets of development. Soligenix's collaborators and contractors include SRI International, Wadsworth Center of the New York State Department of Health, University of Kansas, Division of Microbiology and Infectious Diseases (DMID) of NIH, Lonza, Inc., and Biocon, Inc.