This is the second of two articles on bioterrorism and the companies involved in the field. The first article was on Smallpox. This one is on Anthrax.
Anthrax is caused by the gram-positive bacterium Bacillus anthracis. The bacterium exists in nature in two forms: vegetative and spore. A spore can persist for long periods of time (even decades) in the environment. When it enters a human or animal host, the spore becomes a vegetative cell that produces three toxins. Anthrax Protective Antigen [PA] initiates the onset of the illness by attaching to cells in the infected person where it then facilitates entry of the two additional destructive toxins - Lethal Factor [LF] and Edema Factor [EF] into the cell. Anthrax in humans can be pulmonary, cutaneous, or gastro-intestinal depending on the mode of entry (inhalation, contact, or consumption of tainted food).
Anthrax is currently considered one of the most serious bioterrorism threats. Beginning in the second half of the twentieth century, anthrax was developed by several countries (including the Soviet Union and the United States) as part of a biological weapons program. Since that time, the U.S., Russia, and many other countries have discontinued these programs. However, rouge programs still may be in operation (source).
Groups not aligned with countries have used anthrax. Most dramatically, in October 2001, anthrax attacks were perpetrated in the U.S. via the mail, when seven envelopes containing B. anthracis spores were sent through the U.S. postal system. Twenty-two cases of anthrax resulted (11 inhalational, 11 cutaneous), and 5 people died from inhalational anthrax. Investigations into the origin of the attacks are ongoing, and the perpetrator(s) have yet to be identified (source).
A number of factors contribute to concern about the use of anthrax as a biological weapon:
- Availability of B. anthracis in laboratories
- Evidence that techniques for mass production and aerosol dissemination of anthrax have been developed
- High fatality rate
- Low infectious dose (as few as 1 to 3 spores may cause infection)
- Genetic manipulation so as to make anthrax resistant to antibiotics
An analysis in 1993 by the Office of Technology Assessment of the U.S. Congress estimated that 130,000 to 3 million deaths could occur following the release of 100 kilograms of aerosolized anthrax over Washington, DC, making such an attack as lethal as a hydrogen bomb (Office of Technology Assessment, U.S. Congress. Proliferation of Weapons of Mass Destruction. Washington, DC: U.S. Government Printing Office. 1993;53-55. Publication OTA-ISC-559.)
Antibiotics are the first line of defense against anthrax infection. Early identification and treatment are critical for successful outcome. To highlight the issue, even with aggressive antibiotic therapy five of the eleven victims of the 2001 anthrax postal attacks died. Ciprofloxacin, doxycycline, and penicillin are FDA-approved antibiotics for the treatment of anthrax. Combination therapy with additional antibiotics is recommended for treatment of both inhalational and cutaneous anthrax.
The anthrax vaccine currently available for use in the U.S. is anthrax vaccine adsorbed [AVA]—commercial name BioThrax®, made by Emergent BioSolutions, Inc. There are approximately 10 million doses in the Strategic National Stockpile [SNS] for emergency use. Delivery of 18.75 million additional doses of AVA is part of a 3 year U.S. Department of Health and Human Services [HHS] contract with Emergent BioSolutions. According to an October 23, 2007, GAO report, SNS supplies of the previously stockpiled BioThrax® will begin to expire in 2008 (source).
AVA consists of filtered proteins from a weakened strain of B. anthracis and does not contain whole bacteria. The traditional course for the vaccine is 6 injections given over an 18-month period. AVA is currently recommended only for persons who are at occupational risk of acquiring anthrax, such as laboratory personnel, livestock handlers, and members of the military (source).
According to testimony delivered by the HHS Deputy Assistant Secretary for Preparedness and Response before the U.S. House of Representatives Committee on Government Reform, the SNS holds enough “anthrax antibiotics” to “provide 60-day regimens for post-exposure prophylaxis to approximately 41.5 million people,” and enough “intravenous antibiotics to treat approximately 831,000 symptomatic anthrax patients” (source).
The U.S. government has purchased 20,000 treatment courses of ABthrax™ antitoxin from Human Genome Sciences and 10,000 therapeutic courses of AIG antitoxin from Emergent Biosolutions for the SNS. These countermeasures potentially could be used against drug resistant strains of B. anthracis and as adjunctive therapy in addition to antibiotics for severely ill patients.
ABthrax: This is a human monoclonal antibody that blocks the binding of Bacillus anthracis protective antigen to the cell surface. This prevents the anthrax toxin from entering and killing the cells. ABthrax is developed under a contract with the U.S. Government, which was secured in June 2006. In December 2007, HGS announced study results that provide the scientific evidence required to establish the efficacy of ABthrax. The Company has also demonstrated that ABthrax was generally safe and well tolerated in two clinical trials in healthy adults. HGS plans to submit the final data package to the FDA by mid-2008 to support authorization for delivery to the Strategic National Stockpile, and is manufacturing ABthrax on schedule to begin delivery by fall 2008 (source).
Anthrax Immune Globulin [AIG]: Emergent Biosystems, Inc (EBS) is developing anthrax immune globulin [AIG] as a single dose intravenous therapeutic for treatment of patients with symptoms of anthrax resulting from the release of anthrax toxins into the body. If successfully developed, it can be used as a monotherapy or in conjunction with an antibiotic.
A few (though by no means all) companies in this space are listed below:
Human Genome Sciences (HGSI) has several programs in addition to ABthrax. These include Albuferon (Hepatitis B), LymphoStat B (lupus), and TRAIL receptor antibodies (oncology). It also has collaboration with Glaxo SmithKline (GSK). It trades on the NASDAQ as HGSI with price around $5.5. The all time high was around $100 in 2001.
BioPort/Emergent BioSolutions (EBS) has several different programs in addition to BioThrax and AIG. It has vaccines for typhoid, hepatitis B, Streptococcus group B, Chlamydia, Botulism, and Meningococcus (the last with Sanofi-Pasteur). It trades as EBS in the NYSE. Present price is around $10.50, 2 year low was $4.73 (12/07) and two year high was $17.40 (1/07).
PharmAthene (PIP) is developing a second-generation rPA anthrax vaccine consists of recombinant Protective Antigen (rPA) adsorbed onto Alhydrogel and packaged as a liquid filled syringe for intramuscular injection. It is a highly purified protein that offers the potential for improved safety and convenience. It is intended to protect individuals before or after exposure to the anthrax bacterium. Preclinical studies suggest that two or three doses administered several weeks apart should be sufficient to induce protective immunity followed by an annual booster shot. Phase II clinical trials have been completed and showed that the vaccine is safe, well tolerated and induces an immune response in humans. In preclinical studies this vaccine has demonstrated the capability to protect non-human primates against a lethal aerosol challenge of the anthrax Ames strain.
In 2002, PharmAthene UK was awarded a multi-year contract, from the National Institute of Allergy and Infectious Disease [NIAID]. Total government funding to date for the rPA anthrax program is approximately $134 million. On February 29, 2008, the Department of Health and Human Services [DHHS] issued a formal solicitation by Request for Proposals [RFP] for an “Anthrax Recombinant Protective Antigen [rPA] Vaccine for the Strategic National Stockpile [SNS].”
The solicitation outlines a requirement to procure 25 million doses of an rPA anthrax vaccine. PharmAthene believes that the second-generation rPA vaccine meets the mandatory qualification criteria for responding to this RFP. Based upon historical awards for similar RFP’s, PharmAthene believes that this award could have a potential value of between $350 and $400 million and is preparing a response to this solicitation.
The company is also developing a third generation rPA vaccine. The objective of the third generation program is to develop an rPA anthrax vaccine that can maintain stability for three years at 35º C and induce protective immunity in two or fewer doses. The development of PharmAthene’s enhanced vaccine candidate has been supported by an NIH grant since 2005. A government published Request for Proposal was issued on September 21, 2007 seeking proposals for a third generation rPA vaccine, reaffirming the US government’s commitment to rPA based vaccine development. The primary objective of the program is to develop an rPA-based anthrax vaccine that can be stored, transported and used without the need for a conventional cold chain – an important advantage for civilian bio-defense deployment within the Strategic National Stockpile. The U.S. government has indicated that they will award contracts to fund the development of third generation rPA vaccine candidates in September of 2008
PharmAthene is developing an Anthrax Monoclonal Antibody, Valortim™ in conjunction with Medarex (MDRX). Valortim™ is a fully human monoclonal antibody designed to protect against inhalation anthrax and is to be given intra-muscularly. It targets a protein component of lethal toxins produced by the protective antigen. PharmAthene and Medarex completed a Phase I study suggested that Valortim could provide protection against anthrax for up to two months, comparable to what is observed in previously immunized individuals.
Valortim™ has received Fast Track and Orphan Drug designation from the Food and Drug Administration, indicating that the FDA will facilitate the development and expedite the regulatory review of the product. Total government funding committed to Valortim™ now exceeds $24 million.
PharmAthene trades as PIP on the AMEX. It is currently around $2.6, and the all time high was around $8 in 2Q 2006.
Elusys is a privately held company that is developing targeted immunotherapies for the treatment of infectious disease using high affinity antibodies and bispecific Heteropolymer (HP) Antibodies that utilize complement receptor 1 (CR1) to enhance pathogen clearance and destruction.
Its Anthim™ anthrax anti-toxin is geared towards pre-exposure and post-exposure prophylaxis, as well as active treatment of disease, both as a stand-alone therapy and in conjunction with antibiotics. An IND was filed on February 24, 2005, and Anthim has received Fast-Track and Orphan Drug status at FDA. The first in human safety study was completed in April 2006. An Emergency Use Authorization application was filed on October 5, 2005, and supplemental information was submitted to that application in August 2006.
Elusys also has a pipeline of antibodies to Staph Aureaus (preclinical stage, in collaboration with Pfizer), Staph non-MRSA (preclinical stage, with MedImmune), and Candida (pre-clinical, with MedImmune).
Advanced Life Sciences Holdings (ADLS) is developing cethromycin, a once-a-day antibiotic that recently disclosed phase III results in 5400 subjects for the treatment of community acquired pneumonia [CAP]. ADLS is in the final stages of compiling a New Drug Application for cethromycin to treat CAP, which it anticipates submitting to the FDA in the third quarter of 2008.
ADLS is also evaluating cethromycin for the prophylactic treatment of patients exposed to bioterror pathogens such as Bacillus anthracis, Fransicella tularensis, Yersinia pestis and Burkholderia pseudomallei. In May of 2007, cethromycin completed a non-human primate study in which it was determined that a 30-day course of oral cethromycin was 100% protective against a lethal dose of inhaled anthrax as compared to the standard of care, Cipro® (ciprofloxacin), which demonstrated 90% protection. The FDA has designated cethromycin as an orphan drug for the prophylactic treatment of inhalation anthrax post exposure, but has not yet approved the drug for marketing in this or any other indication.
In the process of evaluating cethromycin as a broad-spectrum countermeasure for biodefense, ADLS has established collaborations with the United States Army Medical Research Institute for Infectious Diseases [USAMRIID], the National Institute of Allergy and Infectious Diseases [NIAID], the United Kingdom ’s Defence Science and Technology Laboratory [DSTL], and Colorado State University. Through these collaborations, data has been generated to show that, in addition to protecting against inhalation anthrax, cethromycin may be a promising candidate for the treatment of additional CDC category A and B threat agents including tularemia, plague and melioidosis.
Other than cethromycin, it is developing drugs for melanoma and ARDS (respiratory distress syndrome).
It trades under ADLS at Nasdaq. Present value is around $0.98, with the low earlier this year at $0.67 and high of $5.75 in 9/05.
To end where I began, while bioterrorism remains a threat, where and when an attack may take place is anyone’s guess. Therefore, it is better to invest in a company that has a broad portfolio and is not dependent on the benevolence of the US Government or the malevolence of terrorists. While picking a company to invest in, pay particular attention to the management team – perhaps more than in any other industry, an experienced team is critical. The underlying technology is also very important – a good team can’t do a whole lot with bad products. Ask how unique is the technology, what is the competitive edge? For example, but what is the edge of one company’s antibody over the others? Equally important, check out the financial situation. Is the company running out of cash? Last thing one wants to do is to throw good money after bad.