DTRA Researching Hemorrhagic Fever Anti-Viral Compounds
Significant progress at AVI Biopharma? (Aug 22/10)
The Defense Threat Reduction Agency at Fort Belvoir, VA is awarding contracts to find new anti-viral compounds that are effective against hemorrhagic fever viruses, a class that includes Ebola and other diseases.
Drug development is a long and expensive process ($100 million is often mentioned as the table stakes to get a drug through approvals), and promising therapies do not all make it through the research and testing stages. Even so, the research is interesting:
- AVI BioPharma’s AntiSense Approach [updated]
- Alnylam Pharmaceuticals & Tekmira’s RNAi Approach
- Functional Genetics’ TSG101 Approach
- Peregrine Pharmaceuticals’ Bavituximab
- Contracts & Key Events [updated]
AVI BioPharma’s AntiSense Approach
AVI BioPharma is exploring options with its NeuGene “antisense” technology. Using modern methods of chemical synthesis, compounds can be prepared that recognize target gene sequences in a pathogen or pathogenic process. When these compounds bind tightly to the disease-causing sequence, they inhibit the process. This is called antisense technology because the strands of genetic material that get translated into a protein are called “sense” strands, and so “antisense” drugs are meant to stop that translation process.
Antisense compounds are made up of an “antisense backbone” polymer of repeating subunits linked together. Each subunit carries a genetic letter that matches with its pair on the gene target. Although genetic letters are common to all antisense compounds, the chemical structure of the subunits and the linkages that string them together vary widely. NeuGene antisense technology is based on synthetic subunits, as opposed to modified natural materials which have had trouble crossing cellular membranes to enter the cells that contained their genetic target, and/or were easily degraded or broken down by enzymes in the blood.
Their delivery system revolves around a technology they call “PMOplus chemistry,” an advanced generation of the phosphorodiamidate morpholino oligomer. The PMO platform is designed to provide a stable, charge-neutral chemistry backbone for AVI’s advanced RNA-based therapeutics, including specific molecular charges intended to improve both targeted cell penetration, and continued antiviral performance despite viral mutations.
Note the chart on AVI BioPharma’s corporate profile page, which sees the hemorrhagic fever virus market for NeuGene approaches as a small, $300 million total estimated market segment.
Compare this to multi-billion markets like cardiovascular diseases, Hepatitis-C, and flu. Without targeted government funding to tip the scales, it’s clear that a small biotech firm will be pushed hard by investors to pursue larger markets instead.
Alnylam Pharmaceuticals & Tekmira’s RNAi Approach
The discovery of RNAi by Drs. Andrew Fire and Craig Mello won them the 2006 Nobel Prize in Physiology or Medicine. Why does RNAi matter? As Alynlam explains:
“The central dogma of biology is that DNA makes RNA which in turn, makes protein. The abnormal production of proteins is the cause of most human disease. Today’s drugs act by blocking the action of disease-causing proteins. RNAi creates the opportunity to silence the production of disease-causing proteins and therefore, represents a whole new approach for innovative medicines…
RNA interference is a natural mechanism for silencing specific genes. Genes provide cells with the instructions for making proteins, and when a gene is silenced, the cell stops making the protein specified by that gene. RNA interference was first observed in plants, but the first crucial breakthrough in understanding the RNAi mechanism came from studies of worms. This came in 1998 with the recognition that double-stranded RNA (dsRNA) played a pivotal role in RNAi.
Induction of RNA interference using dsRNA quickly became a powerful tool for scientists to study the function of genes in many lower organisms, including worms and fruit flies. However, this approach initially seemed unworkable in mammalian cells, because of the tendency of dsRNA to provoke the interferon response and cause cell suicide. Such cell suicide makes biological sense in the normal situation where dsRNA is encountered – viral infection – because it prevents replication and spread of the virus to neighboring cells. For a time, however, it was a major obstacle to experimental induction of RNAi in mammalian cells.
This obstacle was overcome by Alnylam scientific founders, who developed a new strategy to trigger RNAi in mammalan [sic] cells using relatively small synthetic dsRNAs – long enough to induce RNAi, but small enough to avoid inducing the interferon response. Alnylam founders were the first to show that smaller dsRNAs, known as “small interfering RNAs” (siRNAs), bind to messenger RNAs (mRNAs) with complementary sequences and trigger mRNA degradation with the RNAi mechanism.”
Tekmira also uses RNAi, but the focus of their research contracts revolves around their delivery system. SNALP (stable nucleic acid-lipid particle) are specialized lipid nanoparticles that fully encapsulate a variety of nucleic acid molecules such as siRNAs. SNALP technology relies on something called the “enhanced permeability and retention effect.” SNALP particles have a long circulation time in the blood, and tend to gather at leaks. That’s god because tumor cell growth, infection, and inflammation tend to produce “vascular leaks.” Once at the target site, cells take up the SNALP through endocytosis, and the nucleic acid payload is delivered inside the cell.
Tekmira’s contract builds on a Lancet paper published in May 29/10, in collaboration with the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). “Post exposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof of concept study” described treatment of Ebola using small interfering RNA (siRNA) delivered by Tekmira’s SNALP technology. When used to treat previously infected non-human primates, Ebola SNALP reportedly resulted in 100% protection from an otherwise lethal dose of Zaire Ebola virus.
Functional Genetics’ TSG101 Approach
In September 2006, Functional Genetics Inc. in Rockville, MD won a pair of those contracts. Another contract was announced in May 2007. Their research is based on a new discovery and some promising lab tests, and the key to Functional Genetics’ proposed therapies is a compound called TSG101. Among other things, it’s involved in the routine recycling/ degradation of cellular proteins. When a cell is infected with a virus, the normally intercellular TSG101 is hijacked to orchestrate the release of viral particles from the infected cell. Since that’s a really key stage of successful viral infection spread, TSG101 becomes an obvious target for antibody therapeutics. The TSG101 is also outside of both the virus and the host cell – which means that if you can successfully target it, the approach sidesteps any drug resistance the virus has built up.
The Company expects to file an anti-viral IND in 2007. Their lead candidates reduce the release and infectivity of Ebola and HIV (including drug resistant HIV), and the lead antibodies have demonstrated the ability to rescue animals from an otherwise lethal dose of acute Ebola infection. These candidates have also demonstrated efficacy against Influenza A & B (the flu), and RSV (Respiratory Syncytial Virus). Company strategies for targeting TSG101 also include peptides, vaccines and small molecules.
In addition to the TSG101 target, the Company has an ongoing program devoted to the identification of additional host targets suitable for influenza therapeutic development and has to date identified 10 novel host genes. Functional Genetics has been issued 6 patents and has another 8 in various stages of prosecution protecting its Random Homozygous Knockout platform and target discoveries, including TSG101.
Peregrine Pharmaceuticals’ Bavituximab
A Macguffin created by Mr. Mxyzptlk? Or the result of too many registered brand trademarks?
There is a sort of backward component to Bavituximab, Peregrine Pharmaceuticals’ anti-phosphatidylserine (anti-PS) monoclonal antibody. It targets a component of cell membranes that’s usually found only on the inside of cells, but which often becomes exposed on the cell surface in viral diseases and in cancer. Bavituximab helps activate the body’s own immune system to destroy the affected cells.
This treatment is currently in clinical trials for the treatment of Hepatitis-C infections (including Hep-C in HIV patients) and cancer. In preclinical animal models, bavituximab has also demonstrated encouraging anti-viral activity as a potential treatment for viral hemorrhagic fevers.
Contracts & Developments
“Currently, no vaccines or therapeutics are licensed to counter Ebola or Marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. Here we show that administration of positively charged phosphorodiamidate morpholino oligomers (PMOplus), delivered by various dosing strategies initiated 30-60 min after infection, protects >60% of rhesus monkeys against lethal Zaire Ebola virus (ZEBOV) and 100% of cynomolgus monkeys against Lake Victoria Marburg virus (MARV) infection. PMOplus may be useful for treating these and other highly pathogenic viruses in humans.”
The control groups in this study all dropped dead. In addition to improved survival rates, AVI-6002 and AVI-6003 subjects reportedly demonstrated less viremia, harmful inflammatory indicators and measurements of virus-induced liver damage. See also AVI Biopharma | Frederick News Post | Foreign Policy magazine. Note also that an Aug 24/10 corporate release cites positive results from their PMOPlus AVI-7100 treatment candidate from Pandemic H1N1 flu virus – which is not a hemorrhagic fever, but was part of the TMT program.
July 20/10: AVI Bophirima, Inc. in Corvallis, OR receives a $80.4 million cost-plus-incentive-fee contract. The firm will develop and license treatments for Ebola and Marburg hemorrhagic fevers.
Work will be performed in Corvallis, OR (51.85%); Fort Detrick, MD (2.7%); and Fort Devens, MA (42.45%), with an estimated completion date of May 24/16. Bids were solicited on the World Wide Web, with 10 bids received by the U.S. Army Space and Missile Defense Command in Frederick, MD (W9113M-10-C-0056).
A subsequent AVI Biopharma release places the contract’s maximum value at $291 million. Work will cover advanced development of the Company’s AVI-6002 (Ebola) and AVI-6003 (Marburg) candidate treatments, and is the largest contract awarded to date under the Transformational Medical Technologies (TMT) program for bio-warfare defenses.
July 20/10: Tekmira Pharmaceuticals Corp. in British Columbia, Canada received a $34.7 million cost-plus-incentive-fee contract to develop and license treatments for hemorrhagic fevers, as part of the Transformational Medical Technologies (TMT) program. Tekmira says the contract could be worth up to $140 million if all options are exercised, adding that more than 15% of the estimated value will be subcontracted to U.S. businesses via its Protiva U.S. affiliate based in Washington state.
In the initial phase of the contract, Tekmira is eligible to receive up to $34.7 million from 2010-2013, for the development of an Ebola SNALP product candidate. They will conduct pre-clinical development, file an Investigational New Drug (IND) application with the United States Food and Drug Administration (FDA), and complete of a Phase 1 human safety clinical trial. The TMT program has the option of extending the contract beyond the initial funding period to support the advancement of the Ebola SNALP product right through clinical development and FDA approval, which could be worth up to $140 million.
Work will be performed in Canada (68.72%), and Fort Detrick, MD (31.28%), with an estimated completion date of July 19/16. Bids were solicited on the World Wide Web with 10 bids received by the U.S. Army Space and Missile Defense Command in Frederick, MD (W9113M-10-C-0057). See also Tekmira release.
July 1/08: Peregrine Pharmaceuticals, Inc. in Tustin, CA received a cost plus fixed fee contract for research on anti-phosphatidylserine antibodies. Work will be performed in locations across the USA, as well as the United Kingdom, and is expected to be completed by June 29/13. Web bids were solicited on Dec 1/06, and 50 bids were received by the Defense Threat Reduction Agency at Fort Belvoir, VA (HDTRA1-08-C-0003).
Under the terms of the contact, DTRA funds are available to cover testing and development efforts totaling up to $22.3 million over a 24-month base period, with $5 million appropriated immediately for the current federal fiscal year ending Sept 30/08. The remainder of the $22.3 million is expected to be appropriated over the remainder of the 2-year base period ending June 29/10. The contract can be extended beyond the base period to cover up to $44.4 million in funding over the 5-year contract period. Peregrine Pharmaceuticals release.
May 4/07: Small business qualifier Functional Genetics Inc. in Rockville, MD received a $6.5 million cost-plus-fixed-fee contract to perform research on host-oriented broad-spectrum small molecule inhibitors for biothreat viruses.
Work will be performed in Gaithersburg, MD (40.32%), Wilmington, NC (5.44%), Alexandria, VA (1.14 percent), Chicago, IL (6.80%), Florence, SC (0.01%), and Frederick, MD (46.30%), and is expected to be complete by April 26, 2009. Bids were solicited via the World Wide Web on Dec. 1, 2006, and 50 bids were received (HDTRA1-07-C-0080).
Dec 4/06: Small business qualifier AVI BioPharma in Corvallis, OR received a $28 cost-plus-fixed-fee contract for a new Antiviral (AntiSense) platform targeting hemorrhagic fever viruses. Work will be performed in Corvallis, OR (61.10%), Frederick, MD (13.63%), Sperryville, VA (1.11%), La Jolla, CA (2.04%), and Subcontractors to be determined (22.11%), and is expected to be complete on Nov. 29, 2008. Bids were solicited via the world wide web on Oct. 31, 2005, and 130 bids were received (HDTRA1-07-C-0010).
Sept 21/06: Small business qualifier Functional Genetics Inc. in Rockville, MD received a $13 million cost-plus-fixed-fee contract. Work will be performed in Rockville, MD (98%), and Frederick, MD (2%), and is expected to be complete by Aug. 15, 2009. Bids were solicited via the World Wide Web on Oct. 31, 2005, and 130 bids were received (HDTRA1-06-C-0034).
Sept 21/06: Small business qualifier Functional Genetics Inc. in Rockville, MD received a $28 million cost-plus-fixed-fee contract. Work will be performed in Rockville, MD (75%), Frederick, MD (8%), and Evolva, Switzerland (17%), and is expected to be complete by Aug. 15, 2010. Bids were solicited via the World Wide Web on Oct. 31, 2005, and 130 bids were received (HDTRA1-06-C-0035).
Aug 13/06: Alnylam Pharmaceuticals Inc. in Cambridge, MA received a $10.9 million cost-plus-fixed-fee contract for Research on the Development of Broad-Spectrum Host-Directed Ribonucleic Acid Interference Therapeutics for Ebola Virus and Other Hemorrhagic Fever Viruses.
Work will be performed in Cambridge, MA (52%), Frederick, MD (13.7%), Cincinnati, OH (9.1%), Tacoma, Wash. (6.3%), New York, NY (3%), Raleigh, NC (1.2%), Rockville, MD (0.3%), and British Columbia, Canada (7.4%), and Montreal, Quebec, Canada (7%). and is expected to be completed by Aug 7/10. Bids were solicited via the World Wide Web on Dec. 1, 2006, and 50 bids were received by the Defense Threat Reduction Agency at Fort Belvoir, VA (HDTRA1-07-C-0082).