"This acquisition significantly broadens our strategic focus and provides Upstream with important new capabilities", stated Joel L. Bellenson, Chief Executive Officer of Upstream. "We believe the innovative technology platform pioneered by Pacific Pharma may have substantial commercial potential in a number of therapeutic areas and it fits well with our existing core competencies in computational-based approaches to biomarker identification. Pacific Pharma has also generated novel compounds that have exhibited activity against targets relevant to cancer, the focus of our biomarker programmes."
In screening studies in vitro, Pacific Pharma's lead compounds have demonstrated encouraging signs of efficacy against leishmaniasis and African sleeping sickness or trypanosomiasis. These parasites, which belong to a family of protozoa species that include Chagas disease and malaria, infect millions of individuals in Africa, South Asia and South America.
Current treatments are often toxic, ineffective, inconvenient and expensive. In addition, recent reports document the spread of leishmaniasis to United States troops and contractors in Iraq and Afghanistan. Upstream also intends to begin screening compounds against malaria shortly and to test compounds from related classes as potential therapies for tuberculosis. The millions of individuals affected by these two diseases are increasingly infected with multiple drug resistant strains, highlighting the need for new therapies.
Mr. Bellenson continued: "These parasitic diseases take an enormous personal, social and economic toll on communities in the developing world, affecting millions of individuals and also decimating the cattle herds that are an integral part of rural economies. We believe the growing interest in addressing global health issues makes this an ideal time to pursue new drugs for these devastating conditions, and we intend to work collaboratively with a variety of public and private organisations to ensure the timely and cost-effective clinical development of drug candidates generated by our new technology platform. We also expect to pursue other therapeutic applications of this potentially powerful drug discovery technology going forward."
Pacific Pharma's proprietary technology platform takes existing compounds that have demonstrated efficacy against the target disease and uses artificial intelligence, computer simulation and pattern recognition techniques to identify key structural elements associated with their efficacy. Screening analyses and diversity generation chemistry are then applied to produce an array of potential drug candidates. The technology can also be used to identify novel applications for existing drugs. It was developed by Artem Cherkasov, Ph.D., a faculty member in the Department of Infectious Diseases in the Faculty of Medicine at the University of British Columbia. At the recent annual meeting of the American Chemical Society in Boston, Dr. Cherkasov gave a scientific presentation describing how this technology may be effective for the rapid identification of drugs that can be used to fight antibiotic-resistant "super-bug" pathogens or emerging new infectious agents.
This technology is particularly applicable to these difficult-to-treat protozoan diseases because it does not require knowing the disease target a priori", noted Professor Cherkasov. "By combining state-of-the-art computational approaches with advanced chemistries, we have already demonstrated that we can successfully produce novel compounds with good drug-like properties and the potential for enhanced efficacy and reduced toxicity. I look forward to working with Upstream to advance these promising new drugs into clinical development, as well as to exploring other drug discovery applications of the technology platform."
Professor Cherkasov is an expert in computer-aided drug design, in applications of artificial intelligence to structure-activity modelling for bioactive substances and in the development of large-scale bioinformatics and genomics tools and molecular modelling techniques. He is a member of Upstream's Scientific Advisory Board. Terms of the acquisition include upfront and milestone payments. Further details were not disclosed.
Drug "repurposing" or "reprofiling" is not new. Pharmaceutical companies have been seeking new uses of old drugs to extend patent protections and whenever new, off-label uses of the drugs are found. But reprofiling to deliberately develop emergency drugs is a new concept, made possible by advances in chemo-informatics, a new field that merges chemistry with computer science, according to the study presenter Artem Cherkasov at the 234th meeting of the American Chemical Society.
"In the case of new infectious threats, there might be no time to develop a completely new drug from the ground up, as the corresponding toxicological studies and regulatory investigations will take years to complete properly", stated Professor Cherkasov. "Finding an already existing, well-studied therapeutic agent that will kill an emerging bug might provide a rapid, first line of defense response option."
Under the new computer-aided system, the researchers plan to first identify vulnerable cellular components of a pathogen using proteomics, or the study of proteins and their interactions. They will enter these key structures into the computer and, using elements of modern "Artificial Intelligence", will identify drugs that have the highest potential for activity against the target and for antimicrobial activity, according to Dr. Cherkasov. Those compounds with the highest "ranking" can then be quickly tested in the laboratory against the pathogen and eventually used to treat infected individuals, the researcher stated.
The new approach is still in development for possible future use during an actual outbreak, as Dr. Cherkasov noted. However, many non-antibiotic drugs have been shown to have antibiotic-like properties using this technique, he said. For example, computer studies have suggested that lovastatin, a drug marketed to lower cholesterol, and gentisic acid, an anti-inflammatory drug related to aspirin, both show promise as strong antibiotics. But more studies are needed before these compounds can be recommended for use as antibiotics in a clinical setting, he added.
"It is not totally unexpected as there are thousands of existing drugs that are already enriched with target-binding structural features", Dr. Cherkasov stated. "Many of them were not designed as antibiotics but have the potential to act as such. The chemical structures of compounds we identify usually look nothing like known antibiotics. But if a compound behaves like antibiotic in a computational model, it may act as one in a real life", stated Dr. Cherkasov, who has programmed his computer system to identify "antibiotic likeness", or those chemical structures which have the most potential for antibiotic activity.
There is a growing need to expand and complement the range of available antimicrobial compounds, as many big pharmaceutical companies have withdrawn from the field of anti-infective agents, according to Dr. Cherkasov. Only two novel antibiotics have entered the market in the last 20 years, he said.
The researchers plan to soon begin testing some of the newly identified antibiotic candidates against methicillin-resistant Staphylococcus aureus (MRSA). Also known as "superbugs", these bacteria are an increasingly worrisome cause of serious hospital-based infections and infections acquired in community settings.
Although Dr. Cherkasov's research team specializes in battling bacterial infections, similar techniques can be applied to emerging viral infections, such as SARS and bird flu, he said. Likewise, the technique also provides a potential means of identifying quick treatments for bioterrorism agents, such as new strains of anthrax, as well as rare infectious diseases such as those sometimes encountered in third-world countries.
Genome Canada, a funding and information resource of the Canadian government, supported the study as a part of the PREPARE project - PRoteomics for Emerging PAthogen Response, a non-government programme based at the University of British Columbia.
According to the World Health Organization (WHO), over 300 million people are infected globally by these parasitic diseases, which are responsible for an estimated 2,8 million deaths annually and cause great suffering and economic hardship to millions more. In addition, the combination of global warming and increased migration is beginning to bring these diseases to the developed world. For example, the American Red Cross recently reported that in 2006 it detected blood-borne Chagas pathogens in 1 in every 3800 blood donors in Los Angeles.
Chagas disease is caused by the parasite Trypanosoma cruzi, which is transmitted to animals and people by triatomine insects. It is estimated that as many as 8-11 million people in Mexico and Central and South America are infected. If untreated, infection is lifelong and can be life threatening. Cardiac complications can include an enlarged heart, heart failure, altered heart rate and cardiac arrest, and intestinal complications include an enlarged esophagus or colon. The average lifetime risk of Chagas-infected individuals developing these complications is about 30 percent. Anti-parasitic medications are usually only effective when given during the acute stage. They can be very toxic, and resistance has already been reported. In the chronic stage of Chagas disease, treatment is limited to managing the clinical manifestations. The scale of the problem is highlighted by the fact that chronic heart disease caused by Chagas is now a major reason for heart transplantation surgery in South America.
Leishmaniasis is a severe, geographically widespread parasitic disease caused by a protozoan flagellate and spread by the bite of infected sand flies. There are several different forms of leishmaniasis - cutaneous and visceral. The cutaneous type causes skin sores, while the visceral type affects internal organs such as the spleen, liver and bone marrow. Leshmaniasis is increasing in incidence with an estimated two million cases per year, and 350 million people in 88 countries are estimated to be at risk. More than 90 percent of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil. Leishmaniasis is also found in Mexico, Central America, and South America. Visceral leishmaniasis can be lethal if untreated.
Sleeping sickness is a parasitic disease in people and animals caused by protozoa of the Trypanosomiasis genus and transmitted by the tsetse fly. The disease is endemic in regions of sub-Saharan Africa covering 36 countries and 60 million people. There are an estimated 300.000 new cases each year. Early symptoms include anemia, endocrine, cardiac, and kidney disorders. The symptoms of the second neurological phase give the disease its name; besides confusion and reduced co-ordination, the sleep cycle is profoundly disturbed. Without treatment, the disease is fatal, with progressive mental deterioration leading to coma and death. Damage caused in the neurological phase can be irreversible. Available treatments are toxic and require lengthy intravenous infusion and hospitalization. Trypanosomiasis also is a major source of serious illness in cattle and other livestock, which is estimated to cost the economies of sub-Saharan Africa about $4,5 billion annually from lost farm income and increased malnutrition.