Our research and development program is based on the following proprietary platform technologies:
MCC
Mycobacterial Cell Wall-DNA complex (MCC) is a cell wall-DNA composition prepared from a pure culture of the bacterium Mycobacterium phlei. The cell wall complex has been fractionated and purified to optimize the presence of the active molecule, DNA, which is responsible for the range of immunomodulatory and direct anti-cancer activities.
Bioniche has focused its preclinical and clinical research on the use of its MCC technology in the treatment of cancer. These research programs have demonstrated MCC's effectiveness as an immunomodulator and anti-tumour agent in a range of models. The company has achieved a research breakthrough by identifying mycobacterial DNA as the active component of Mycobacterium phlei cell wall preparations.
MCC has a dual mode of action in that it induces apoptosis in cancer cells as well as stimulates anti-cancer cytokine production by immune effector cells.
APOPTOSIS:
The mycobacterial DNA in MCC induces apoptosis (programmed cell death) in cancer cells. The induction of apoptosis occurs in cancer cells including multi-drug resistant cancer cells and in cells with mutations in cell cycle regulators. The induction of apoptosis is associated with a dose-dependent inhibition of cancer cell division, and this activity has been demonstrated in a wide range of cancer cells including bladder, breast, leukemia, melanoma, ovarian and prostate.
IMMUNOMODULATORY ACTIVITY:
MCC induces macrophages to produce cytokines including IL-6 and IL-12. IL-12 is known to possess anti-angiogenic activity (prevention of blood vessel formation in tumours) and activates NK (natural killer) and cytotoxic T lymphocytes that are associated with anti-cancer responses. Bioniche believes that MCC's ability to induce apoptosis in cancer cell lines regardless of the presence of mutations in tumour suppressor genes and multi-drug resistance is significant. Accumulated mutations in cancer cells can often lead to significantly greater resistance to treatment, eventually making conventional chemotherapeutic strategies ineffective.
UrocidinTM - a formulation of MCC - is currently being tested in a Phase III clinical program in bladder cancer. The first trial was conducted by Bioniche involving 129 patients with non-muscle-invasive bladder cancer that was refractory (unresponsive) to the current standard therapy – BCG. This trial was an open label, single-arm trial, meaning there was no comparator therapy used in the trial. This design was ethical and permitted by regulators and ethics committees due to the fact that no approved therapy was available for patients with non-muscle-invasive bladder cancer who failed prior BCG therapy.
The Company identified a goal of achieving a clinically meaningful complete response rate with a safety measure of less than 10% of patients unable to tolerate treatment. This trial enrolled its first patient in November, 2006 and the last patient was enrolled in April, 2009. The preliminary results were reported at urology association meetings in March, May and June, 2011.
In terms of efficacy, the trial resulted in a 12-month 25% disease-free survival outcome. The therapy was well-tolerated, with most adverse events being mild to moderate.
Escherichia coli (E. coli) O157 Bacterial Extract Vaccine
Hundreds of E. coli strains exist, most of which inhabit the intestine and cause no disease. E. coli O157 produces powerful toxins that can cause severe illness in humans. E. coli O157 is also referred to as Enterohemorrhagic E. coli (EHEC) or Verotoxinogenic E. coli (VTEC) or Shiga-toxigenic E. coli (STEC). VTEC is an important human pathogen causing severe diarrhea and Haemolytic Uremic Syndrome (HUS). Non-O157 E. coli strains such as O26, O111 and others have also been associated with human illness However, the O157 serotype is most prevalent as the causative agent of human infection ( 99.6% in the UK, 93.7% in Canada) and 90% of childhood HUS cases are associated with infection caused by the O157 strain.
Cattle are the primary reservoir of E. coli O157:H7 and as such, are a major source of infection in humans, through direct contact or the consumption of contaminated meat, water, or produce. A study conducted on beef cow-calf farms in Ontario in 2009 found E. coli O157 on 52% of the farms surveyed. Cattle are not long-term carriers of E. coli O157. The duration of shedding averages about 26 days in cattle presumably colonized by these bacteria. More than 80% of the spread of E. coli O157 arises from less than 20% of the most infectious individuals. Persistent, high shedders (shedding>103 cfu/g) make up approximately 4% of a herd. E. coli O157:H7 infection of cattle requires type III secreted proteins (TTSP) which enable the bacteria to colonize the intestinal mucosa. Bioniche has developed an E. coli O157 TTSP vaccine that contains the TTSP proteins such as EspA, EspB and Tir. The efficacy of this vaccine has been evaluated in more than 30,000 cattle using natural exposure and controlled challenge studies.
Bioniche’s E. coli O157 vaccine, named Econiche®, is the first of its kind in the world and a unique scientific development for Canada. The vaccine has been developed in collaboration with the University of British Columbia, the Alberta Research Council and the University of Saskatchewan.
Controlled challenge studies demonstrate that vaccinating cattle with Econiche® results in:
a reduction in number of days the bacterium is shed in the feces;
a 64% reduction in duration of shedding;
a 71% reduction in the proportion of animals shedding; and
a 2.28 log10 (99.4%) reduction in number of bacteria shed in the feces.
Human illnesses stemming from E. coli O157 have been linked to a variety of vectors, including: ground beef, spinach, alfalfa and bean sprouts, unpasteurized milk and apple juice, water, cookie dough, walnuts and direct contact with animals at petting zoos, farms and fairs. According to the U.S. Centers for Disease Control (2008), 61% of human illnesses from E. coli O157 are foodborne and 15% are caused by consuming contaminated drinking water. Beef (44%) and produce (34%) are the two most frequent causes of foodborne illnesses.
E. coli
Approximately 100,000 cases of human infection with the E. coli O157 organism are reported each year in North America. This E. coli contains a powerful toxin (“shiga toxin”/”vero toxin”) that enters the circulatory system through a person’s damaged intestinal lining. Between 2% and 7% of infected individuals develop HUS, a disease characterized by kidney failure. 5% of HUS patients die, many of these children and senior citizens whose kidneys are more sensitive to damage.
The Canadian Picture
The most recently released data in Canada states the rate of laboratory confirmed human infections in Canada is 1.39 per 100,000.
The cost of primary human infections with E. coli O157 in Canada, factoring in medical costs, lost productivity and premature death, amounts to $26.7 million per year. When long-term health outcomes are accounted for, the medical costs alone rise to approximately $213 million per year, for a combined total cost of approximately $240 million per year (based on a study on the long-term health costs associated with E. coli O157 released by the Canadian Food Safety Alliance on October 9, 2012).
Several publications link higher disease prevalence to areas with high cattle densities in proximity to significant human population. This is especially visible in southern Alberta, Canada, where the province’s public health data indicates a trend of higher incidence of E. coli O157 coinciding with the location of higher cattle densities in “feedlot alley” where it has reached 28.12/100,000 in a single year.
A 2009 study conducted by the Guelph, Ontario-based George Morris Centre examines direct health care costs associated with foodborne illness related to E. coli O157 in Canada, which are estimated to be $21 million per year. In addition to the health care costs, the impact of controlling the prevalence of this organism in terms of recalls, consumer confidence and demand is estimated to be an additional $82 million per year.
A 2012 study on the long-term health costs associated with E. coli O157 has estimated the cost of primary and secondary illness in Canada to be $240 million per year. The research indicated 22,329 cases of primary VTEC infections occur in Canada annually, costing Canada $26.7 million in medical costs, lost productivity and premature death. The estimated annual medical cost of the long-term health outcomes attributed to E. coli O157 infection is $213 million annually, making the combined total costs approximately $240 million per year.
The United States Department of Agriculture’s Food Safety Inspection Service (FSIS, May, 2010) published a guidance document entitled: “Pre-harvest management and control intervention options for reducing E. coli O157 shedding in cattle”, where they recommend that slaughter facilities obtain cattle that have received one or more pre-harvest interventions to reduce shedding of E. coli O157.
Four published modeling papers have demonstrated a direct link between prevalence of E. coli O157 in cattle and the human illness. All modeling papers measure the reduced risk to human health through consumption of contaminated beef. Investigations of verotoxigenic illness has attributed approximately a third to consumption of contaminated beef, a third of human illnesses to be associated with produce and the remaining third linked to other sources such as water contamination and direct contact with cattle.
Three of the four papers modeled the human risk reduction achieved through cattle vaccination; two of which specifically investigated the TTSP. A study funded by the Public Health Agency of Canada study assessing the effects of various interventions on the management of E. coli O157:H7 in Canadian beef came to a favourable conclusion with regard to pre-harvest vaccines such as the Company’s Econiche® cattle vaccine. In their study, three researchers developed a stochastic, quantitative risk assessment model to evaluate the public health risks associated with consumption of ground beef and beef cuts contaminated with Escherichia coli (E. coli) O157:H7 in Canada. The researchers evaluated the relative effects of pre-harvest and processing interventions on public health risks, comparing the baseline risks from consumption of beef products. The pre-harvest interventions that were assessed included probiotics, an SRP vaccine, and a Type III protein vaccine. Production/processing interventions that were analyzed included hot water wash, steam pasteurization, acid spray chill, dry-aged chill, and water spray chill. The researchers concluded that the most effective strategy for E. coli O157:H7 management includes a pre-harvest intervention and several processing interventions: “Specifically, application of Type III secreted protein vaccination along with a suite of processing interventions … provided the greatest relative reduction in risks.” The Company’s Econiche® vaccine is a Type III protein vaccine.
E. coli O157:H7 Infection
Escherichia coli (E. coli) bacteria are normal organisms found in the intestinal tract of all animals. There are hundreds of strains, most of which are non-pathogenic (disease causing) to their host; however, certain types cause digestive disturbances and occasionally, other significant systemic disease.
The O157:H7 variant of E. coli is a mutant that has acquired an extremely potent toxin from another bacterium: Shigella Dysenteriae. There are a number of theories about how this bacterium mutated, but the exact cause is not known. E. coli O157:H7 has been found in the intestines of healthy cattle, deer, goats, and sheep.
Ruminant livestock (e.g. cattle) are considered the major reservoir of E. coli O157:H7 worldwide. Numerous studies have demonstrated that the prevalence of E. coli O157:H7 in beef and dairy cattle is widespread and that the organism is found in, on, and around cattle in all parts of the world. Use of manure as fertilizer for crop production and run-off from beef and dairy cattle operations are a source of contamination for the general environment, as well as surface and ground water. Surface contamination of whole cuts of meat and internal contamination of ground meats also occurs regularly. This E. coli O157:H7 contamination of food and water as a result of fecal shedding by livestock is a well-recognized and documented threat to human health.
Incidence of E. coli O157:H7 Infection
The Centers for Disease Control and Prevention (CDC) [1] estimates that 73,000 cases of E. coli O157:H7 infection occur annually in the United States. Every year, 2,100 Americans are hospitalized and 61 people die as a direct result of E. coli infections and their complications. Health Canada identified 1,038 reported cases of E. coli O157:H7 infection in Canada in 2004 [2].
People generally become ill from E. coli O157:H7 two to eight days (average of 3-4) after being exposed to the bacteria. Escherichia coli O157:H7 infection often causes severe bloody diarrhea and abdominal cramps. Sometimes the infection causes non-bloody diarrhea or no symptoms. Usually little or no fever is present, and the illness resolves in 5 to 10 days.
In some persons, particularly children under 5 years of age and the elderly, the infection can also cause a complication called hemolytic uremic syndrome (HUS), in which the red blood cells are destroyed and the kidneys fail. About 8% of persons whose diarrheal illness is severe enough that they seek medical care develop this complication. In the United States, HUS is the principal cause of acute kidney failure in children, and most cases of HUS are caused by E. coli O157:H7.
Persons who only have diarrhea usually recover completely. A small proportion of persons with HUS have immediate complications with lifelong implications, such as blindness, paralysis, persistent kidney failure, and the effects of having part of their bowel removed. Many persons with HUS have mild abnormalities in kidney function many years later.
E. coli O157:H7 Outbreaks
E. coli O157:H7 was first recognized as a foodborne pathogen in 1982 during an investigation into an outbreak of severe bloody diarrhea associated with consumption of hamburgers from a fast food restaurant. Since that time, the meat industry and the United States Department of Agriculture (USDA) have invested hundreds of millions of dollars in equipment, testing, and training in an effort to eliminate the organism from commercial product. Their efforts have been successful in significantly reducing the amount of E. coli O157:H7 leaving slaughter facilities.
However, meat packers (slaughter houses) continue to absorb losses due to regular contamination of meat that is contained to the plant (contaminated meat must be cooked or sterilized and disposed of), from the occasional recall or foodborne outbreak associated with commercial product, and from litigation arising out of foodborne disease outbreaks.
In addition to beef related outbreaks, human exposure to E. coli O157:H7 has been associated with contaminated fruit, vegetables (alfalfa sprouts, lettuce, spinach), unpasteurized milk and fruit juice, potable and recreational water, and from direct contact with animals at fairs and petting zoos.
Economic Impact
The economic impact of this disease is thought to be considerable. A number of large-scale recalls of hamburger meat have occurred as a result of E. coli contamination. Since January, 2000, more than 20 million pounds of beef have been recalled in North America. Of still greater concern is the cost of treating infected individuals. A recent U.S. study estimated the annual cost of E. coli O157:H7 illnesses to be $405 million (in 2003 dollars). Those costs that contributed to this estimate included $370 million for premature deaths, $30 million for medical care, and $5 million for lost productivity.
In addition to the direct human costs due to E. coli O157:H7 infection, cattle and dairy producers, meat packers and dairy processors, meat and milk distributors and wholesale and retail food outlets all incur direct and indirect costs (reduced demand for their product) associated with this foodborne disease threat.
Review the Dynamics of E. coli 0157:H7 White Paper
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