Biotec Pharmacon’s clinical development program is based on comprehensive studies of the ability of SBG to heal ulcers in diabetic patients and strengthen the immune mechanisms that kill cancer cells.
The immune system
The body’s immune system consists of a large number of white blood cells that protect against disease. Together they constitute the immune system— 2-3% of the body’s weight—which extends throughout the body, although mostly in surface tissue. As many as two-thirds of all immune cells are found in the intestines.
It is customary to describe the immune system as two different systems: One is called the innate immune system, the other the adaptive immune system. The Innate system is already fully developed at birth and is found in all animal species. This functions as the first line of defense and respond swiftly to arrest most infections. The white blood cells that constitute the innate human immune system are equipped with biochemical killer mechanisms that can destroy microorganisms and cancer cells. They also play the main role in eliminating dead cells from the body and in repairing damaged tissue.
The adaptive immune system is activated when an infection is about to overpower the defense mechanisms of the innate system. It takes a week or more for the white blood cells that belong to this system to begin producing antibodies against microorganisms that have succeeded in penetrating the outer defenses. But if the same infection recurs, this system responds swiftly and effectively. It “remembers” previous infections and strikes back immediately if an infection recurs. This is the basis of vaccination: protection against later infection by giving the body substances (antigens) that are specific to a particularly dangerous organism, and to which the immune system reacts as if an infection were present. The innate immune system functions as a central regulatory and monitoring system for the body’s total immune defense. Via its action on the innate system, the adaptive system can, for example, be regulated to improve the efficiency of vaccines. The action on the innate system can also be regulated to have an inhibiting effect on immune reactions so that otherwise dangerous inflammations are held in check.
Biotec Pharmacon has based its pharmaceutical development program on research into how the innate immune system functions and how beta-1,3/1,6-glucan SBG can strengthen or suppress immune reactions. The action of the innate immune system when SBG is administered affects quite fundamental immune mechanisms that, in turn, can affect many different pathological conditions. For millions of years, animals and humans have made use of a chemical structure corresponding to SBG as a general alarm signal for mobilizing the immune system’s fight against infections. We now know that white cells such as macrophages, dendrite cells, natural killer cells, and granulocytes, which are all part of the innate immune system, are equipped with quite special surface structures called receptors that bind SBG. Not only does the binding of SBG to white blood cells in mucosa result in a general mobilization of defenses against infection, it also strengthens the body’s ability to repair tissue damage and triggers mechanisms that are active in killing cancer cells. Biotec Pharmacon has given high priority to the treatment of diabetic ulcers and to the immunotherapy of cancer in its pharmaceutical development program. Due to SBG’s effect on fundamental mechanisms in the innate immune system, the product will also be of potential use in other clinical indication areas.
Treatment of ulcers
Skin wounds usually heal without complications in humans with well-functioning immune systems. The white blood cells in the skin’s connective tissue, especially macrophages, play a key role in normal wound healing. We have found that the functioning of these cells is impaired in diabetics, which may explain why diabetics, more than other persons get ulcers that do not heal. The effect of SBG on this disease is based on knowledge of the mode of action and physical qualitaties of this type of substances. This knowledge was the reason for the company’s decision to give priority to the treatment of diabetics in its development program. The first studies with a limited number of patients, carried out in Archangelsk in Russia, yielded very good results and created the confidence needed for the company’s decision to go ahead developing a product for this area. In 2006, the phase II study was conducted in Archangelsk and St. Petersburg on a total of 60 patients. The study yielded good results compared to studies with the best preparations available on the market. The results were not statistically significant after twelve weeks of treatment (primary end point), but additional non-prespecified analyses showed statistically significant differences in favor of SBG after eight weeks of treatment. This early induction of healing is very important because the major cost of treating diabetic ulcers is the number of days a patient is hospitalized. Two phase III studies was then initiated, where both studies failed to show significant effect of SBG against the comparator used. The work following these results revealed that the product had become broken during long time storage in Polyethylene ampoules. A sub analyses of patients treated with a freshly manufactured SBG versus a long time stored SBG showed significant differences between the two, where the former showed over 50% healing after 8 weeks, whereas the latter only just above 20% healing ratio. Animal studies performed in parallel also demonstrated that SBG stored in PE ampoules had lost healing capabilities, whereas more stable SBG gels had improved healing capabilities.
The Company is thus pursuing this indication with a stabilized gel product.
To treat cancer patients with pre-made antibodies that are specific for their particular cancer types has become a large market for cancer treatment products. Such monoclonal antibodies (mAbs) can be made by biotechnological methods, using a uniform (mono-clonal) cell line. Such mAb products have become block-buster commercial products with total sales worth more than USD 10 billion in 2009. Still the life extension of cancer patients treated with mAbs is far from being satisfactory and it is apparent that a more overall immune response is needed to mount an aggressive attack on the tumor.
Already in the 1980-ies, professor Seljelid at the University of Tromsø, demonstrated in experiments with mice that beta-glucans were effective in tumor eradication when there was a concomitant specific, but in itself ineffective, immune reaction against the tumor. Beta-glucans were thus able to elicit a response that acts in concert with adaptive immunity to eradicate cancer cells most likely through the concomitant activation of innate immune responses, especially phagocytic cells like macrophages.
Since 2004 a clinical development agreement between the Company and Memorial Sloan-Kettering Cancer Center in New York was established based on these ideas and on encouraging pre-clinical studies carried out with oral administration of SBG and injected cancer mAbs.
The current cancer immunotherapy concept of Biotec Pharmacon is to combine the established practice of injecting cancer specific human antibodies (mAbs) with oral administration of SBG. Three early phase clinical safety studies have been performed with commercial antibodies like Herceptin (breast cancer) and Rituximab (Non-Hodgkin’s lymphoma) together with the anti-GD2 antibody for treatment of neuroblastoma in children. All studies have confirmed that the combination of SBG and mAb is safe. The company is currently evaluating how these studies is to be followed up with phase II clinical studies to further establish efficacy data for the combination.
Inflammatory bowel disease
In collaboration with the immunology group at Laboratory for Immunology and Immunopathology at the National Hospital in Oslo, the company has initiated a research program on how Soluble Beta-Glucan could affect the development of inflammatory bowel disease. As for diabetic ulcer there are very limited medicinal products available for effective treatment of IBD, there is thus a need for novel products that can help this large patient group. The studies performed showed significant effect of administering beta-glucan in preventing development of ulcerative colitis in an experimental animal model. The collaboration also lead to novel insight into the mode of action of beta-glucans when administered to mucosal surfaces, as well a new IP on the potential use of Soluble Beta-Glucan in treatment inflammatory bowel disease.
Oral mucositis is an inflammation of the mucosa of the mouth and pharynx, ranging from redness to severe ulceration. Oral mucositis is a common and very painful complication of radiation- and chemotherapy of cancer, because such treatments destroy immune cells involved in regeneration of mucosal tissues. Biotec Pharmacon has performed two clinical trials to test the effect of SBG against oral mucositis. Unfortunately the product used in the phase III trial suffered from the same stability problems as did the product for diabetic ulcer, and further development within this area has been put on hold for the time being. The Company has an Orphan drug designation for the use of SBG in this indication.