Science

Applied Carbohydrate Chemistry Platform

Carbohydrates have been shown to play a fundamental role in normal cell functions as well as in major disease pathologies including cancer, cardiovascular disease and inflammatory diseases. As a class of molecules, carbohydrates have an enormous range of shape, orientation and composition. Due to this structural diversity, carbohydrate chemistry can be applied to develop a broad range of complex therapeutic molecules and drugs, including pure carbohydrates as well as protein-linked carbohydrates, or glycoproteins. However, as a consequence of their structural complexity, carbohydrates have not received as much scientific attention as nucleic acids and proteins. We view this technology gap as a unique opportunity to apply our expertise in carbohydrate engineering to develop therapeutic molecules for unmet medical needs.

Boston Therapeutics’ technology platform in applied carbohydrate chemistry has been pioneered by our CEO David Platt and his scientific collaborators over the last 20 years and is summarized in two recent books that he co-edited, "Carbohydrate Drug Design (2006)" and "Galectins (2008)". Our deep domain experience in engineering complex carbohydrates has enabled us to pursue a unique pipeline of carbohydrate-based therapeutics that addresses unmet medical needs both safely and effectively for both oral and injectable applications.

Mannan and the Glycemic Index

The active ingredient in PAZ320 is a mannan. PAZ320 is a non-systemic, non-toxic, chewable drug candidate for prevention of diabetes and its complications. PAZ320 inhibits the enzymes that release glucose from complex carbohydrates in foods during digestion, reducing the amount of available glucose absorbed through the intestine. PAZ320 is a proprietary fractionated mannan. Mannans are a group of plant-derived complex carbohydrates, or polysaccharides, which consist mainly of polymers of the sugar mannose. Some of the plants from which mannans are derived are guar, locust bean, fenugreek, barley and konjac. Published studies on mannans have shown that they possess significant biological activity ranging from inhibition of cholesterol absorption to promoting wound healing and inhibiting tumor growth. Studies have also shown that consuming mannan before a meal can lessen the rise in blood glucose after the meal. Therefore, supplementation with mannan may be beneficial in the management of diabetes by supporting healthy blood sugar levels.

The modified mannan in the PAZ320 chewable tablet works to lower the rise in post-meal blood glucose in several ways. First, it binds to long-chain starch polysaccharides in food and to the digestive enzymes that cleave these large sugars into glucose. Second, it temporarily coats the lumen of the small intestine to slow the absorption of glucose. Finally, BTI's mannan induces satiety, thereby facilitating portion control as a secondary benefit.  Together, these mechanisms of action lower the rate of absorption of glucose from the small intestine into the blood.

In a research effort to find out which foods are best in terms of blood sugar control for those with diabetes, the concept of the glycemic index, or GI, was developed at a leading university in Toronto, Canada in 1980. Foods containing carbohydrates that break down quickly and easily during digestion, and thus release glucose rapidly into the bloodstream, have a high GI; foods containing carbohydrates that break down more slowly resulting in a gradual release of glucose, have a low GI. A lower GI may also result in a lower insulin response and thereby, improves long-term blood glucose control in both healthy and diabetic individuals.

Based on the body of scientific evidence for the mechanisms of how mannans work, we have optimized the formulation of mannans in PAZ320 chewable tablets to slow down the post-meal digestion and absorption of glucose in order to moderate blood sugar levels. Therefore, the dietary addition of PAZ320 chewable tablets may effectively reduce the total glycemic load in a high glycemic meal and may aid in the control of blood glucose levels in people with diabetes and pre-diabetes, and others with metabolic syndrome.

IPOXYN™: Prevention of Necrosis and Treatment of Limb Ischemia

Cell death can occur through two main mechanisms, apoptosis and necrosis. Apoptosis is a tightly regulated process in the body and many of the intracellular proteins and enzymes involved are well characterized. Necrosis has been viewed in the past as an accidental pathological mode of cell death. Recently, evidence has indicated that some forms of necrotic cell death could be related to intrinsic cellular mechanisms.

Necrosis is the outcome of severe and acute injury. It is involved in many pathological conditions such as, heart attack, brain injuries and stroke, neurodegenerative diseases such as Alzheimer’s, dementia, Lou Gherig’s disease (ALS), septic shock, liver cirrhosis, chronic hepatitis, pancreatitis, muscle necrosis, diabetes mellitus, acute or critical limb ischemia, gangrene, chronic pressure ulcers and many others.

Necrosis occurs following ischemia (shortage of oxygen supply to the tissue due to restriction in blood supply). The only treatment available at present for necrosis is providing oxygen by a high pressure facility. Thus, there is a crucial need to develop drugs for prevention and treatment of this pathology.

Limb ischemia is a chronic condition of severe obstruction of the peripheral circulation that results in severe pain in the extremities. Due to the constriction of blood vessels, especially capillaries, red blood cells are unable to flow through them and this disruption in the microcirculation leads to the deprivation of oxygen, or ischemia. Complications include gangrenous sores and wounds that won’t heal, typically in the legs and feet. If left untreated, these lesions can result in amputation of the affected limb. Lower limb ischemia is a life-threatening complication for patients with poorly-controlled diabetes and affects 10% of the diabetic population. Brem Harold, Tomic-Canic Marjana (2007). Cellular and Molecular basis of wound healing in diabetes. JCI 117 (5): 1219–1222. doi: 10.1172/JCI32169. PMC 1857239. PMID 17476353. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1857239

For decades, oxygen carriers have been developed for perfusion and oxygenation of ischemic tissue None have yet succeeded. These products were either blood-derived elements, synthetic perfluorocarbons or red blood cell modifiers. Several of the Hemoglobin-Based Oxygen Carriers (HBOC), contained nonfunctional methemoglobin impurities. These products failed to secure FDA approval based upon either poor outcomes in clinical trials or poorly formulated product.

Our approach to treatment of ischemic tissue and prevention of necrosis is fundamentally different. Boston Therapeutics’ injectable drug, IPOXYN™ is a New Chemical Entity (NCE) and not a biologic blood substitute. IPOXYN™ is a modified Heme chemical structure. A significant improvement over HBOCs, IPOXYN™ prevents methemoglobin formation associated with the adverse effects of vasoconstriction and myocardial infarction.

Furthermore, because of IPOXYN™’s extremely small molecular size, roughly 1/5,000th the size of a red blood cell, IPOXYN™ is able to perfuse constricted, ischemic capillaries which are inaccessible to red blood cells. This small molecular size has particular significance in treating vascular complications of diabetes since red blood cells may already be enlarged and lower limb vasculature may be compromised.

We also intend to file a registration for IPOXYN™ for veterinary applications under the name OXYFEX™. We are unaware of any drug currently on the market for animals that can deliver oxygen, and there is only limited “blood banking” for animals despite a constant need. OXYFEX™ can serve as the only available oxygen delivery mechanism for animals suffering ischemia or traumatic and surgical blood loss events.

We expect to commence marketing OXYFEX™ for veterinary applications, which we view as a potentially lucrative market in 2014 in various locations around the world. We estimate that there are at least 15,000 small animal veterinary practices in the U. S., another 4,000 mixed animal practices treating small and large animals in the U.S. and approximately 22,000 small animal practices in Europe. We believe that the average veterinary practice treats only a small percentage of canine anemia cases with red blood cell transfusion. The remaining animals receive either cage rest or treatment such as fluid administration, iron supplements, nutritional supplements or inspired oxygen. The FDA Center for Veterinary Medicine approved a bio-similar product to OXYFEX™ named Oxyglobin in 1998 and the European Commission approved Oxyglobin in 1999, in both cases for the treatment of canine anemia, regardless of the cause of the anemia. Oxyglobin is no longer in use. Based upon the prior, limited efforts of the now bankrupt third party that developed Oxyglobin, we believe that the potential veterinary market for OXYFEX™ in the U.S. alone could exceed $250 million in sales annually within a few years after introduction.

Polysaccharides and Inflammation

Several chronic diseases such as Type 2 diabetes, metabolic syndrome and cardiovascular diseases have been shown to be associated with inflammation attributable to increases in TNF-α, IL-6 and C-reactive proteins, in addition to others. Furthermore, evidence strongly supports a link between inflammatory bowel disease (IBD) and various medical indications.

It has been shown that pectin, a plant-derived carbohydrate, has a favorable effect on a broad range of pathological conditions. In IBD, pectin may aid in decreasing the inflammatory response in the colon by moderating the amounts of pro-inflammatory cytokines and immunoglobulins, and may work to reduce inflammation in a dose-dependent manner.

Our proprietary carbohydrate new chemical structure called BTI-9 is a patented, polysaccharide which has been shown to bind to TNF-α and thereby block immune system activation and inflammation. We expect BTI-9 to be available in late 2014 as a dietary supplement to support colon health.