Introduction
The laboratory discovery that NV-07α has potent anti-inflammatory properties in other sites in addition to skin suggested the possibility that this compound may also be a useful anti-inflammatory therapeutic for systemic use. Thus the development of a prescription systemic anti-inflammatory drug based on NV-07 technology has provided significant new therapeutics with low toxicity and high tolerability for long term use in chronic inflammatory disease conditions, diseases such as rheumatoid arthritis, osteoporosis and chronic back pain.
The Anti-inflammatory Drug Development Program, is founded on preliminary in vitro observations that, in a number of standard anti-inflammatory assays, these compounds produced unusually potent antagonism of inflammatory pathways, including the arachidonic acid pathways and some cytokine cascades. A series of experimental models is being used to determine the likely effects in joint inflammation, major areas of health concern which are currently addressed by a range of often poorly efficacious anti-inflammatory interventions many of which have serious side effects.
The US market for non-steroidal anti-inflammatory drugs (NSAIDs) in 2006 was close to $US10 billion and this is expected to grow to greater than $US18 billion by 2015.
The FAIM Program
The term 'FAIM' is an acronym for Flavonoid Anti-Inflammatory Molecule, a new family of drug candidates developed by Novogen from its patented flavonoid technology platform. They have a high safety profile and an unusually pronounced anti-inflammatory effect, lending them to likely use in general pain relief.
Currently, the most commonly used anti-inflammatory agents are non-steroidal anti-inflammatory drugs (NSAIDs) and they work by inhibiting the enzyme cyclooxygenase (COX). While they are effective at reducing inflammation, their long term use has always been limited by gastrointestinal side effects such as gastric ulceration, perforation and bleeding, as well as acute renal failure and hypertension. These shortcomings were addressed by the development of agents which selectively inhibit one of the COX enzymes involved in the inflammatory process, cyclooxygenase 2 (COX-2). These drugs, known as COX-2 inhibitors or COXIBs, reduce the risk of gastrointestinal side effects but inadvertently promote production of another inflammatory mediator, thromboxane (TXA2), which causes blood clotting. It is now well understood that COXIBs in particular, and in fact all NSAIDs in general, are associated with an increase in cardiovascular risk factors.
Novogen’s FAIM candidates display anti-inflammatory activity without inhibiting COX. Copnsequently the associated cardiovascular, gastrointestinal or renal side effects that are caused bu COX inhibition will be absent. They have the potential to be used as safer alternatives to NSAIDs and COXIBs to treat diseases such as osteoarthritis, rheumatoid arthritis, and other inflammatory conditions causing chronic pain. Currently a number of these unique drug candidates are progressing through preclinical screening prior to entry into human clinical trials.
Chronic inflammatory bowel conditions and current treatments
A novel compound, NV-52, had been developed to address the specific problem of inflammatory bowel disease (IBD). IBD is the term used to describe two diseases: ulcerative colitis (UC) and Crohn’s disease (CD). UC causes inflammation of the inner lining of the large bowel (colon and rectum). CD causes inflammation of the full thickness of the bowel wall and may involve any part of the digestive tract from the mouth to the anus. CD can cause recurrent bowel obstruction, fistulae and abscess formation and sepsis as well as extra-intestinal manifestations such as arthritis. The Crohn’s and Colitis Foundation of America estimates as many as 1,000,000 Americans have IBD costing directly and indirectly around $US552 billion annually. It is estimated that about 61,000 Australians have IBD - approximately 33,000 have UC and 28,000 have CD
The cause of IBD is unknown. However, both syndromes would appear to be immunologically mediated and the inflammatory process is influenced by environmental and genetic factors. Medical therapy aims to control the inflammatory process, and is administered for active and chronic disease, as well as remission maintenance. No management strategy is totally effective, but current therapy is targeted at reducing inflammation and/or the immune response using anti-inflammatories (corticosteroids, aminosalicylates), immunosuppressives, immunotherapies or surgery. All of these therapies are accompanied by marked side effects.
The treatment of UC depends on the amount of large bowel affected and the severity of inflammation. Within one year, approximately 80% of patients will relapse without therapy. If remission cannot be successfully managed, the large bowel is removed surgically, requiring a colostomy.
CD is treated similarly to UC except that maintenance therapy is not as effective as in UC. With no remission therapy, relapse rates can be as high as 60% within a year, reducing to 10-30% with surgery plus control therapy. Whilst CD cannot be cured surgically, as the disease involves the entire gastrointestinal tract, many patients have multiple surgical interventions where portions of their bowel are removed. As well, CD patients have an increased risk for cancer of both the small and large bowel.
NV-52
NV-52 is a synthetic anti-inflammatory drug based on an isoflavan ring structure and is being developed as an orally-delivered non-toxic agent to be used to maintain remission of IBD. It is a selective thromboxane synthase (TXS) inhibitor, and will therefore play a major therapeutic role in IBD due to its apparent ability to inhibit pro-inflammatory thromboxanes. Thromboxanes are produced in excess in inflamed gut mucosa of IBD patients and even in the uninflamed bowel in CD.
NV-52 administered orally is protective in a mouse model of IBD, and treatment is as effective when the drug is administered prior to the onset of disease alone, as when given throughout the induction and resolution of colitis. Thus maintenance of remission, currently an area of unmet clinical need, seems a highly achievable therapeutic target for this new drug.
NV-52 has not displayed any toxicity in in vitro and extensive animal toxicological studies. Phase 1a and 1b clinical trials in healthy human volunteers have been completed, where it demonstrated no detectable side effects and indications from the pharmacokinetic profiles observed in these studies are that it may only need to be taken as a once a day dose.
NV-52 is now a principal developmental drug of interest for the prevention of relapse in IBD, particularly for the large portion of patients who have mild-to-moderate disease. Novogen believes that this compound will become a leading therapy for the treatment and maintenance of remission in IBD.
