Most organ damage is the result of acute and chronic inflammatory reactions resulting from various underlying causes. Therapeutic areas characterized by organ damage and related diseases are largely underserved with drug products . Chronic liver disease (CDL) or liver dysfunction is characterized by liver damage which is a major concern in organ damages. Crohn’s disease is an inflammatory bowel disease.

Crohn's disease (CD)

CD is an inflammatory bowel disease (IBD) and an autoimmune inflammatory condition that primarily affects the lower part of small intestine, called the ileum. The disease, which is chronic and incurable, usually presents in adolescence or early 20's. People of Jewish heritage have an increased risk of developing Crohn’s disease, while African Americans are at decreased risk for developing Crohn’s disease. The prevalence of the disease is 100–200 cases per 100,000 in Europe and North America. IBD accounts for significant morbidity and lower quality of life and is responsible for nearly $2.0 billion in annual medical costs in the United States.

This disease is characterized by recurrent inflammation, intestinal adhesion and bowel obstruction. The major symptoms of Crohn’s disease include abdominal pain, diarrhea, gastrointestinal bleeding, malabsorption, and weight loss. Although the etiology of Crohn’s disease remains unknown, research evidences suggest that it involves a complex interplay of environmental, genetic, microbial, immune, and nonimmune factors. The current standard of treatment includes anti-Inflammation drugs, steroids, immunosuppresants, and anti-TNF biological drugs e.g. Infliximab (Remicade) that relieve disease symptoms but may induce adverse events. Currently, no effective treatment of the disease is available in the market place.

TLR4 expression on intestinal epithelial cells is upregulated in both CD and UC, whilst expression of TLR2 and TLR5 remain unchanged. Furthermore, expression of TLR4 and TLR2 on lamina propria macrophages is also increased. A large North American study found a positive association between TLR4 polymorphisms and CD.

In a published pilot Phase 2 study, JKB-122, a TLR4 antagonist, has exhibited efficacy in treating patients with active CD.

Chronic Liver Disease (CLD)

The term "chronic liver disease" (CLD) encompasses a large number of conditions having different etiologies and existing on a continuum between hepatitis infection and cirrhosis. Chronic liver disease is the 10th leading cause of mortality in the US and is responsible for the deaths of more than 25,000 Americans each year. Liver inflammation is characterized by the destruction of a number of liver cells and the presence of inflammatory cells in the liver tissue and it can be caused by diseases that primarily attack the liver cells. Hepatic fibrosis is a reversible scarring response to chronic liver injury which produces inflammation initially.

Progression of liver inflammation leads to hepatic fibrosis followed by cirrhosis, liver cancer and liver failure. However, the current treatment of hepatic inflammation/fibrosis has been focused on removing the underlying cause of the liver injury. This would include anti-viral therapy in HCV- or HBV-induced viral hepatitis, exercise or diet control in non-alcoholic steatohepatitis (NASH) and abstaining from alcohol in alcoholic liver disease.

Drug treatments aimed at reversing fibrosis are usually too toxic for long-term use (e.g., corticosteroids,) or have no proven efficacy (e.g., colchicine). Anti-viral therapies such as interferon are not effective in treating fibrosis or cirrhosis and CLD remains with HCV patients despite of HCV eradication. Other anti-fibrotic treatments are under study. To date there are no FDA approved therapies for liver fibrosis which can reduce the progression of fibrosis or cirrhosis nor for liver inflammation.

Chronic liver disease associated with chronic hepatitis C

According to the Centers for Disease Control and Prevention, approximately 200 million people worldwide including 3.2 million in the United States are infected with the hepatitis C virus (HCV). Among HCV-infected patients, 15-20% spontaneously clears the infection without treatment within 6 months, but the majority becomes chronically infected. Over a period of decades, about 50%-60% of chronically infected people develop a mild to moderate form of chronic liver disease that can result in fibrosis. Approximately 5 to 20% of chronically infected patients develop cirrhosis over periods of approximately 20 to 25 years and 1–5% will die from the consequences of chronic infection (liver cancer or cirrhosis). Chronic hepatitis C is the leading cause of cirrhosis and liver cancer and the most common reason for liver transplantation in the US and in the Western World. HCV related chronic liver disease accounts for estimated 8,000–10,000 deaths each year in the US.

Triple combination therapy using pegylated interferon (IFN), and ribavirin with newly approved specifically targeted antiviral therapy against HCV (STAT-C) will be the standard treatment of choice for HCV eradication. Monotherapy of the potent STAT-C therapy has been complicated by rapid development of drug-resistant mutants and side effects. Efficacy of triple combination therapy in sustained viral eradication is increased to 60-70 in patients with genotype 1 only and 80% or higher with genotypes 2 and 3. Treatment can be accompanied by side effects such as influenza-like symptoms, severe depression or other neuropsychiatric symptoms, and serious hematological abnormalities. Drug resistance and limited improvement in efficacy in the triple combination with an increase in side effects and dropouts are key challenges facing this emerging field.

Hepatitis C virus (HCV) infection is the leading cause of CLD and the most common indication for liver transplantation. Approximately 200 million people worldwide are infected with the hepatitis C virus. Standard interferon therapy is very expensive, not well tolerated and not very effective. Few options exist for patients who either do not respond to the therapy, who respond and later relapse, or who are intolerant to therapy, and deterioration of the liver continues. Given the morbidity associated with the HCV infection, there is an urgent need for an effective, well tolerated, and inexpensive non-antiviral therapy to treat CLD (inflammation and fibrosis) associated with chronic hepatitis C

TLR4 (toll-like receptor 4) is a key mediator of the release of proinflammatory cytokines and inflammatory responses and a member of TLR family which are mainstays of the innate immune system and best known for their role in host defenses against infections. Lipopolysaccharide (LPS), an endotoxin, is a specific agonist for TLR4 and patients infected with chronic HCV infection display more than a 10-fold-increase in serum levels of endotoxins than the healthy people and an increased expression of TLR4. The high serum levels of endotoxin become normal upon eradication of HCV virus. Hepatitis C virus can selectively activate innate immune system TLR4 to produce an inflammatory state. In addition, TLR4 is expressed in two key liver cell types involved in hepatic fibrosis: hepatic stellate cells and Kupffer cells. The implication of TLR4 signaling in chronic liver disease has been reviewed and suggests that a TLR4 antagonist is of potential in treating CLD.

The clinical relevance of TLR4 antagonists is clearly indicated in this important, but very underserved medical market. The availability of such small-molecule antagonist products delivered by the oral route presents a unique market opportunity that has thus far been elusive. The market size for the disease is estimated to be $7.5 billion in U.S. by 2015 and suggests remarkable product opportunities.

NASH (Non-alcoholic Fatty Liver Disease)

Nonalcoholic steatohepatitis (NASH) is a common, often "silent" liver disease. It resembles alcoholic liver disease but occurs in people who drink little or no alcohol. NASH is characterized by lipid accumulation in hepatocytes and inflammatory cell infiltration, which leads to hepatic fibrosis and cirrhosis. Most people with NASH may feel well and not be aware that they have a liver problem. Blood lipid tests may suggest the condition is present and physicians may then elect to perform a liver biopsy.

NASH affects 2 to 5 percent of Americans. An additional 10 to 20 percent of Americans have fat in their liver, but no inflammation or liver damage, a condition called "fatty liver." Left untreated, NASH can lead to the more serious cirrhosis, permanently damaging the liver with scarring and no longer able to fully function. For example, more than 30 million of the obese adult population in the U.S. may have ongoing process of steatosis, ongoing excessive fat deposition in the liver, and of those, more than 9 million may have progressed to steatohepatitis, excessive accumulation of fat in the liver. Diabetes mellitus affects more than 10% percent of the U.S. adult population and 50% of those patients, as many as 10 million people, may have NASH.

The underlying causes of NASH remain unclear. The morbidity of NASH is not simply due to obesity, for example, that then affects the liver. Several pathologies may also contribute, including insulin resistance, release of toxic inflammatory cytokines by adipocytes, and intracellular oxidative stress to liver cells. Currently, there are no FDA-approved treatments for NALFD and NASH. Experimental approaches under clinical evaluation in patients with NASH include antioxidants (for example, vitamin E), selenium, and betaine, as well as newer antidiabetic medications. In two pilot trials, pentoxifylline, which inhibits TNF-alpha? production, was reported to show beneficial effects in improving aminotransferase levels, hepatic steatosis, fibrosis and necro-inflammation among patients with NASH.

TLR4 and NASH As described above, NASH is characterized by lipid accumulation in hepatocytes and inflammatory cell infiltration, which leads to hepatic fibrosis and cirrhosis. In addition to its role in hepatic fat accumulation, the TLR4 ligand LPS is also involved in the development of NASH. A crucial role for LPS signaling in NASH was first demonstrated by the increased hepatic sensitivity of genetically obese rodent models (fa/fa rats and ob/ob mice) to low doses of LPS. The predominant role of TLR4 signaling in NASH is further emphasized by the ability of the TLR4 ligand LPS to exacerbate liver injury in mice treated with a methionine–choline-deficient (MCD) diet, a model of NASH. This finding has been further confirmed in TLR4-mutant mice which were fed with a high-fat diet (MCD). In this study on wild type mice fed the MCD diet, enhanced TLR4 expression was observed, while loss of TLR4 in TLR4-deficient mice attenuated liver injury, lowered hepatic mRNA levels of fibrosis markers such as TGF?1 and collagen ?1 (I), and decreased lipid accumulation. These results indicate that activation of the TLR4 signaling pathway plays an important role in the pathogenesis of NASH. The literature evidence clearly points to the inhibition of the TLR4 signaling pathway by antagonists as an effective therapy in the prevention of inflammatory hepatic injury in NAFLD, the progression to NASH and fibrosis, and ultimately cirrhosis.