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Monday, November 23, 2015

Can-Fite Advances CF102 Into NASH Market

On November 23, 2015, Can-Fite BioPharma (NYSEMKT:CANF) announced development of CF102 will be expanded into non-alcoholic steatohepatitis (NASH) based on compelling preclinical data.  The drug is currently being investigated in a Phase 2 program for hepatocellular carcinoma (HCC), the most common form of liver cancer, an indication for which the drug has granted both Orphan Drug designation and Fast Track development status. Can-Fite has filed a method-of-use patent for CF102 in the treatment NASH and expects to begin initial human clinical studies under the current active Investigational New Drug (IND) application in 2016.

I was able to obtain from management some additional information about the "compelling" preclinical data cited in the company's press release. Below are the data from the preclinical study, along with some background information on CF102 and the NASH market.

Quick Backgrounder On CF102

As noted above, CF102 is currently being investigated in a Phase 2 clinical trial for advanced HCC in patients with Child-Pugh B cirrhosis (NCT02128958). Standard of care for these patients is Nexavar® (sorafenib), a billion-dollar drug with an approved label for both HCC and renal cell carcinoma (RCC). Phase 3 data on Nexavar® shows the drug extends lives of patients with advanced HCC by about 2-3 months (Llovet et al, 2008Cheng et al, 2009), but is rather ineffective in patients with Child-Pugh B cirrhosis (DA Fonseca et al, 2015). In contrast, based on data from Can-Fite's Phase 1/2 clinical program, CF102 offers a meaningful survival benefit in advanced HCC patients with Child-Pugh B cirrhosis (Stemmer SM, et al, 2013), along with good safety and tolerability. Based on the available data, the U.S. FDA granted CF102 Fast Track development status. More about the Phase 2 HCC program can be learned by reading my article from September >> HERE <<.

Can-Fite's CF102 is an A3 adenosine receptor (A3AR) agonist that has demonstrated impressive anti-cancer activity in a host of various solid tumor animal studies, including melanoma (Fishman et al. 2002; Madi et al. 2003), prostate cancer (Fishman et al, 2003), colon cancer (Fishman et al, 2004), and liver cancer (Bar-Yehuda et al, 2008; Cohen et al, 2011). A3AR is highly expressed in liver cancer cells, and up-regulation by CF102 triggers cell apoptosis through decreased production of cyclic AMP and Protein Kinas A. The preclinical liver cancer data is among the most impressive generated by the company. With today's news, it now seems as though the mechanism of action for CF102 has utility far earlier in the progression of liver disease, starting with non-alcoholic steatohepatitis (NASH).

What Is NASH?

NASH, also called "fatty liver", is a condition in which fat builds up inside the liver causing inflammation. Prior to the presence of inflammation, the disease is simply referred to as non-alcoholic fatty liver disease (NAFLD), the most common form of liver disorder in the United States. The accumulation of macroglobular fat inside the liver causes oxidative stress that reduces the efficiency of the liver and can lead to increased liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Loss of liver efficiency and oxidative stress leads to inflammation, liver cell ballooning, and the development of NASH. Prolonged inflammation results in cirrhosis (scar tissue), liver failure, or liver cancer. 

Rates of NAFLD and NASH are increasing in the U.S. in concert with increasing rates of obesity and diabetes. In fact, NASH is now the third leading cause of liver transplant in the U.S. According to the U.S. National Institutes of Health, an estimated 15-30% of Americans have fatty liver, with approximately 20% going on to develop NASH. The American College of Gastroenterology estimates 2-5% of adult Americans and up to 20% of those who are obese may suffer from NASH, putting the target population in the country between 5 and 10 million individuals. Despite the progression of several interesting clinical-stage candidates by companies such as Gilead, Genfit, and Intercept, there are currently no U.S. FDA approved treatment options for NASH.

CF102 Preclinical Data

New preclinical data studying CF102 in a mouse model of liver disease revealed the drug's capability to improve liver pathology in NAFLD and NASH. The data showed:

- CF102 had a statistically significant reduction in NAFLD Activity Score (NAS) compared to placebo. NAS was developed to provide a numerical score for patients who most likely have NASH. Accordingly, NAS is the sum of the separate scores for steatosis (0–3), hepatocellular ballooning (0–2), and lobular inflammation (0–3), with the majority of patients with NASH having a NAS score of ≥ 5. This system was developed as a tool to quantify changes in NAFLD during therapeutic trials. The CF102 preclinical data shows statistical significance for both the high and low doses.

- CF102 reduced liver-to-body weight compared to placebo. Because of the excess accumulation of globular fat and inflammation of the liver, a NASH liver becomes enlarged and heavier than a normal healthy liver. A reduction in liver-to-body weight is evidence of reduced fat and inflammation in the liver, and a sign that the drug is the improving disease condition.

- Liver sections from the placebo group exhibited severe micro- and macrovesicular fat deposits, hepatocellular ballooning and inflammatory cell infiltration, whereas the CF102 treated group showed a significant decrease in steatosis, ballooning and lobular inflammation compared to the placebo group.

- CF102 decreased plasma ALT and triglycerides levels in the livers of NASH-model compared to placebo. This is a sign of improved liver function and efficiency. Separate studies with CF102 demonstrated efficacy in the treatment of liver regeneration and function following liver surgery.

- Representative photomicrographs of H&E-stained liver sections showed improved pathology in animals receiving CF102 vs. placebo. 


Previous Phase 1/2 data with CF102 demonstrated excellent safety, tolerability, bioavailability, and pharmacokinetics at doses up to 25 mg BID. Results also showed encouraging signs of improving survival in patients with advanced HCC, particularly in Nexavar® (sorafenib) failure patients with more advanced cirrhosis. The mechanism of action for CF102 now looks like a pan-hepatic improver of liver pathology, applicable to earlier-stage liver diseases such as NAFLD and NASH.

NASH is believed to be the next big global pandemic given the soaring rates of obesity, diabetes, and metabolic syndrome all over the world. Deutsche Bank market research pegs the current NASH market at approximately $1.5 billion, but projects the addressable market could approach $40 billion in 10 years as incidence and diagnosis increase. Until recently, investors have been focusing on Can-Fite's Phase 3 assets, piclidenoson (formerly CF101), for the treatment of rheumatoid arthritis and psoriasis; however, given recent advancement of the CF102 program in HCC and now new data showing potential utility in NASH, I suspect the market will start to pay more attention to this drug going forward, as it represents a tremendous opportunity for the company.

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