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Liver diseases such as hepatitis B, hepatitis C, primary liver cancer and liver cirrhosis represent some of the most widespread and serious diseases in the world. Our proprietary HepDirect® prodrug technology gives us a competitive advantage for treating many of these important diseases. Together, liver and metabolic diseases comprise a large segment of the global pharmaceutical markets. We currently have two product candidates moving through clinical development for liver diseases, but consider these non-core to our new strategic focus and do not plan to independently develop any additional product candidates in this category.
Primary Liver Cancer represents the fifth most common and third most deadly cancer worldwide and is reported to claim as many as one million lives a year.1,2 In addition, up to one million new cases of primary liver cancer are diagnosed worldwide each year.3,4 In Europe and the U.S., incidence of HCC has tripled in the last 15 years and is increasing at 6-8% per year. In 2006, there were 15,000-20,000 cases of HCC reported in the U.S. and 35,000-40,000 in Europe, while there were almost 500,000 in parts of Asia.2
Hepatitis B is the most common serious liver infection in the world, with over one-third of the global population having been infected at one time, with over 400 million of those patients becoming chronic carriers of the disease. Hepatitis B can be a deadly disease. It may lead to cirrhosis of the liver and can greatly increase a patient's chances of developing liver cancer. Despite its prevalence, hepatitis B remains a poorly treated disease.5
MB07133, a HepDirect Oncolytic for the Treatment of Primary Liver Cancer
MB07133 is an intravenously administered product candidate for the treatment of patients with unresectable primary liver cancer (hepatocellular carcinoma, or HCC). Few treatment options exist for these patients with only one recently approved drug treatment, Nexavar, a member of a class of drugs that work by inhibiting angiogenesis in patients with HCC. MB07133 is a HepDirect prodrug of an activated form of cytarabine (araC), an anti-cancer drug that is used to treat leukemia but is ineffective against primary liver cancer in its native form. AraC's anti-cancer activity is associated with its ability to be converted to its biologically active form, araCTP. However, araC is only slowly converted to araCTP in the liver or in primary liver tumors due to low levels of an enzyme in the liver that is required for the conversion of araC to araCMP, the first step in the activation pathway of the drug. Higher doses of araC cannot be used to overcome this limitation due to bone marrow toxicity resulting from rapid activation in that tissue. MB07133 uses our HepDirect technology to target a prodrug form of araCMP specifically to the liver. Once in the liver cell, the prodrug is rapidly cleaved, producing araCMP, bypassing the rate-limiting enzyme. Once generated in the target tissue, araCMP is rapidly converted to araCTP, the cancer-killing active form.
We recently completed a Phase 1/2 clinical trial for MB07133. We presented results from that trial in a poster presented at the Annual Meeting of the American Association for Cancer Research (AACR) in April 2007. The results of this first dose escalation trial showed that MB07133 at doses up to 2400 mg/m2/day IV infusion was well tolerated in patients with unresectable HCC and that there were no clinically important dose-limiting toxicities associated with the therapy. Few treatment-related hepatic adverse events were observed. A pharmacokinetic analysis was conducted, and the results are consistent with MB07133's expected liver-targeting mechanism.
This trial also revealed encouraging signs of drug activity as evidenced by tumor shrinkage and disease stabilization. Sixty-eight percent of patients were previously treated by surgery and/or other non-surgical therapies including systemic chemotherapy in 29% of patients. The mean baseline tumor burden was 16.0 centimeters. A total of 92 cycles of treatment were administered, with 11 patients receiving three or more cycles of treatment and three patients receiving at least 12 cycles. Giving a patient multiple cycles is evidence of disease stabilization. Intra-hepatic tumor regression ranging from 0.4% to 35.1% reduction was observed in eight patients (29%). Additionally, all patients who responded to the drug showed increased survival as compared to the other patients in the study. Although not the primary goal of the trial, in the setting of primary liver cancer, an aggressive, deadly disease, these indications of tumor shrinkage and disease stabilization were viewed as promising.
We believe that MB07133, a cytotoxic therapy, may provide a means to effectively treat primary liver cancer while minimizing systemic exposure and the resulting side effects that are associated with araC, either alone or in combination with Nexavar a cytostatic agent. Recent clinical evidence has suggested that the combination of a cytostatic agent and a cytotoxic agent may be the most effective approach for treating this deadly disease.
The FDA granted MB07133 Orphan Drug Designation in September 2007, and the European Commission (EC) granted Orphan Medicinal Product Designation in October 2007. The FDA and EC grant orphan status to encourage development of treatments for diseases affecting small portions of society, which would otherwise often make development of such treatments economically difficult. Orphan drug status in the United States will entitle the Company to seven years of market exclusivity for MB07133 in the event it is approved for the treatment of HCC. Additional incentives include tax credits related to clinical trials expenses and an exemption from the FDA prescription drug user fee. This designation granted by the Europe Commission for MB07133 would entitle the Company to ten years of market exclusivity for MB07133 in the event it is approved for the treatment of HCC. Additional incentives include protocol assistance to advise on the development of orphan medicinal products, fee reductions for marketing authorization and eligibility for grants.
We plan to seek a strategic partner to continue the development and commercialization of this product candidate, but currently retain full worldwide commercialization rights to MB07133.
Pradefovir, a HepDirect Prodrug for the Treatment of Hepatitis B
Pradefovir mesylate is our oral product candidate for hepatitis B. Pradefovir is a HepDirect prodrug of the proven antiviral drug adefovir. Hepsera®, a hepatitis B treatment sold by Gilead, is also a prodrug of adefovir, but it is not liver-targeted. While Hepsera offers advantages over existing drugs based on its viral resistance profile and its activity in both naïve patients as well as patients who have failed on previous therapy, toxicity issues related to renal exposure with adefovir limit the doses that can be administered and therefore limit its efficacy for treating this disease. Pradefovir, on the other hand, uses our proprietary HepDirect technology and is designed to deliver high concentrations of adefovir to the liver, while limiting the amount of adefovir outside of the liver. Evidence from preclinical and clinical studies suggests that this hepatic targeting could act to improve efficacy without increasing renal toxicity.
Pradefovir has performed well in clinical trials that have evaluated the product candidate in patients infected with hepatitis B virus. The largest trial completed to date was a Phase 2b clinical trial conducted and completed by Valeant, a previous licensee for the candidate, in 2006. The Phase 2b trial was an open-label, randomized, multiple dose 48-week study with 242 patients. Approximately half of the patients had been previously treated and developed resistance to other drugs, and were thus considered to be more difficult to treat. The Phase 2b clinical trial consisted of five treatment groups: pradefovir (5,10, 20 and 30 mg/day), and Hepsera (10 mg/day). The results of the completed Phase 2b clinical trial were presented in April 2006 at EASL showing that patients treated with escalating doses of pradefovir orally, once a day, showed a significant reduction of viral DNA, a measure of viral load. The results specifically showed that pradefovir decreased serum HBV DNA -4.09, -4.84, -4.89 and -5.54 log10 copies/mL, respectively, whereas Hepsera showed a decrease of -4.19 log10 copies/mL. The reductions were statistically significant compared to Hepsera for the three highest doses. No evidence of kidney toxicity was noted and there were no serious adverse events related to treatment. The most frequently reported adverse events were similar across all treatment groups, including Hepsera. No dose-related trends regarding safety were identified, and no events resulted in a patient being withdrawn prematurely from treatment. In addition, pradefovir treatment led to circulating levels of adefovir that were low compared to Hepsera, as expected for a HepDirect prodrug. In fact, the 30 mg dose, which resulted in about twice as many patients clearing virus as seen with 10 mg Hepsera, resulted in lower blood levels of adefovir than Hepsera. A post-Phase 2 meeting was held with the FDA, and a plan for Phase 3 development was discussed and no significant objections were raised.
Prior to initiation of a Phase 3 clinical trial, preliminary findings from a two-year carcinogenicity study in rats and mice were reported. Higher tumor burden was reported at the middle and high doses tested, but not at the low dose. Such findings are not considered unusual for this class of drug, and Metabasis is reviewing the pradefovir data, including the recently reported carcinogenicity findings, to establish future plans for the product candidate. We plan to license pradefovir to a company or companies capable of completing development and commercializing the product.
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