MIV-818 is being developed for patients with hepatocellular carcinoma (HCC). HCC represents the fifth most common cancer worldwide1) but is a rare disease in Europe and the US. MIV-818 has received a positive opinion on orphan medicinal drug designation by EMA and has been granted orphan drug designation by the FDA for the treatment of HCC.
1) Childs A. et al., Chin Clin Oncol;2(4):44; 2013
MIV-818 is Medivir's proprietary prodrug with the liver as the target organ. Based on promising preclinical and clinical data, Medivir has chosen to focus on MIV-818 for clinical development on its own.
Although existing therapies for advanced hepatocellular carcinoma (HCC) are capable of extending the lives of patients, treatment benefits are often marginal, and mortality remains at a high level. Molecularly directed substances have had limited success in HCC because these tumors have a wide range of mutations. The lack of overall benefit together with the generally poor prognosis for patients with HCC results in a large medical need. Through its mode of action MIV-818 has the potential to be effective independent of type of mutations.
Other forms of liver cancer that could be treated with MIV-818 are intrahepatic cholangiocarcinoma - bile duct cancer - accounting for about 3 to 5 percent of liver cancer cases. Bile duct cancer has a poor prognosis and lacks treatments that effectively increase survival rates. Liver metastases from other tumor sites (principally from colorectal cancer, but also from breast, ovarian and pancreatic cancer) are also a major cause of cancer-related death.
MIV-818 is being developed as an orally administrated drug for the treatment of primary liver cancer. The intention is to achieve maximum concentration of the active substance in the liver, while minimizing the levels of the active substance in the rest of the body in order to reduce the risk of side effects. MIV-818 has the potential to be the first liver cancer-targeted, orally administered drug that can help patients with HCC and other forms of liver cancer.
The purpose of this first-in-human trial is to study the safety, tolerability, pharmacokinetics, pharmacodynamics, and signs of antitumor effect of MIV-818 in patients with advanced liver cancer. It will enroll patients with hepatocellular carcinoma (HCC), as well as patients with intrahepatic cholangiocarcinoma and patients with liver metastases from solid tumors.
The phase I study of MIV-818 consists of two parts: a phase Ia study in which individual patients receive escalating doses of MIV-818 with the primary objective to evaluate safety and tolerability of MIV-818. This will be followed by a phase Ib study in which the dose is escalated in cohorts of three patients in a 3+3 design in order to identify the recommended phase II dose.
The phase Ia study has been completed and evaluated doses in phase Ia were generally well-tolerated by patients. Liver biopsies showed selective DNA damage in liver tumor tissue while normal liver tissue was minimally or not affected by the treatment. From the patient biopsies we also observed DNA damage in oxygen-poor cancer tissue, which are generally difficult to treat. The tumor selective DNA damage effect was observed at low plasma concentrations of MIV-818 and acceptable exposure to troxacitabine in plasma. Five out of nine enrolled and evaluated patients showed a stable disease in the liver after MIV-818 treatment. In summary, the data collected from the phase Ia study indicate that the intended effects were achieved, i.e. the study provided an early proof-of-concept. This provides strong support for the continued clinical development of MIV-818.
The first patient in the phase Ib study was dosed in March 2020.
Today's standard treatment of primary liver cancer is sorafenib and similar drugs. Unfortunately, the treatment effect is limited and there is a large need for more effective treatment. MIV-818 has shown efficacy in several preclinical cancer models. In a mouse model of liver cancer, the effect of various treatments on tumor growth has been studied. Treatment with sorafenib provides slightly slower tumor growth compared to no treatment at all. Treatment with MIV-818 results in significantly slower tumor growth and when sorafenib and MIV-818 are combined, the strongest effect is achieved. When treated with sorafenib, the tissue becomes oxygen-poor. Many cancer drugs have poor efficacy in oxygen-poor tissue, but MIV-818 works well also in such tissue.