Liver cancer is the third leading cause of cancer-related deaths worldwide1). MIV-818 is developed for patients with advanced liver cancers for whom existing treatment options provide very little survival benefit.
1) Globocan 2018
Although existing therapies for advanced hepatocellular carcinoma (HCC) are capable of extending the lives of patients, treatment benefits are low while death rates remain high. HCC is a very diverse disease with multiple cancer cell types and without specific mutations seen in other tumor types. This has contributed to the lack of success of molecularly targeted agents in HCC. The limited overall benefit, taken together with the poor overall prognosis for patients with intermediate and advanced HCC, results in a large unmet medical need.
Intrahepatic cholangiocarcinoma, a cancer of the bile duct located inside the liver tissue, accounts for about 15 percent of liver cancers. It has a poor prognosis and no treatment that effectively improves survival. 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, the first oncology drug in clinical development from Medivir’s in-house research, has been specifically designed for liver cancers. It has the potential to become the first liver-targeted, orally administered drug to benefit patients with HCC and other forms of liver cancer.
MIV-818 is a liver-targeted nucleotide prodrug of troxacitabine. It has been developed to be an orally administered therapeutic with a high level of anti-tumor activity that is targeted for delivery to the liver. The rationale is to maximize delivery of the drug to the tumor(s), while minimizing the systemic exposure and thereby limit potential systemic side effects.
The purpose of this first-in-human trial is to study the safety, tolerability, pharmacokinetics, and preliminary antitumor activity 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/II study of MIV-818 consists of three parts: a phase Ia study in which individual patients receive escalating doses of MIV-818 with the primary objective to evaluate the tolerability, safety and pharmacokinetics 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. In the phase II part of the study two cohorts of patients with liver cancer, will receive the recommended dose of MIV-818.
Phase Ia is currently ongoing at sites in United Kingdom and Belgium and the results of an analysis of data from the first six patients with advanced cancer in the liver treated with increasing MIV-818 doses are available. Evaluated doses have been shown to be well-tolerated by patients. An effect signal, measured as DNA damage, has been observed in liver biopsies from tumor tissue in MIV-818 treated patients. In contrast to the tumor, normal liver tissue does not appear to have been affected by the treatment. This tumor selective effect was observed at low measured levels of MIV-818 in plasma and is an early indication that MIV-818 works as expected, i.e. the substance has the intended liver-directed effect. The plan now is initiate the phase Ib part of the study as soon as the independent safety committee has given its recommendation on an appropriate starting dose.
More information about the study is available at www.clinicaltrials.gov, reference number NCT03781934.