Nucleotide DNA polymerase inhibitor (oral)
Hepatocellular carcinoma
Hepatocellular carcinoma
Fostrox 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. Fostrox 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
Fostrox 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 fostrox 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 fostrox has the potential to be effective independent of type of mutations.
Fostrox 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 to reduce the risk of side effects. Fostrox has the potential to be the first liver cancer-targeted and orally administered drug that can help patients with HCC and other forms of liver cancer.
The first-in-human study of fostrox is an open label, multi-center dose escalation/expansion study in 3 parts. The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and signs of antitumor effect of fostrox in patients with advanced liver cancer. In phase 1a individual patients received escalating doses of fostrox and in phase 1b monotherapy the dose was escalated in cohorts of three patients in a 3+3 design to identify the recommended phase 2 dose (RP2D) for monotherapy. In the phase 1b combination part of the study fostrox is administered in combination with Lenvima®, a tyrosine kinase inhibitor or Keytruda®, an anti-PD-1 check-point inhibitor.
Phases 1a and 1b monotherapy enrolled patients with hepatocellular carcinoma (HCC), as well as patients with intrahepatic cholangiocarcinoma and patients with liver metastases from solid tumors and have been completed. Evaluated doses were generally well-tolerated. 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 fostrox and acceptable exposure to troxacitabine.
The ongoing phase 1b combination part of the study includes patients diagnosed with HCC who have progressed on, or are intolerant of, first line standard therapy. It comprises two arms with inter-patient dose escalations of MIV-818 in combination with either Lenvima® or Keytruda® using a 3+3 dose escalation design.
In February 2023, the initial dose escalation part (phase 1b) of the 1b/2a study with fostrox in HCC, in combination with Lenvima®, was successfully completed. The preliminary results from the dose cohorts are positive with a good safety and tolerability profile and no dose-limiting toxicity has been observed. The recommended dose (RP2D) for the first combination arm of the phase 2a part of the study has been determined to 30 mg for fostrox. In March 2023, the first patient with HCC started treatment in phase 2a with fostrox in combination with Lenvima®.
Further cohorts of up to a total of 30 patients may be enrolled in the phase 2a part of the study.
The study is currently conducted at 14 clinics in the UK, Spain and South Korea.
Abstract published at ESMO 2021
MIV-818 phase I data presented at ASCO GI Cancers Symposium 2021
MIV-818 stimulates an anti-tumorimmune response in vitro and enhances the effects of pembrolizumab
Synergistic and additive anti-tumor effects of MIV-818 in combination with sorafenibin nonclinical hepatocellular carcinoma models
Selective targeting of the liver with nucleotide prodrugs for the treatment of liver cancers