Fostroxacitabine bralpamide (fostrox)

  • Mechanism

    Nucleotide DNA polymerase inhibitor (oral)

  • Disease areas

    Hepatocellular carcinoma

    Hepatocellular carcinoma

Fostroxacitabine bralpamide (fostrox) - for the treatment of liver cancers

Fostrox is under development for patients with primary liver cancer (hepatocellular carcinoma (HCC), with a fast-growing incidence and currently the sixth most common cancer type and the third most common cause of death, worldwide1. In Europe and the USA, HCC is still counted as a rare disease2, and fostrox has received orphan medicinal drug designation by EMA and the FDA for the treatment of HCC.

1) Serraino D. et al., Epidemiological Aspects of Hepatocellular Carcinoma. Springer International Publishing, 3–9, 2023

2) Hepatocellular carcinoma, Nature Review 2021



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How fostrox complements current therapy options

Fostrox is Medivir's proprietary drug for the treatment of tumors in the liver. Fostrox is a liver-targeted inhibitor of DNA replication that delivers the cell-killing compound selectively to the tumor while minimizing the harmful effect on normal cells. This is achieved by coupling an active chemotherapy (troxacitabine) with a prodrug tail. This design enables fostrox to be administered orally and travel directly to the liver where the active substance is released locally in the liver. With this unique mechanism, fostrox has the potential to become the first liver-targeted, orally administered drug that can help patients with various types of liver cancer. A phase 1b monotherapy study with fostrox has previously been conducted and a phase 1b/2a combination study in HCC was completed in November 2024, where it has shown encouraging anti-cancer efficacy with a good safety and tolerability profile. (Chon et al. ESMO 2024, Poster 986).

Promising strategies in order to overcome treatment limitations - Interview with Dr Hong Jae Chon

In order to get a specialized clinician’s view on what future developments we might see that could improve the situation for liver cancer patients, we have talked to Dr. Hong Jae Chon about the treatment alternatives that are currently used for liver cancer and where fostrox will fit in the treatment landscape. Dr. Hong Jae Chon is a Professor at Digestive Cancer Center at CHA Bundang Medical Center, CHA University in Korea. He specializes in liver cancer and pancreatic cancer. He is an investigator in the fostrox program and an experienced investigator in numerous national and international clinical trials of new cancer therapies within his specialty indications.

Liver-directed anti-tumor activity

Fostrox is being developed as an orally administrated, liver-targeted and tumor selective drug for the treatment of HCC. 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, reducing the risk of side effects. With fostrox being tumor selective, the normal liver cells are spared, which is  particularly important for patients with HCC, where a majority of patients suffer from liver cirrhosis and poor liver function. Fostrox has the potential to be the first liver cancer-targeted and orally administered drug that can help patients with HCC as well as those with cholangiocarcinoma or liver metastases from other types of cancer.

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Clinical development of fostrox in patients with advanced liver cancer

The first-in-human study of fostrox was an open label, multi-center dose escalation/dose expansion study. The objectives of the study was to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and antitumoral effect of fostrox in patients with tumors in the liver, as well as to identify the recommended phase 2 dose (RP2D) for fostrox.

The study was conducted in several parts and the phase 1a/1b monotherapy part enrolled patients with advanced hepatocellular carcinoma (HCC), patients with intrahepatic cholangiocarcinoma and patients with liver metastases from solid tumors. Investigated doses were generally well-tolerated and liver biopsies showed selective DNA damage in liver tumor tissue while normal liver tissue was minimally or not affected by the treatment. In these biopsies, DNA damage was observed also in hypoxic (oxygen-poor) regions in the tumor, which generally provides difficulties for drugs to be effective. The tumor selective DNA damage effect was observed at low plasma concentrations of fostrox and acceptable exposure to the active metabolite. The monotherapy study was published in the Journal of Hepatocellular Carcinoma; Plummer, R. et al. Journal of Hepatocellular Carcinoma (2024):11 2033–2047.

Combination study in phase 1b

In the phase 1b combination study, fostrox was initially given in combination with two other medicines, either with Lenvima® or with Keytruda®, to patients with advanced HCC for whom current first-line treatment had shown to be ineffective or intolerable. The aim of the study was to evaluate safety, tolerability and clinical benefit in each combination. Patients were included at 15 clinics in the UK, Spain and South Korea.

The dose escalation part (phase 1b) for the combination with Keytruda established a safe dose for the treatment of fostrox in combination with Keytruda. For strategic reasons, Medivir chose to focus on the combination fostrox and Lenvima in the expansion part of the phase 2a study.

The first part (phase 1b), the dose escalation part, for the combination with Lenvima was completed in February 2023. The preliminary results were positive with a good safety and tolerability profile with no dose-limiting toxicity observed. The recommended phase 2 dose could thus be determined to 30 mg for 5 days in cycles of 21 days, which was the dose when the expansion part (phase 2a) of the fostrox + Lenvima combination study was initiated.

Combination study in phase 2a

During the course of the phase 2a study, data from the study have been presented at scientific conferences. These data have been very positive in terms of response (ORR) and time to progression (TTP) as well as safety and tolerability. The data indicate a significant improvement compared to what has been shown in second-line HCC in previous studies.

The study was closed in November 2024 and the three patients who remained on treatment after more than 15 months were transferred to compassionate use (a program where the patient receives continued access to study medication) to enable continued benefit from the treatment1). The final safety and efficacy data from the study were presented at the European Association for the Study of the Liver (EASL) Liver Cancer Summit in Paris in February 2025.

The results in summary

The 21 patients in phase 1b/2a who received fostrox, in combination with Lenvima, had a median age of 62 years and 86% had received Tecentriq/Avastin as prior therapy. 19% of patients had received two prior therapies and 67% had metastases outside the liver. The median follow-up time was 10.5 months. Treatment with fostrox in combination with Lenvima demonstrated continued good safety and tolerability, with only one patient terminating the study due to adverse events related to fostrox. The median time to progression (TTP) was 10.9 months (95% CI 4.1 - 18.1), significantly longer than previously seen in second-line liver cancer, and the median overall survival (OS) was 13.7 months (95% CI 7.6 - NR). The combination showed an Objective Response Rate (ORR) of 24% with a median duration of response of 7 months. Tumor shrinkage was noted in >75% of patients and clinical benefit from treatment lasted on average 11.3 months2).

The phase 1b/2a study is finalized and the data reported provide strong support for accelerating the fostrox development program in second-line HCC in 2025 with the opening of a multicenter global randomized phase 2b trial in second-line HCC patients comparing the combination of fostrox and Lenvima to Lenvima + placebo.

In December 2024 Medivir received FDA approval of the US Investigational New Drug application (IND) for evaluating fostrox + Lenvima vs Lenvima alone in a phase 2b study in 2nd line advanced HCC.

In March 2025 the European patent authority granted Medivir's patent application covering claims for the combination of fostroxacitabine bralpamide (fostrox) with lenvatinib (Lenvima) for the treatment of hepatocellular carcinoma and cancer metastases to the liver. The patent provides protection and market exclusivity until April 2041.

Next step - FOcuS-2 (randomized phase 2b study)

An IND-approved study in two parts to enable breakthrough therapy designation and application for accelerated marketing approval.

The planned randomized phase 2b study will include patients with locally advanced or metastatic primary liver cancer who have received a first-line immunotherapy combination and who have liver function acceptable for this type of treatment (Child-Pugh A). The study design is approved by the FDA and an IND (Investigational New Drug) has been opened in the US. Patients will be randomly assigned to receive fostrox + Lenvima or placebo + Lenvima and will be followed to evaluate the primary endpoint (response/ORR) for 6 months and for survival for 24 months. The first part of the study will also evaluate the optimized dose of fostrox in accordance with FDA recommendations. Every 6 weeks, an evaluation of any response/ disease progression will be carried out with MRI and/or CT. However, patients who have disease progression can continue in the study as long as they have clinical benefit from the treatment.

1) Data cut, November 30, 2024.

2) Evans et al., EASL Liver Cancer Summit, poster PO2-13.

Medical need and market potential

Primary liver cancer is the third leading cause of cancer-related death worldwide and HCC is the most common form. Although existing treatments for HCC can prolong patients' lives, treatment benefits are often limited and mortality remains at a high level. Each year, approximately 860,000 patients with primary liver cancer are diagnosed globally, and the current five-year survival rate is below 20 %1), 2), 3), 4).

The HCC market is expected to grow by up to 20 % per year with significant risk of further increase as HCC caused by fatty liver disease is expected to increase dramatically by 2030. In China, the increase is expected to be 82 % and in the United States 122 %2).

HCC is a heterogeneous disease with different etiologies and without specific mutations observed in many other cancers. This has contributed to the lack of success of molecularly targeted agents in HCC. The lack of overall benefit, together with the generally poor prognosis of patients with advanced HCC results in a large unmet medical need.

1) Liver and Intrahepatic Bile Duct Cancer — Cancer Stat Facts.

2) Bray et al., CA Cancer J Clin. 2024;74:229-263

3) Rumgay et al.,European Journal of Cancer 2022 vol.161, 108-118.

4) Yang, J.D., Hainaut, P., Gores, G.J. et al. A global view of hepatocellular carcinoma: trends, risk, revention and management. Nat Rev Gastroenterol Hepatol 16, 589–604 (2019).

Scientific Advisory Counsil

In August 2023 a Scientific Advisory Council with world-leading liver cancer experts was formed to support the company in moving the clinical development of fostrox forward.

The Scientific Advisory Council members are;

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Publications

Fostrox - Final safety and efficacy results from the phase 1b/2a study of fostrox plus lenvatinib in second/third line advanced hepatocellular carcinoma progressed on immunotherapy

986P Fostrox (fostroxacitabine bralpamide) plus lenvatinib in patients with locally advanced unresectable or metastatic hepatocellular carcinoma (HCC) progressed on immunotherapy combinations. Results from a multi-center phase 1b/2a study

Population pharmacokinetic modeling of orally administered fostroxacitabine bralpamide (fostrox, MIV-818) and its metabolite troxacitabine in a phase I/IIa liver cancer study

First safety and efficacy data from phase Ib/IIa study of fostroxacitabine bralpamide (fostrox, MIV-818) in combination with lenvatinib in patients with hepatocellular carcinoma (HCC)

Combinations of fostrox (MIV-818), a novel nucleotide prodrug, with lenvatinib or sorafenib shows increased efficacy in nonclinical hepatocellular carcinoma (HCC) models in vivo

A triple combination of fostrox (MIV-818) with immune checkpoint and kinase inhibition shows increased anti-tumor efficacy in vivo

Fostrox (MIV-818) in combination with anti-PD-1 shows increased efficacy in nonclinical tumor models in vivoLiver biopsy biomarkers in a phase 1 study of the prodrug MIV-818 demonstrates proof-of-concept for cancer in the liver.

Phase 1 study of the novel prodrug MIV-818 in patients with hepatocellular carcinoma (HCC),intrahepatic cholangiocarcinoma (iCCA) or liver metastases (LM)MIV-818 phase 1b

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

The biomarker potential of Ki67 and pH2AX immunohistochemistry in guiding use of the liver-targeting nucleotide MIV-818 in patients with hepatocellular carcinoma

Liver targeting and anti-tumourefficacy of the nucleotide prodrug MIV-818 in nonclinical models of hepatocellular carcinoma

Liver-targeting with the novel nucleotide prodrug MIV-818 designed for the treatment of liver cancers

Defining exposure-PD and efficacy relationships with the novel liver-targeting nucleotide prodrug MIV-818 for the treatment of liver cancers

Selective targeting of the liver with nucleotide prodrugs for the treatment of liver cancers

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