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 second part of the study, phase 1b/2a combination therapy, enrolled patients with advanced HCC who had progressed on, or were intolerant of, first or second line standard therapy. It comprised two arms with dose escalation of fostrox in combination with either Lenvima® or Keytruda® and a subsequent dose expansion cohort with recommended phase 2 dose of fostrox in combination with Lenvima.

The results from the dose escalation part showed a good safety and tolerability profile with no dose-limiting toxicity observed. The recommended dose for phase 2(RP2D) was determined to 30 mg once daily for 5 days in a 21 day cycles for fostrox in combination with standard dose for Lenvima.

The dose escalation part for the combination with Keytruda was completed in June 2023, establishing a safe dose for treatment with fostrox in combination with Keytruda. However, considering a treatment landscape where an immune combination is used in first line HCC, a decision was made to focus on the fostrox and Lenvima combination for treatment of HCC in second line. The possibility of combining fostrox with immune therapy is intended to be explored in earlier treatment-lines.

The study was conducted at 15 clinics in the UK, Spain and Korea. The study closed on November 26th, 2024 and the three remaining patients in the Lenvima combination were transferred to compassionate use, allowing continued benefit from the treatment.

The phase 1b dose escalation and the phase 2a dose expansion part has shown encouraging clinical efficacy data for fostrox in combination with Lenvima® that has continuously improved since the first presentation. Data has been presented during 2024 at ASCO Gastrointestinal Cancers Symposium in San Francisco in January, at ESMO Gastrointestinal (GI) Cancers Congress in Munich in June and latest at ESMO in Barcelona in September 2024.

The latest data showed a median time to progression (TTP) of 10.9 months1 (4.1 – 18.1) and an ORR of 24%, with a median duration of response of 7.0 months. The data show substantially improved efficacy compared to study data with Lenvima as monotherapy in second line or any other treatment options in second line after current standard of care with a first line immunotherapy. The patient who has benefited the longest from fostrox + Lenvima still remain on treatment for almost 2.5 years, with an ongoing partial response. Biopsies confirm selective DNA damage to tumor cells without impact on normal liver cells, which was clinically confirmed with measurement of liver function over the duration of treatment, based on measured liver enzyme values (ALT/AST) along with stable ALBI values (which measure liver function). Safety and tolerability of the combination is a prerequisite for efficacy and there were no new unexpected side effects reported. 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 monotherapy.

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.

1) Chon et al., ESMO 2024, Poster 986

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

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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