Fostroxacitabine bralpamide (fostrox)

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.

Which are the major challenges when treating advanced/unresectable hepatocellular carcinoma (HCC) today?
Most HCC patients have underlying liver disease, that is, liver cirrhosis. Therefore, unlike other solid tumors, it is important to treat HCC patients not only to target the cancer itself, but also to protect liver function from deterioration. In advanced/unresectable HCC, systemic
therapy is the main treatment, but it is not easy to develop an anticancer drug that satisfies both of these requirements. Therefore, I think systemic therapy for HCC is more difficult overall compared to treatment for other solid tumors.

With a changing treatment landscape and a new preferred treatment with immunotheraphy combinations (IO) in 1L, what is most important for those who progress and need a 2L treatment?
According to data recently presented by our team, at ESMO on more than 1,000 Asian-Pacific patients treated with Tecentriq®/Avastin® as first-line therapy, only 50% of patients whose disease progressed after the first-line treatment with Tecentriq/Avastin had a chance for a second-line treatment and only 26% had a chance for a third-line treatment. This figure is lower than for other solid tumors and is largely thought to be due to the decline in liver function that occurs after systemic therapy. Similar to the answer to the previous question,
1) a less toxic agent that does not worsen liver function is important, and 2) as the cancer progressed on the IO combination as first-line treatment, it may be more appropriate to use agents with different mechanisms rather than agents with the same mechanism in subsequent lines.

How important is local treatment of the tumor in the liver despite having metastases outside the liver? Does this differ from other tumor types and why so?
According to data presented by our team at ASCO GI this year, the treatment efficacy of 1st line Tecentriq/Avastin in advanced/unresectable HCC was well stratified in terms of survival outcomes according to intrahepatic tumor burden, regardless of the tumor's systemic spreading status. In other words, it is difficult to expect good therapeutic efficacy from systemic therapy in patients with a large intrahepatic tumor burden. Of course, this result cannot be applied consistently to all systemic therapies, but considering that liver function reserve decreases proportionally as intrahepatic tumor burden increases, it seems to be generally applicable to some extent in HCC.In the recent EMERALD-1 trial, the combination treatment of TACE and IO satisfied the primary endpoint. This result suggests synergistic efficacy of combined local treatment in the liver and systemic therapy at the intermediate stage. Therefore, it is likely that combination treatment of local therapy and systemic therapy will be actively attempted in the near future, even in advanced stages, especially in patients with a large intrahepatic tumor burden.

You are an investigator in the fostrox development program and has enrolled patients in the fostrox plus Lenvima® study: What would you say is most interesting with this combination?
In my patient's cases, the fostrox & Lenvima combination treatment seems to exceed the efficacy I expected from Lenvima monotherapy. A total of 9 of my patients were enrolled in this study. Among them, 6 patients were treated with fostrox plus Lenvima, and currently 4 patients are showing good therapeutic efficacy and are still undergoing treatment in the study.

What unmet need could the fostrox + Lenvima treatment cover?
Upon reviewing the data of the Asian-Pacific patients we analyzed, patients who showed early progression in the first Tecentriq/Avastin treatment tended to have poor therapeutic efficacy no matter what tyrosine kinase inhibitor (TKI) was applied in subsequent treatment. Therefore, one of the questions that HCC experts are most interested in is what systemic therapy can be appropriately applied in patients who show early progression on 1st line Tecentriq/Avastin treatment. However, in my experience from the patients I treated with fosrox + Lenvima, the results were slightly different from what has been seen with previous subsequent TKIs. In fact, some patients enrolled in this study showed early progression on the previous first-lineTecentriq/Avastin treatment, yet showed long-lasting effects on fostrox & Lenvima treatment.

Considering its mechanism of action, how do you see fostrox potential to fit into the future treatment landscape?
After 1st line immunotherapy combination, the use of TKI as subsequent treatment is currently a common treatment strategy. Fostrox is a type of new smart chemotherapy, with an orally administered prodrug, based on the nucleoside analog troxacitabine. With a liver targeted approach, fostrox achieves 100-fold higher liver exposure to the active metabolite versus IV troxacitabine, leading to effective and selective cytotoxicity in liver tumors, while minimizing systemic exposure. Therefore, fostrox is expected to maximize the treatment efficacy without further increasing side effects through a synergistic effect with Lenvima.

What are your thoughts about new possibilities for HCC patients and how will that impact overall outcome in the coming years?
Although systemic therapy for HCC has made remarkable progress in recent years, it is still not satisfactory from the perspective of physicians who are treating HCC on the front line. Recently, I participated in various HCC clinical trials and was able to identify several strategies as an investigator. The first strategy is to overcome limitations through combination treatment with existing drugs. An example is the recent addition of tiragolumab to Tecentriq/Avastin, which improved the objective response rate from 30% to over 40% in first-line treatment of HCC. It is expected that fostrox will be able to play a similar role through various combination treatments. The second strategy is to target new HCC targets. For example, recently, various global pharmaceutical companies are conducting clinical studies using drugs that target GPC-3 in various ways. The third strategy is to apply existing successful treatments to early stages. AstraZeneca recently demonstrated the effectiveness of combined treatment of TACE and durvalumab + bevacizumab in the intermediate stage through the EMERALD-1 study, and Roche demonstrated the effectiveness of Tecentriq/Avastin adjuvant therapy after surgery in the early stage through the IMbrave050 trial. Moreover, clinical trial is currently underway to apply this combination treatment as
preoperative neoadjuvant therapy. Through these various strategies, the overall outcome of HCC patients will improve, and investigators' efforts to find optimal treatment sequences and biomarkers will continue.

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.

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 2^nd 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;

Dr. Jeff Evans is a Professor of Translational Cancer Research in the School of Cancer Sciences, University of Glasgow, and Honorary Consultant in Medical Oncology at the Beatson West of Scotland Cancer Centre, Glasgow, UK. He is the Lead of the Glasgow Experimental Cancer Medicine Centre (ECMC) and National Clinical Lead of the NHS Scotland Cancer Research Network. He is an investigator in the fostrox clinical development program.

Dr. Richard Finn is a Professor of Medicine at the Geffen School of Medicine at UCLA Department of Medicine, Division of Hematology/Oncology. Dr. Finn splits his time between patient care and directing the Translational Research Laboratory in the Division of Hematology/Oncology. His research interests are focused on the development of targeted therapeutics for solid tumors across histologies. Dr Finn has been the primary investigator of several, ground-breaking studies in HCC, including the ground-breaking ImBrave 150 study.

Dr. Jeong Heo is a Professor of Internal Medicine at Pusan National University School of Medicine and Director of Gastroenterology and Hepatology at Pusan National University Hospital. During his career, Professor Heo has held a number of academic positions, university and hospital appointments and has been principal investigator in many clinical trials for phase I-IV of hepatitis B, C and hepatocellular carcinoma. He is an investigator in the fostrox clinical program.

Dr. Maria Reig is the Head of the BCLC and Liver Oncology Unit at Hospital Clinic of Barcelona in Spain. Her expertise and area of interest is the development of prognostic models for patients with liver cancer and evaluation of treatment options with special emphasis in systemic therapy as well as new research about immune modulation and cancer emergence after antiviral treatment. She is an investigator in the fostrox clinical program.

Dr. Arndt Vogel is managing senior consultant and Professor in the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School. He is also head of the GI-Cancer Center and of the Center for Personalized Medicine at Medical School Hannover. His scientific focus is the translational and clinical research in gastrointestinal cancer. Professor Vogel is member and chairman of Hepatobiliary Cancer Study Group of the AIO, a collaborative group in clinical oncology in Germany. Within ESMO, he is member of the ESMO Guidelines Steering Committee. Furthermore, Professor Vogel has responsibilities in the establishment of the national guideline and is the coordinator of the ESMO clinical practice guideline on the management of hepatocellular carcinoma and biliary tract cancer.

Fostroxacitabine bralpamide (fostrox)