Fostroxacitabine bralpamide (fostrox)

How fostrox complement current therapy options

Fostrox is Medivir's proprietary, liver-targeted drug for the treatment of tumors in the liver. Fostrox is a type of smart chemotherapy and has been developed to achieve a tumor-selective, targeted effect in the liver, while minimizing the effect on normal cells. This mechanism makes it possible to direct a high concentration of fostrox to the liver with reduced risk of side effects in the rest of the body. Based on promising preclinical and clinical data in primary liver cancer (HCC), Medivir has chosen to initially focus fostrox clinical development on this cancer type.

Although existing therapies for advanced HCC can extend the lives of patients, treatment benefits are often insufficient, and death rates remain at a high level. Molecularly targeted drugs have had limited success in HCC because of the heterogenous character of the tumor, with a wide range of mutations, leading to lack of effective actionable targets. The low overall benefit with current treatment regimens, together with the generally poor prognosis for patients with HCC, results in a large unmet medical need. Through its mode of action, fostrox has the potential to be effective independent of type of mutations.

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 to reduce the risk of side effects. By sparing the normal liver cells, the tumor selective effect of fostrox 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 liver cancer

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

The first completed part of the study, phase 1a/1b monotherapy, 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. From the patient biopsies, we also observed DNA damage 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 and ongoing part of the study, phase 1b/2a combination enrolled patients with advanced HCC who have progressed on, or are intolerant of, first or second line standard therapy. It comprises 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 study is currently conducted at 15 clinics in the UK, Spain and South Korea.

In February 2023, the enrolment of patients into the dose escalation part with fostrox in combination with Lenvima, was successfully completed. The preliminary results were encouraging with a good safety and tolerability profile and no dose-limiting toxicity observed. The recommended dose (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. In March 2023, the first patient in the dose expansion cohort started treatment with fostrox RP2D in combination with 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 phase 1b/2a clinical data of fostrox in combination with Lenvima, were first presented in October 2023 where efficacy was evaluated by investigators and local radiologists in 18 of a total of 21 included patients, with at least 12 weeks of follow-up. These data indicate a marked improvement compared to what was shown in second-line HCC in previous studies, with an overall response rate of 22% and a median time to progression of ~5 months. No new, unexpected side effects were reported and the need to reduce the dose of Lenvima, when combined with fostrox, was lower but relatively similar to what is seen with Lenvima used as monotherapy.

Medivir presented updated data from the phase 1b/2a study at the ASCO Gastrointestinal Cancers Symposium, on January 19, 2024 in San Francisco, USA. This analysis included 20 patients with more than 18 weeks of follow-up. The data evaluated by investigators and local radiologists, show further improvement with an Objective Response Rate (ORR) that had increased to 25% (RECIST v1.1) and the median time to progression extended to 5.4 months. Importantly, continued good tolerability with no new unexpected side effects were seen at this time point.

Efficacy data has since continued to improve with >40% of patients still on treatment as of Q4 report on February 16, 2024. This means, among other things, that the median time to progression has improved further to 6.3 months and that the patient who benefited the longest remains on treatment after 18 months with continued tumor response. Results that indicate that the addition of fostrox to Lenvima is tolerable with a maintained good safety profile in this study and that the combination has provided an improved clinical effect when compared to treatments used in this patient population.

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)