On June 26, 2015 4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for cancer and autoimmune diseases, reported that the first patient has been treated with resminostat in a Japan-based Phase I clinical study conducted by 4SC’s exclusive Japanese partner Yakult Honsha (Press release, 4SC, JUN 26, 2015, View Source [SID:1234506545]). The multi-centre open-label study will investigate safety, pharmacokinetics, biomarkers and efficacy of various dose regimens of resminostat in monotherapy or in combination with the S-1 chemotherapy in up to 44 Japanese patients with advanced pancreatic or biliary tract cancer. The main goal of the study is to determine the recommended regimen for subsequent Phase II trials in these indications.
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In Part 1 of the study, dose limiting toxicities (DLTs) of various dose regimens of resminostat in monotherapy and the resminostat/S-1 combination therapy will be determined in up to 24 patients. In Part 2, the tolerability and safety of the regimen/s selected in Part 1 will be further evaluated in 20 additional patients in order to determine the recommended regimen/s for subsequent Phase II studies. Furthermore, the study will investigate pharmacokinetics, biomarkers and efficacy criteria including best overall response, progression-free survival (PFS), and overall survival (OS).
The overall development rationale behind the study is to test the epigenetic agent resminostat in further gastrointestinal indications and in particular in combination with the S-1 chemotherapy, which is approved for the treatment of pancreatic and biliary tract cancer in Japan. S-1 contains a prodrug of the chemotherapeutic agent 5-FU. Resminostat has already been tested clinically in a Phase I study in combination with the 5-FU-based FOLFIRI chemotherapy regimen in Western patients with colorectal cancer. The administration of resminostat in combination with the standard FOLFIRI regimen was well tolerated without any dose limiting toxicity. Moreover in preclinical models, resminostat has shown first positive results in pancreatic and biliary tract cancer. 2
Enno Spillner, Chief Executive Officer of 4SC AG, said: "We very much appreciate that our partner Yakult Honsha has started developing resminostat in combination therapy with an established cancer drug in additional two gastrointestinal solid cancer indications in Japan. There is high unmet medical need in both pancreatic and biliary tract cancer. These new indications are a perfect match to the ongoing Phase II trials by Yakult investigating resminostat in combination therapies in the indications liver cancer (HCC) and non-small-cell lung cancer (NSCLC). While Yakult is evaluating resminostat in a number of mostly gastrointestinal solid cancer indications in Asian patients, 4SC intends to focus, as the immediate next step, on developing resminostat in the heamatological indication of CTCL in Europe where we also see a high medical need and an attractive opportunity for a fast-tomarket option for resminostat. We are currently preparing a European Phase II study in CTCL."
About pancreatic cancer and biliary tract cancer
Pancreatic cancer is characterized as a disease with some of the highest unmet need in oncology. is The disease is responsible for 331,000 deaths per year, and is thus the seventh most common cause cancer-related mortality in both sexes combined. Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 months and a five-year survival rate of below 5%, representing one of the poorest prognoses across gastrointestinal (GI) cancers. Approved drugs for first line setting in Western countries comprise the chemotherapies gemcitabine and FOLFIRINOX. In Japan, S-1 has been approved for the treatment of pancreatic cancer since 2006.
Primary bile duct cancer is a relatively rare cancer, however, with the number of new cases increasing. In Japan, the incidence of biliary tract cancer and intrahepatic bile duct cancer is about 10 out of every 100,000 people, which is higher than the incidences in other countries. These cancers typically have a poor prognosis, with 5-year survival rates in the range of 5% to 15%. In Japan, chemotherapies gemcitabine, cisplatin and S-1 have been used in this indication.
About resminostat
Resminostat (4SC-201) is an oral protein-deacetylase (HDAC) inhibitor with an innovative epigenetic mechanism of action that potentially enables the compound to be deployed as a novel, targeted tumour therapy for a broad spectrum of oncological indications, both in monotherapy and, in particular, in combination with other cancer drugs. Like other epigenetic therapies, resminostat modifies transcription of genes in cancer cells and, thereby, reprograms the phenotypes of such cancer cells. Additionally, resminostat has immunotherapeutic effects by activating NK cells, restoring MHCI and MHCII proteins and suppression of unspecific immunosuppression. Resminostat is assumed to be able to halt tumour progression and induce tumour regression. Furthermore, due to its epigenetic 3 mode of action resminostat is supposed to develop additional synergetic effects when combined with classical cancer therapies and to counteract the development of tumour cell resistance. For example, in preclinical trials, resminostat has been shown to effectively inhibit epithelial-mesenchymal transition (EMT). EMT, which may be promoted through the administration of certain conventional cancer therapies, leads to the formation of particularly aggressive tumour cells, which ultimately may result in greater proliferation of cancer cells in patients and the patients’ death. On the whole, a reinforcing positive therapeutic effect is expected to be achieved through a well-tolerated combination of a traditional cancer therapy with an epigenetic compound such as resminostat.
Resminostat – by 4SC and its Japanese partner Yakult – has been investigated in a broad clinical campaign comprising liver cancer (hepatocellular carcinoma, HCC), Hodgkin’s Lymphoma (HL), colorectal cancer (CRC), and non-small-cell lung cancer (NSCLC). In the Phase II SAPHIRE trial in patients with advanced Hodgkin’s Lymphoma (HL), resminostat monotherapy has demonstrated antitumour activity, with an overall response rate of 34% and a clinical benefit in 54% of the patients in a heavily pre-treated patient population together with very good safety and tolerability. In the Phase IIa SHELTER study resminostat has been evaluated as monotherapy and in combination with sorafenib as a second-line treatment in advanced Western HCC patients after proven radiological disease progression under first-line sorafenib therapy. Patients receiving the resminostat/sorafenib combination therapy showed a median overall survival of 8.0 months and a progression-free survival rate (PFSR) after 12 weeks of 62.5% and a median time-to-progression (TTP) of 6.5 months. Notably, in both tumour indications, HCC and HL, gene expression levels of the new biomarker ZFP64 measured prior to study treatment start in blood cells of patients, were identified to be potentially indicative of survival outcome upon treatment with resminostat. Hereby, the set of patients with a high level of ZFP64 gene expression at baseline showed a statistically significant increase of median overall survival compared with patients with low ZFP64 expression levels. Resminostat was further studied in a Phase I dose escalation approach in advanced colorectal cancer (CRC) patients evaluating resminostat in combination with the standard chemotherapeutic FOLFIRI regimen. Positive results for safety and tolerability as well as promising signs of clinical activity of this combination were published at the 2013 ASCO (Free ASCO Whitepaper) conference. Yakult Honsha is currently developing resminiostat in two randomised clinical Phase II trials in Asian patients in HCC and NSCLC and in a Phase I trial in patients with pancreatic and biliary tract cancer. Resminostat is partnered with Yakult Honsha for Japan and with Menarini in the Asia Pacific (APAC) region excluding Japan. 4SC is currently in preparations of a randomised, controlled Phase II trial in the indication of advanced cutaneous T-cell lymphoma (CTCL) in Europe.
About the resminostat partnering agreement with Yakult Honsha for Japan
4SC granted an exclusive license to Yakult Honsha for the development and commercialization of resminostat in Japan in April 2011. 4SC has received an upfront payment from Yakult Honsha of €6 million and is eligible for up to approximately €127 million payable upon achieving specified milestones 4 including clinical and regulatory events in Japan. In addition to milestone payments, Yakult will pay 4SC double-digit royalties linked to product sales of resminostat. Yakult Honsha will be responsible for all clinical requirements for resminostat development in Japan in oncology indications. 4SC is aiming to partner this compound in other territories, including Europe and the USA.