4SC's partner Yakult Honsha starts clinical Phase I/II study with cancer compound resminostat in liver cancer (HCC) in Japan

- Phase I/II study to investigate safety and efficacy of resminostat/sorafenib combination vs. sorafenib alone as first-line treatment of advanced liver cancer (HCC)
- Clinical development of resminostat in Japan is of high strategic importance to 4SC because of its alliance with Yakult and the high incidence of liver cancer in this region

PLANEGG-MARTINSRIED, Germany I May 21, 2013 I 4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for autoimmune diseases and cancer, today announced that the first patient has been treated with resminostat in a Japan-based Phase I/II liver cancer (hepatocellular carcinoma, HCC) clinical study by its exclusive Japanese partner Yakult Honsha. The multi-centre study will investigate safety and efficacy of resminostat in combination with the cancer drug sorafenib as a potential novel first-line treatment of advanced liver cancer in up to 164 patients. All patients enrolled have to be previously untreated with systemic chemotherapy.

The dose-escalation Phase I part of the study will assess safety, tolerability and pharmacokinetics as well as determine the maximum tolerated dose (MTD) and potential dose-limiting toxicities (DLT) of the resminostat/sorafenib combination in order to establish a recommended dose (RD) for the Phase II part.

The randomised Phase II part will compare the efficacy of sorafenib alone with the combination therapy of resminostat and sorafenib as a first-line treatment of patients with advanced HCC. A total daily dose of 800 mg sorafenib will be administered as monotherapy in the control arm of the study or in combination with up to 600 mg/day resminostat in the second study arm. The primary endpoint of the Phase II part is to measure time-to-progression (TTP), secondary endpoints of the Phase II part are, inter alia, overall survival (OS), progression-free survival (PFS) and safety.

The development of resminostat in the Japanese market is of high strategic importance to 4SC and its partner Yakult Honsha. In 2011, 4SC granted an exclusive license to Yakult Honsha, the Japanese market leader in gastro-intestinal cancer therapeutics, for the development and commercialization of resminostat in Japan. Liver cancer (HCC), a disease with a particularly high incidence in Japan as well as in the whole of Asia, is one of the main indications of clinical development with resminostat. There is a high medical need for new treatment options for advanced HCC, with sorafenib being the only approved systemic treatment available.

Enno Spillner, Chief Executive Officer and Chief Financial Officer of 4SC AG, said: 'We are very pleased that our Japanese partner Yakult Honsha has started clinical development of resminostat in advanced liver cancer (HCC) in Japan. Given the high incidence of HCC in Japan and the whole of Asia, advancing the drug towards market approval in this region is a key strategic goal for us. Moreover, this is the first time resminostat is being investigated in the first-line treatment of advanced HCC. This is of high relevance to 4SC, as we are currently in preparations of the next advanced clinical development steps for resminostat in combination with sorafenib in first-line HCC in the Western population as well.'


About Resminostat

Resminostat (4SC-201), 4SC's lead oncology compound, is an oral pan-histone-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 as a monotherapy and, in particular, in combination with other cancer drugs. HDAC inhibitors have been shown to modify the DNA structure of tumour cells to cause their differentiation and programmed cell death (apoptosis) and are therefore considered to offer a mechanism of action that has the particular potential to halt tumour progression and induce tumour regression. Additionally, resminostat is also assumed to induce what is known as tumour cell (re-)sensitisation to other anti-cancer compounds. This process can suppress or reverse certain tolerance and resistance mechanisms which tumour cells often develop against other cancer drugs. Supplementary treatment with resminostat can be expected to restore or significantly improve the efficacy of a previously administered cancer therapy which was no longer effective; furthermore, combining resminostat and common cancer drugs right from the very beginning can also be expected to effectively enhance the success of such a treatment.

Resminostat is currently being investigated in a broad clinical Phase II programme in the three indications liver cancer (hepatocellular carcinoma, HCC), Hodgkin's Lymphoma (HL), and colorectal cancer (CRC). In the Phase II SAPHIRE trial in patients with advanced Hodgkin's Lymphoma, resminostat in monotherapy has demonstrated substantial anti-tumour activity, with an overall response rate of 35.3% and a clinical benefit in 55.9% of the patients in a heavily pre-treated patient population together with very good safety and tolerability. In the Phase I/II SHORE study, which evaluates resminostat in combination with the chemotherapeutic FOLFIRI regimen as a second-line treatment of KRAS-mutant CRC patients, positive interim results for safety and tolerability have been published in December 2012. Final Phase I results are expected to be published soon. Furthermore, in the Phase II SHELTER study resminostat has been evaluated as monotherapy and in combination with sorafenib as a second-line treatment in advanced HCC 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 (as reported at the annual meeting of the International Liver Cancer Association (ILCA) on 16 September 2012). As presented at the ASCO annual meeting on 4 June 2012, the resminostat/sorafenib combination therapy had shown a progression-free survival rate (PFSR) after 12 weeks of 70.0% and a median PFS of 4.7 months. The primary study endpoint was achieved ahead of schedule in both the combination and the monotherapy group.

4SC is currently in discussions with regulatory agencies and potential partners in order to prepare the next clinical steps to develop resminostat in combination with sorafenib towards market approval as a first-line treatment for patients with advanced HCC.

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 EUR6 million and is eligible for up to EUR127 million payable upon achieving specified milestones 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 HCC, CRC and other chosen oncology indications. 4SC is aiming to partner this compound in other territories, including Europe, the USA and Asia.

About 4SC

The Group managed by 4SC AG (ISIN DE0005753818) discovers and develops targeted, small-molecule drugs for treating diseases with high unmet medical needs in various autoimmune and cancer indications. These drugs are intended to provide innovative treatment options that are more tolerable and efficacious than existing therapies, and provide a better quality of life. The Company's balanced pipeline comprises promising products that are in various stages of clinical development. 4SC's aim is to generate future growth and enhance its enterprise value by entering into partnerships with leading pharmaceutical companies. Founded in 1997, 4SC had 86 employees at the end of 2012. 4SC AG has been listed on the Prime Standard of the Frankfurt Stock Exchange since December 2005.


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