4SC's Anti-Cancer Drug Resminostat achieves Median Overall Survival of 8.0 Months in Second-Line Advanced Liver Cancer (HCC) Patients

 4SC's Anti-Cancer Drug Resminostat achieves Median Overall Survival of 8.0 Months in Second-Line Advanced Liver Cancer (HCC) Patients

- Overall survival (OS) data from Phase II SHELTER trial in advanced liver cancer (HCC) to be presented at 2012 ILCA Conference in Berlin, Germany, on 16 September 2012

- Median OS of 8.0 months in resminostat/sorafenib combination group is highest OS value to date in clinical trials in comparable second-line HCC patient populations

- OS correlates with previously reported median progression-free-survival of 4.7 months

- Innovative epigenetic mode of action (tumour re-sensitisation), convincing signals of efficacy and favorable safety profile underline further development of resminostat as a combination therapy with sorafenib in first- and second-line advanced HCC

- Pivotal Phase III trial in second-line HCC planned to start by mid 2013 preferably with a partner

Planegg-Martinsried, Germany, 13 September 2012 - 4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for autoimmune diseases and cancer, announced today the publication of convincing overall survival data from a Phase II study with its lead anti-cancer drug resminostat applied as a novel combination therapy approach with sorafenib in second-line advanced liver cancer at the 2012 annual meeting of the International Liver Cancer Association in Berlin, Germany, on 16 September 2012.

The international, open-label, two-arm SHELTER study enrolled patients with advanced liver cancer (hepatocellular carcinoma, HCC) who had shown proven radiological tumor progression under first-line therapy with the cancer drug sorafenib (Nexavar(R)). The study investigated safety and efficacy of resminostat as a monotherapy and in combination with sorafenib in this patient group with currently no approved treatment option.

Final median overall survival (OS) of 8.0 months was determined in the resminostat/sorafenib combination 'intend-to-treat' (ITT) population (n=26), i.e. all study patients who were treated with the combination of 600 mg resminostat total daily dose (TDD) and 400 mg sorafenib TDD. In the resminostat monotherapy group (ITT population, n=19), the final median OS value has been determined as 4.1 months. All presented data are subject to review upon database lock. In both study arms, resminostat has proven to be safe and well tolerated. Notably, the overall health condition of the patients enrolled in the SHELTER study was particularly severe (measured by the clinical parameters ECOG status, BCLC stage and Child-Pugh class) compared to other clinical studies with alternative investigational drugs in second-line HCC patient populations.

To the Company's best knowledge, the 8.0 months median OS in the resminostat/sorafenib combination group is the highest median OS value achieved to date in clinical studies investigating the efficacy of new treatment options for second-line advanced HCC in comparable patient populations who have shown proven radiological tumour progression on first-line sorafenib therapy. Moreover based on survival data reported from the SHARP trial (which led to the approval of sorafenib), the survival expectation of advanced HCC patients after developing progressive tumour disease on this treatment is only 5.2 months.

There is a particular high medical need for the development of new therapies for advanced HCC. To date, sorafenib is the only therapy approved for the first-line treatment of advanced HCC. However, the median time to tumour progression under sorafenib treatment has been reported to be 5.5 months (source: SHARP study). For these HCC patients who have shown progressive disease on sorafenib there is no approved second-line treatment available.

Resminostat progression-free survival (PFS) efficacy data of the SHELTER study have been presented earlier this year at the Annual Meeting of the American Society of Clinical Oncology (ASCO) on 4 June 2012 in Chicago (USA). The data for the resminostat/sorafenib combination therapy showed a progression-free survival rate (PFSR) after 12 weeks of treatment of 70.0% and a median PFS of 4.7 months - one of the highest PFS figures recorded to date by any second-line therapy in advanced clinical HCC studies. For the resminostat monotherapy group, the final PFSR at 12 weeks is 35.3% and the median PFS is 2.2 months. As previously reported, the primary study endpoint PFSR at 12 weeks had been achieved ahead of schedule in both the combination and the monotherapy group.

Professor Dr. Michael Bitzer, lead investigator of the SHELTER trial from the Medical University Clinic in Tuebingen, Germany, will present the data at the 6th Annual Conference of the International Liver Cancer Association (ILCA) in Berlin, Germany (14-16 September 2012, www.ilca-online.org) during an oral session on Sunday, 16 September 2012, from 10.30 am-12.00 pm (CEST). The presentation will be available at http://www.4sc.de/product-pipeline/publications-posters/resminostat when the session begins at 10.30 am (CEST).

Dr. Ulrich Dauer, Chief Executive Officer of 4SC, commented: 'We are very pleased with this study outcome. There is an enormous medical need in HCC especially after several investigational drugs, mostly protein kinase inhibitors, have recently failed in pivotal trials in this indication. Resminostat, as a leading HDAC inhibitor in advanced clinical development, offers a new and exciting therapeutic approach for advanced HCC: the use as a combination drug with sorafenib both in first-line and second-line HCC. We expect that the supplementary treatment with resminostat will restore or significantly improve the efficacy of the administered sorafenib therapy. I am confident that the impressive overall survival results from the SHELTER trial will give us further momentum for the preparation of our planned Phase III registration trial in combination with sorafenib in second-line HCC which we intend to start, preferably together with a partner, by mid 2013.'

Dr. Bernd Hentsch, Chief Development Officer of 4SC AG, added: 'The median overall survival value of 8.0 months in the resminostat/sorafenib combination group represents a strong signal of efficacy and provides a substantial clinical benefit for second-line HCC patients who otherwise have no alternative treatment option. Importantly, these data show a successful translation of the earlier reported median PFS of 4.7 months in the combination group into an overall survival advantage. Moreover, these data support the drug's innovative epigenetic mode of action: the re-sensitising effect of resminostat towards HCC tumour cells which have previously become tolerant and/or resistant to first-line sorafenib treatment. The good safety and pharmacokinetic properties of resminostat as well as the high 'combinability' due to the (re-) sensitising mode of action offer great potential for resminostat as a combination therapy with a broad range of chemotherapeutic and targeted therapies in numerous cancer indications where drug tolerance and resistance is assumed to be modulated by epigenetic mechanisms.'

Press Release Ends

Details of the Presentation:

Oral Presentation No.: O-030
Title: 'Efficacy, Tolerability and Pharmacokinetics of the Oral Histone Deacetylase Inhibitor Resminostat in Patients with Advanced Hepatocellular Carcinoma: Clinical Data from the Phase 2 Shelter Study'
Session title: General Session 5 - Clinical Trials (Oral Communication)
Session date and time: Sunday, 16 September 2012, 10:30 am-12:00 pm (CEST)
Authors/Presenters: M. Bitzer1, E.G. Giannini2, M. Horger3, U.M. Lauer1, T.M. Ganten4, M.A. Woerns5, J.T. Siveke6, M.M. Dollinger7, G. Gerken8, M.E. Scheulen8, H. Wege9, V. Zagonel10, U. Cillo11, F. Trevisani12, A. Santoro13, V. Montesarchio14, A. Mais15, A. Ammendola15, T. Herz15, J. Asche15, S. Henning15, B. Hauns15, B. Hentsch15, Shelter Study Group

1Medical University Clinic, Eberhard-Karls-University, Tuebingen, Germany, 2University Hospital, Genoa, Italy; 3Diagnostic Radiology, Eberhard-Karls-University, Tuebingen, Germany; 4Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany; 5Medical University Clinic, Mainz, Germany; 6Second Department of Internal Medicine, Technical University, Munich, Germany; 7Department of Internal Medicine, Martin Luther University, Halle, Germany; 8Department of Gastroenterology and Hepatology, University of Duisburg-Essen, Essen, Germany; 9University Hospital Hamburg-Eppendorf, Hamburg, Germany; 10Medical Oncology 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy; 11Hepatobiliary Surgery and Liver Transplant Unit, Azienda Università di Padova, Padova, Italy; 12University of Bologna, Bologna, Italy; 13Department of Oncology, Humanitas Cancer Center, Rozzano, Italy; 14UO Oncologia Ospedale Cotugno Napoli, Napoli, Italy; 154SC AG, Planegg-Martinsried, Germany

About the SHELTER Trial

The two-arm, international Phase II SHELTER study evaluates resminostat as a second-line treatment of patients with advanced liver cancer (HCC), alone or in combination with sorafenib (Nexavar(R)), the current standard of care in the first-line treatment of advanced HCC, to see if it can prolong progression-free survival (PFS) and overall survival (OS) in patients who developed progressive disease under first-line treatment with sorafenib. In the first study arm, patients are being treated with the recommended dose of the combination therapy (600 mg resminostat and 400 mg sorafenib total daily dose (TDD)) which was determined through an initial dose-escalation part of the study. In the second study arm, patients receive resminostat as monotherapy, administered orally, once daily, over five consecutive days, followed by a nine day treatment-free period (5+9 dosing schedule). In the combination arm, resminostat is administered in the same 5+9 dosing schedule, while sorafenib is administered twice daily (BID) throughout the cycle. In both study arms, this 14-day-cycle is repeated until there is evidence of progressive disease or until the patient leaves the study for other reasons. The first two radiological tumour assessments are performed after six and 12 weeks; after that, tumour assessments are performed every eight weeks. Patients who experience a clinical benefit, e.g. a stabilization of their progressive disease or even a regression of the tumour, may continue the study treatment. It was the primary study objective to halt the further progression of this particularly aggressive cancer disease in at least 20% of the patients treated and for at least 12 weeks in both therapy arms. The primary endpoint of the study is to determine the progression free survival rate (PFSR) after these initial 12 weeks of treatment. Secondary endpoints include the analysis of time-to-progression (TTP), progression-free survival time (PFS), overall survival (OS), drug safety and tolerability, pharmacokinetics and the investigation of biomarkers.

About Liver Cancer (Hepatocellular Carcinoma, HCC)

Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer. Liver cancer is the fifth most common cancer worldwide and, with approximately 700,000 deaths annually, the third most deadly. The incidence of HCC is particularly high in Pacific-Asia and Southern Europe. The aetiology of the disease varies between different areas. In Asia, hepatitis B virus (HBV) infection is the major risk factor for HCC, whereas in the Western world, hepatitis C virus (HCV) infection and alcohol abuse are the most frequent cause for liver cirrhosis, and subsequently, HCC. Even though over the past 10 years advancements in diagnosis and treatment of HCC have lead to certain improvements in the prognosis for HCC patients, the treatment options for patients with advanced HCC are still very poor. With sorafenib (Nexavar(R)), there is currently only one compound approved for this patient group. With a five-year survival rate of less than 10%, advanced HCC has one of the lowest overall survival rates of all cancer diseases worldwide. Thus, particularly for these patients with advanced HCC, there is still a high unmet medical need for novel, systemic therapy options, especially for patients refractory or intolerant to sorafenib.

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 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 mechanisms which tumour cells often develop against such 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, initial results are expected in 2012. Furthermore, in the Phase II SHELTER study resminostat is being 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. According to the data presented at the ASCO annual meeting on 4 June 2012, resminostat/sorafenib combination therapy showed a progression-free survival rate (PFSR) after 12 weeks of 70.0% and a median PFS of 4.7 months. The primary study endpoint has been 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 a pivotal clinical study programme for resminostat in combination with sorafenib as a second-line treatment for patients with advanced HCC who show tumour progression on first-line treatment with sorafenib.

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 90 employees at 30 June 2012. 4SC AG has been listed on the Prime Standard of the Frankfurt Stock Exchange since December 2005.

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