4SC AG

  • WKN: 575381
  • ISIN: DE0005753818
  • Land: Deutschland

Nachricht vom 31.05.2012 | 07:30

Press Release: 4SC's anti-cancer drug resminostat achieves progression-free survival of 4.7 months in Phase II trial in advanced liver cancer (HCC)


4SC AG / Key word(s): Miscellaneous

31.05.2012 / 07:30


Press Release

4SC's anti-cancer drug resminostat achieves progression-free survival of 4.7 months in Phase II trial in advanced liver cancer (HCC)

- Clinical Phase II results of the SHELTER study in advanced liver cancer (HCC) to be presented at this year's ASCO Conference in Chicago, USA, on 4 June 2012

- Combination of resminostat and sorafenib achieves progression-free survival of 4.7 months and thus demonstrates - to the company's best knowledge - the highest PFS figure recorded to date by any second-line therapy of advanced HCC in clinical Phase II/III studies

- Resminostat/sorafenib combination therapy halts disease progression for at least 12 weeks in 70% of HCC patients (PFSR 70%)

- Preparations are underway for a registration trial in HCC

Planegg-Martinsried, Germany - 31 May 2012 - 4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for autoimmune diseases and cancer, today published convincing results from its clinical Phase II SHELTER study with the cancer drug resminostat as a second-line therapy for patients with advanced liver cancer (hepatocellular carcinoma, HCC). The open-label, two-arm, international SHELTER study enrolled only patients who had exhibited radiologically proven tumour progression under first-line therapy with sorafenib (Nexavar(R)). The study investigated the safety and efficacy of resminostat both as a monotherapy and in combination with sorafenib for this difficult to treat patient group, for which no approved treatment option is currently available. The trial's lead investigator, Prof. Dr. Michael Bitzer of Tübingen University Hospital, Germany, will present the data in a poster at the upcoming Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago (USA). The poster will be available at http://www.4sc.de/product-pipeline/publications-posters/resminostat when the presentation begins at 8:00 a.m. CDT (3:00 p.m. CEST) on 4 June 2012.

Results of resminostat/sorafenib combination therapy

The determination of the primary trial endpoint of 'progression-free survival after 12 weeks' has been completed for the combination group. The study showed that resminostat in combination with sorafenib was able to prevent progression of the disease for at least 12 weeks in 14 of the 20 evaluable patients and even considerably longer - well over a year - in individual cases. After 12 weeks, the final progression-free survival rate (PFSR) was 70%, which is a further slight improvement on the preliminary trial data published at the ASCO Gastrointestinal Cancer Symposium in San Francisco on 19 January 2012. On that date, 4SC had announced that the primary trial endpoint had been achieved ahead of schedule with a PFSR of 66.7% based on 15 evaluable patients.

Based on the final analysis of the data, median progression-free survival (PFS) is 4.7 months for the combination treatment group. Median PFS describes the (median) length of time for which the progression of the patient's disease can be halted. Thus resminostat as a combination therapy together with Sorafenib has achieved - to 4SC's best knowledge - the highest PFS figure recorded to date by any second-line therapy of advanced HCC in clinical Phase II/III studies. Four patients are currently continuing the combination therapy beyond the first 12 weeks of treatment. The patients are being monitored continuously for the purpose of determining the secondary trial endpoint of 'overall survival' (OS). The median OS figure has not yet been reached in both study arms.

Results of monotherapy with resminostat

Based on the current analysis of the data, the progression-free survival rate (PFSR) for the monotherapy group is 35.7%. This means that in this group, five out of the 14 patients who were evaluable to date demonstrated disease stabilisation for at least 12 weeks. Progression-free survival (PFS) of this patient group is currently 2.2 months. Final results for the two endpoints, PFSR and PFS, could not yet be determined because in this patient group three patients are still undergoing treatment for whom no evaluation after 12 weeks is yet available and one patient is continuing treatment beyond the first 12 weeks of treatment.

Resminostat exhibits very good profiles of safety and tolerability

Resminostat has generally proven to be very safe and well tolerated during the study. The most frequent side-effects observed were of a gastrointestinal nature (diarrhoea, nausea). In the combination arm, in the majority of cases the side effects were attributed to the treatment with sorafenib. The majority of serious adverse events (SAEs) were attributed to the patient's underlying disease; a consistent profile of SAEs which were causally related to the study medication was not observed.

Dr. Ulrich Dauer, Chief Executive Officer of 4SC AG, commented:

'Our convincing trial results indicate that resminostat can offer a clear clinical benefit for liver cancer patients who no longer respond to sorafenib, the only approved cancer therapy available to them today. With a progression-free survival (PFS) of 4.7 months, resminostat as a combination therapy together with Sorafenib has achieved - to the best of our knowledge - the highest PFS figure recorded to date by any second-line therapy of advanced HCC in clinical Phase II/III studies. Therefore in our opinion this combination therapy clearly offers a promising, new second-line therapy option for advanced liver cancer. Accordingly, we are now aiming for the final stage of clinical development prior to market approval of resminostat for treating this patient group, for whom there is still no approved drug available. Resminostat addresses an urgent medical need and has significant commercial potential. We are doing everything in our power to launch a registration trial in this indication, preferably together with a partner, within the next twelve months.'

Dr. Dauer continued: 'The results presented from our SHELTER study impressively demonstrate the growing applicability of the new epigenetic mechanism of action offered by our compound resminostat. We believe that the tumour cell sensitisation to other anti-cancer drugs mediated by resminostat is highly relevant for clinical practice, since the supplementary administration of resminostat can, for example, permit the continued and effective treatment of patients with a cancer drug to which patient response is no longer adequate - in the case of HCC, treatment with the drug sorafenib. We expect resminostat to be generally capable of effectively enhancing other existing cancer therapies in combination treatment as a result of sensitisation.'

Increasing clinical relevance of epigenetically induced tumour cell sensitisation

Resminostat, 4SC's lead oncology compound, is an oral pan-histone-deacetylase (HDAC) inhibitor with an innovative, epigenetic mechanism of action that enables this compound to be deployed as a novel, targeted tumour therapy for a broad spectrum of oncological indications, particularly in combination with other anti-cancer drugs. By causing structural changes to DNA, resminostat triggers a differentiation in tumour cells, can induce programmed cell death in cancer cells (apoptosis) and is able to halt tumour growth. Additionally, resminostat induces what is known as tumour cell 'sensitisation' to treatment with other anti-cancer drugs. This process can suppress or reverse certain tolerance mechanisms that tumour cells often develop against other cancer drugs. Supplementary treatment with an HDAC inhibitor such as resminostat can be expected to restore or significantly improve the efficacy of a previously administered cancer therapy; furthermore, combining resminostat and common cancer drugs right from the very beginning can also be expected to be effective in enhancing the success of the treatment. This mechanism of action, i.e. tolerance breakdown through HDAC inhibition, has previously been described in research1. The Phase II SHELTER trial is the first clinical study where this mechanism has been investigated for resminostat in combination with sorafenib, a tyrosine-kinase inhibitor (TKI), in the difficult to treat indication of advanced liver cancer (HCC).

1 See Sharma et al., A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations, Cell 2010;141(1):69-80.

End of press release

Details of the Presentation:

Abstract No: (Permanent Abstract ID): 4115
Abstract Title: Efficacy, safety, tolerability and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study.
Time/Place of Presentation: Monday, 4 June 2012, 8:00 a.m.-12:00 noon CDT, S Hall A2
Poster Session: General Poster Session: Gastrointestinal (Non-colorectal) Cancer
Authors: Michael Bitzer, Marius Horger, Tom M Ganten, Ulrich M Lauer, Marcus A Woerns, Jens T Siveke, Matthias M. Dollinger, Max E. Scheulen, Guido Gerken, Henning Wege, Edoardo G Giannini, Vittorina Zagonel, Umberto Cillo, Franco Trevisani, Armando Santoro, Vincenzo Montesarchio, Bernhard Hauns, Julia Asche, Rüdiger Jankowsky, Anna Mais, Bernd Hentsch, Shelter Study Group

About the SHELTER Trial Design

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) 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 (OD) and 400 mg sorafenib (BID)) 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 daily 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 stagings are performed after six and 12 weeks; after that, tumour stagings are performed every eight weeks. Patients who experience a clinical benefit, e.g. a stabilization of their progressive disease or tumour regression, 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 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 '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 radiologically proven disease progression under first-line sorafenib therapy. According to the data presented at the ASCO-GI annual meeting in January 2012, the primary study endpoint has been achieved ahead of schedule in both therapy arms showing a progression-free survival rate (PFSR) after 12 weeks of 66.6% for the combination therapy group and of 33.3% for 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 31 March 2012. 4SC AG has been listed on the Prime Standard of the Frankfurt Stock Exchange since December 2005.

Legal Note

This document may contain projections or estimates relating to plans and objectives relating to our future operations, products, or services; future financial results; or assumptions underlying or relating to any such statements; each of which constitutes a forward-looking statement subject to risks and uncertainties, many of which are beyond our control. Actual results could differ materially, depending on a number of factors.

For more information please visit www.4sc.com or contact:

4SC AG
Jochen Orlowski, Corporate Communications & Investor Relations
jochen.orlowski(at)4sc.com, Tel.: +49 (0) 89 70 07 63 66

MC Services
Raimund Gabriel
raimund.gabriel(at)mc-services.eu, Tel.: +49 (0) 89 21 02 28 30

The Trout Group
Chad Rubin
crubin(at)troutgroup.com, Tel.: +1 646 378 2947
 



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