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4SC gives update on the clinical development of its lead cancer compound resminostat

(lifePR) (Planegg-Martinsried, ) .
- Data from completed Phase I part of SHORE study in advanced colorectal cancer (CRC) to be presented at upcoming ASCO conference in Chicago, confirming the safety of the resminostat FOLFIRI combination and showing encouraging signs of clinical benefit
- Successful identification of a biomarker (ZFP64) indicative of survival in both advanced liver cancer (HCC) and Hodgkin's Lymphoma (HL) Phase II clinical trials with resminostat
- Main focus of the further clinical development of resminostat to be on pivotal programme in first-line advanced HCC with an intended integrated biomarker program including ZFP64

4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for autoimmune diseases and cancer, today announced an update on substantial progress in the clinical development of its lead oncology drug resminostat.

Results from the completed Phase I part of the SHORE study in advanced CRC

Positive Phase I results on safety, tolerability and pharmacokinetics from its SHORE study with resminostat in combination with FOLFIRI chemotherapy in patients with advanced colorectal cancer (CRC) will be presented at the upcoming 2013 meeting of the American Society of Clinical Oncology (ASCO) in Chicago on 2 June 2013. The SHORE study has been designed to investigate the combination of resminostat and FOLFIRI as a new second-line treatment option for patients with advanced, KRAS-mutant CRC.

Resminostat proved to be safe and well-tolerated in all doses tested, applying its standard 5+9 dosing regimen up to a daily dosage of 600 mg (once daily (OD)) or 800 mg (400 mg twice daily (BID)) in combination with the recommended standard dosage of FOLFIRI, a multi-component chemotherapy regimen that includes e.g. 5-fluorouracil (5-FU) and irinotecan. This again confirmed the clean safety profile of resminostat when applied in combination with established cancer therapies. Observed side effects were generally mild to moderate and occurred, as expected, primarily as gastrointestinal and hematological effects. No dose-limiting toxicities (DLT) occurred and no formal maximum tolerated dose (MTD) of the combination regimen was determined up to the highest dose level of 800 mg (400 mg BID) resminostat. The known side-effect profile of the FOLFIRI regimen did not change as a result of the additional administration of resminostat. The study further confirmed the favorable pharmacokinetic profile of resminostat already observed in other studies, reflected for instance in the dose proportionality of resminostat blood levels. No pharmacological interactions between resminostat and any of the FOLFIRI components were observed.

In addition, the treatment - already in the Phase I part of the study - showed encouraging signs of clinical activity. Patients frequently experienced disease stabilisation as clinical benefit and, accordingly, could be treated with the combination of resminostat and FOLFIRI for several months: 7 of 15 evaluable patients were treated for at least 12 weeks with a maximum of 33 weeks.

Enno Spillner, Chief Executive Officer of 4SC AG, comments: 'We have successfully achieved the study objective of the Phase I part of our SHORE trial. The data have once again confirmed the clean safety profile of resminostat when applied in combination with established cancer therapies. In addition, the resminostat FOLFIRI combination therapy has shown encouraging signs of clinical benefit in colorectal cancer (CRC). After having shown convincing Phase II data in our main indication liver cancer (HCC) last year, these new Phase I results in CRC once again illustrate the great clinical potential of our key compound resminostat.'

The ASCO poster will be available at http://www.4sc.de/product-pipeline/publications-posters/resminostat when the presentation begins at 8:00 am CDT (3:00 pm CEST) on 2 June 2012.

As previously communicated, 4SC will primarily focus on the further development of resminostat toward market approval as a first-line drug for treatment of advanced liver cancer (HCC). 4SC is currently working on the clinical development plan for resminostat, used in combination with sorafenib as a first-line therapy of HCC, and will then discuss the further development steps with potential partners and regulatory authorities in the EU and the US.

Identification of ZFP64 gene expression as a biomarker indicative of survival in clinical trials with resminostat in both liver cancer (HCC) and Hodgkin lymphoma (HL)

4SC also reports promising biomarker data from two Phase II clinical trials with resminostat in advanced liver cancer (hepatocellular carcinoma, HCC) (SHELTER study) and advanced Hodgkin lymphoma (HL) (SAPHIRE study). These observations in both HCC and HL patients point to a role of the gene expression levels of a certain gene, called Zinc Finger Protein 64 (ZFP64), as a potential biomarker suitable to indicate the clinical outcome of cancer diseases when treated with resminostat.

A promising positive correlation between expression levels of ZFP64 in peripheral blood cells of HCC and HL patients at baseline, i.e. before the start of resminostat treatment, and the achieved clinical outcome, was observed. High baseline ZFP64 expression levels were linked to an increased clinical benefit, i.e. patients were more likely to achieve clinical stable disease (SD). More importantly, patients displaying higher ZFP64 baseline levels also experienced a significantly longer overall survival (OS) compared to patients with lower ZFP64 baseline levels.

These findings were observed in patient cohorts from Phase II studies with resminostat in two different advanced cancer indications, liver cancer (hepatocellular carcinoma, HCC) and Hodgkin's Lymphoma (HL). This may suggest a common underlying biological cancer cell background in both tumors types, which might be more responsive to treatment with resminostat. A patent application has been filed in order to provide adequate IP protection for these findings. ZFP64 has been described in the scientific literature as a transcription factor and co-activator of Notch, a protein controlling one of the central signaling pathways involved in the regulation of cancer.

Data were derived from the analysis of changes in gene expression patterns in response to both resminostat monotherapy (SAPHIRE study in HL and SHELTER study in HCC) and in combination with sorafenib (Nexavar(R)) (SHELTER study in HCC). The initial goal of the biomarker analysis was to investigate whether changes in expression levels of these genes in peripheral blood cells may serve as further pharmacodynamic markers for the pharmacological activity of resminostat.

Dr Bernd Hentsch, Chief Development Officer of 4SC AG; comments: '4SC will now conduct further studies to confirm these positive findings. It is our goal to develop resminostat, ideally in conjunction with the use of biomarkers as a personalized cancer medicine, towards market approval. As a part of this strategy, 4SC will integrate these new findings about ZFP64 in a biomarker program for the further development of resminostat in first-line HCC. Therefore, going forward, 4SC will discuss the resulting options with potential partners and regulatory authorities.'

Details of the Presentation:

Abstract No.: 3625
Abstract Title: Phase I dose escalation of the oral histone deacetylase inhibitor (HDACi) resminostat in combination with FOLFIRI in colorectal cancer (CRC) patients: the SHORE trial
Time/Place of Presentation: Sunday, 2 June 2013, 8:00 am - 11:45 am, S Hall A2
Poster Session: General Poster Session, Gastrointestinal (Colorectal) Cancer
Authors: H. Schulze-Bergkamen1, D. Jäger1, HG Kopp2, M. Bitzer2, A. Mais3, K. Resemann3, B. Hauns3, J. Asche3, S.W. Henning3, B. Hentsch3
(1National Center for Tumor Diseases (NCT) Heidelberg, Germany, 2University of Tuebingen Medical Center, Tuebingen, Germany, 34SC AG, Planegg-Martinsried, Germany)

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 and 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 that 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 has been introduced into a Phase II programme in the three indications of liver cancer (hepatocellular carcinoma, HCC), Hodgkin Lymphoma (HL), and colorectal cancer (CRC). In the Phase II SAPHIRE trial in patients with advanced HL, resminostat in monotherapy has demonstrated substantial anti-tumour 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 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 results for safety and tolerability of this combination will be published at this year's ASCO conference in Chicago. 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 had shown a progression-free survival rate (PFSR) after 12 weeks of 70.0% and a median PFS of 4.7 months, resulting in a median overall survival (OS) of 8.0 months.

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

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4SC AG

The Group managed by 4SC AG (ISIN DE0005753818) discovers and develops targeted, small-molecule drugs for treating diseases with high unmet medical needs in cancer and autoimmune 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 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 pharmaceutical and biotech companies. Founded in 1997, 4SC had 86 employees at 31 March 2013. 4SC AG has been listed on the Prime Standard of the Frankfurt Stock Exchange since December 2005.