Corporate | 13 September 2013 07:30
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4SC AG / Key word(s): Miscellaneous
Press Release 4SC presents results from analysis of biomarkers and prognostic factors in Phase II SHELTER trial with resminostat in advanced liver cancer (HCC) – Identification and further characterization of novel potentially predictive biomarker ZFP64 indicative for survival upon treatment with resminostat in patients with advanced HCC – High baseline expression of ZFP64 in peripheral blood (observed in about 2/3 of patients) correlates with doubling of median overall survival compared to low baseline ZFP64 – Additional patient baseline characteristics influencing overall survival in HCC identified – Both ZFP64 biomarker analysis and patient baseline characteristics to be integrated for patient stratification in planned pivotal programme with resminostat in advanced HCC – Oral presentation of detailed results at ILCA conference, 15 Sept. 2013, Washington D.C. Planegg-Martinsried, Germany, 13 September 2013 – 4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for cancer and autoimmune diseases, today announced the presentation of results from an in depth analysis of biomarker data and patient characteristics and their respective relevance for survival outcomes in the Phase II clinical SHELTER trial in advanced liver cancer (HCC). The presentation will be given at the upcoming 7 th Annual Conference of the International Liver Cancer Association (ILCA) in Washington, D.C., USA (13-15 September 2013, ( www.ilca-online.org ) by the coordinating investigator of the SHELTER trial, Prof. Michael Bitzer, University of Tübingen, Germany, during an oral session on Sunday, 15 September 2013 at 11:15 AM EDT (5:15 PM CEDT). The presentation will be available online at http://www.4sc.de/product-pipeline/publications-posters/resminostat at the time of the oral session. As previously reported, in the study the resminostat/sorafenib combination therapy of 2 nd line HCC patients who had shown prior progression on sorafenib monotherapy resulted in an overall survival (OS) of 8.1 months, while resminostat monotherapy of these difficult-to-treat patients resulted in an OS of 4.2 months. High expression of biomarker ZFP64 correlates with statistical significance (p=0.04) with doubling of overall survival in advanced HCC patients treated with resminostat The key finding of the biomarker analysis in the SHELTER trial is the identification of the novel, potentially predictive biomarker ZFP64, which is strongly correlated with overall survival of advanced liver cancer (HCC) patients treated with resminostat. In this trial, patients with high expression of ZFP64 in blood samples at baseline (i.e. before treatment start) showed a doubling of the median overall survival (OS) compared to patients with low ZFP64 expression. The analysis has shown that roughly 2/3 of all HCC patients in the study were ZFP64 high-expressers, while 1/3 of patients showed low ZFP64 expression correlating with a markedly lower overall survival. This correlation between expression levels of ZFP64 in HCC patients at baseline and clinical outcome in the SHELTER trial was statistically significant (p=0.04). This observation was made in advanced HCC patients of the SHELTER study treated with either resminostat monotherapy or in combination of resminostat with sorafenib (Nexavar(R)). Moreover, these findings have been similarly identified in a second Phase II clinical study (SAPHIRE trial) applying resminostat as single agent in patients with advanced Hodgkin lymphoma (HL), thus further confirming the correlation between ZPP64 expression and clinical outcome in a cancer indication different and unrelated to HCC. A patent application has been filed in order to provide adequate IP protection for these findings. Scientific rationale for the role of ZFP64 in cancer: As an epigenetic HDAC modifier of gene transcriptional activity, reminostat strongly suppresses ZFP64, a co-activator of the NOTCH pathway, which plays a key role in tumour growth and progression ZFP64 (zinc finger protein 64) has been published to act as a transcriptional co-activator of NOTCH modulated gene regulations. It thus plays an important role in the NOTCH signalling cascade, which represents one of the key signalling pathways involved in the regulation of various cancers. Moreover, it was shown in 4SC’s clinical trials that upon resminostat treatment gene expression levels of ZFP64 were strongly down-regulated in blood cells of both HCC and HL patients. Preclinically, a comparable down-regulation of ZFP64 expression levels has also been observed in a broad variety of tumour cell lines derived from different haematological and solid cancer indications, indicating that resminostat impacts negatively on ZFP64 gene expression levels not only in blood cells of patients but most likely also in their tumor tissues. According to the findings in the HCC and HL trials, the down-regulation of ZFP64 by resminostat treatment is assumed to result in an inhibition of the NOTCH pathway and therefore leads to a prolongation of patient survival. Therefore, the scientific rationale for the correlation between high ZFP64 expression and patient survival expectation is that the tumours with high ZFP64 levels are expectedly more dependent on ZFP64-controlled NOTCH pathways for their growth than tumours with low ZFP64 levels. Tumours with high ZFP64 levels are thus expected to respond particularly well to resminostat treatment resulting in improved clinical benefit for the patient. Analysis of ZFP64 as a potentially predictive biomarker to be part of planned pivotal development programme with resminostat as a personalized cancer therapy for advanced HCC 4SC is currently designing a pivotal clinical development programme for resminostat applied in combination with sorafenib as new treatment option for advanced HCC patients. Notably, sorafenib on its own has no effect on ZFP64 expression levels according to 4SC’s recent findings. 4SC plans to integrate the new findings about ZFP64 as a potentially predictive biomarker in the study design of a pivotal Phase II/III trial and to further discuss this with potential partners and regulatory authorities. It is 4SC’s goal to develop resminostat, in conjunction with the use of biomarker ZFP64, as a personalized cancer medicine towards market approval.
Dr Bernd Hentsch, Chief Development Officer of 4SC AG, comments:
Further selected baseline characteristics correlate with overall survival of advanced HCC patients in the SHELTER study Other findings from 4SC reported at the ILCA conference will comprise data from the in depth analysis of further patient baseline characteristics and their influence on overall survival in the advanced HCC patient population of the SHELTER study, treated with either resminostat monotherapy or in combination with sorafenib (Nexavar(R)). In the monotherapy arm, ECOG 0 status and pre-treatment with TACE (transcatheter arterial chemo-embolization) correlated with a longer survival outcome. In the combination therapy study population, in addition to ECOG 0, also a Child-Pugh A status and the absence of vascular invasion of the tumour were identified to correlate with a prolonged overall survival. However, in both treatment arms the time interval between the end of first-line sorafenib therapy and the start of treatment in the SHELTER study (so called ‘drug holidays’) had no influence on the median overall survival of SHELTER patients. 4SC plans to integrate these new findings about patients’ baseline characteristics and their influence on patients’ clinical outcome in the study design of the planned pivotal development programme of resminostat in advanced HCC. Ends Details of the Presentation
Abstract No.:
O-032
About Resminostat Resminostat (4SC-201), 4SC’s lead oncology compound, is an oral 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 in 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 to date has been investigated in a broad clinical campaign comprising liver cancer (hepatocellular carcinoma, HCC), Hodgkin’s Lymphoma (HL), and colorectal cancer (CRC), with non-small-cell lung cancer (NSCLC) recently been added as the third solid cancer indication to the programme. In the Phase II SAPHIRE trial in patients with advanced Hodgkin’s Lymphoma (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 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 8.1 months, a value to the company’s best knowledge not reached in any study with a comparable second-line patient population. The resminostat/sorafenib combination therapy had shown a progression-free survival rate (PFSR) after 12 weeks of 70.0% and a median PFS of 5.4 months. The primary study endpoint was achieved ahead of schedule in both the combination and the monotherapy group. 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 indicative of survival outcome upon treatment with resminostat. Hereby, patients with a high level of ZFP64 gene expression at baseline experienced longer survival than 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 have been published at the 2013 ASCO conference. 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 in a pivotal programme in advanced HCC towards market approval. 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 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 83 employees at 30 June 2013. 4SC AG has been listed on the Prime Standard of the Frankfurt Stock Exchange since December 2005. Cautionary statement regarding forward-looking statements This press release contains certain forward-looking statements. Any forward-looking statement applies only on the date of this press release. By their nature, forward-looking statements are subject to a number of known and unknown risks and uncertainties that may or may not occur in the future and as a result of which the actual results and performance may differ substantially from the expected future results or performance expressed or implied in the forward looking statements. No warranties or representations are made as to the accuracy, achievement or reasonableness of such statements, estimates or projections, and 4SC AG has no obligation to update any such information or to correct any inaccuracies herein or omission herefrom which may become apparent. For more information please visit www.4sc.com or contact:
4SC AG
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| Language: | English | |
| Company: | 4SC AG | |
| Am Klopferspitz 19a | ||
| 82152 Martinsried | ||
| Germany | ||
| Phone: | +49 (0)89 7007 63-0 | |
| Fax: | +49 (0)89 7007 63-29 | |
| E-mail: | public@4sc.com | |
| Internet: | www.4sc.de | |
| ISIN: | DE0005753818 | |
| WKN: | 575381 | |
| Listed: | Regulierter Markt in Frankfurt (Prime Standard); Freiverkehr in Berlin, Düsseldorf, München, Stuttgart | |
| End of News | DGAP News-Service |
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