4SC presents summary of biomarker and patient subgroup analysis of prognostic factors for survival in advanced HCC
- Baseline and biomarker characteristics of advanced HCC patients identified that have an impact on overall survival (OS) and are suitable as enrollment or stratification criteria in upcoming pivotal HCC programme with resminostat
- Novel potentially predictive biomarker ZFP64 identified in both, in HCC and in Hodgkin Lymphoma (HL) patients: high baseline expression of ZFP64 observed in about 2/3 of patients correlates with doubling of median OS under resminostat treatment compared to low ZFP64 expression
- Pharmacodynamic activity of resminostat on ZFP64 confirmed in patients and cell lines: HDAC inhibition by resminostat treatment leads to down-regulation of ZFP64, in peripheral blood of HCC patients
- Further information about proposed role of biomarker ZFP64 in HCC tumour progression presented
- Poster presentation at ECCO 2013 conference, 30 Sept. 2013, Amsterdam
4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for cancer and autoimmune diseases, today presents a detailed summary of results of a patient subgroup analysis of prognostic factors for overall survival and biomarkers in the Phase II SHELTER trial in advanced liver cancer (HCC). The data will be presented in a poster presentation today, 30 September 2013, from 2:00 PM - 4:30 PM (CEDT), at the ECCO 2013 (European Cancer Congress 2013) in Amsterdam). The poster will also be online at www.4sc.de/product-pipeline/publications-posters/resminostat when the session begins at 2:00 PM (CEDT).
As previously reported, the SHELTER trial investigated the HDAC inhibitor resminostat both as a monotherapy and in combination with the cancer drug sorafenib (Nexavar(R)) as a 2nd line treatment of advanced HCC patients that had progressed under 1st line sorafenib therapy. In the study, the combination of resminostat and sorafenib achieved a median overall survival (OS) of 8.1 months. This constitutes an additional gain of almost 3 months compared to the expected median OS of 5.2 months after progression on 1st line sorafenib therapy (see data from the 1st line HCC SHORE trial with sorafenib). 4SC is currently in preparation of pivotal clinical development plans for resminostat in combination with sorafenib in advanced HCC.
Dr Bernd Hentsch, Chief Development Officer of 4SC AG; comments: 'The identification of a number of most crucial patient characteristics relevant for survival expectations will now be supportive to guide the setup for our planned pivotal clinical development program with resminostat in advanced HCC. Furthermore, in conjunction with the application of our potentially predictive ZFP64 biomarker 4SC aims at developing resminostat into a personalized cancer medicine for this indication.'
Summary of the results presented at ECCO 2013 in further detail:
1) Selected baseline characteristics correlate with overall survival of advanced HCC patients in the SHELTER study
4SC reports results from the analysis of HCC patient baseline characteristics that appear to have an impact on overall survival in advanced HCC patients of the SHELTER study, treated with either resminostat monotherapy or in combination with sorafenib (Nexavar(R)). In the monotherapy arm, an overall good performance status of the patients (ECOG 0) and pre-treatment with a local ablative therapy (transarterial chemoembolization, TACE) correlated with a longer survival outcome. In the combination therapy arm in addition to ECOG 0 also the absence of liver cirrhosis (Child-Pugh A) and the absence of vascular invasion of the liver tumour was identified to correlate with a prolonged overall survival. Notably, in both treatment arms the time interval between end of 1st line sorafenib therapy and 2nd line treatment start in the SHELTER study ('drug holidays') had no influence on the median OS of SHELTER patients. These and other factors will be considered as important enrollment and stratification criteria for the currently planned pivotal Phase III studies with resminostat in combination with sorafenib as a novel treatment option for advanced HCC.
2) High baseline expression of ZFP64 correlates with prolonged survival in cancer patients treated with resminostat; pharmacodynamic activity of resminostat (i.e. down-regulation of ZFP64 gene expression) confirmed; proposed role of ZFP64 in tumour progression further elaborated
In the search for suitable biomarkers that allow monitoring the pharmacodynamic activity of resminostat 4SC identified a set of genes that showed a robust and reproducible regulation of expression levels in response to resminostat within hours after drug exposure in peripheral blood of cancer patients. One of these highly regulated genes is the DNA binding transcription factor 'zinc-finger protein 64' (ZFP64). According to the current model of ZFP64 activity, this biomarker is expected to play a role in HCC tumour progression by promoting processes of liver inflammation and tumour progression in a dual way by (i) co-activation of NF-kB-mediated pro-inflammatory TLR signaling, and (ii) by co-activating the pro-tumourigenic Notch1 pathway. ZFP64 levels in peripheral blood samples of HCC patients can be conveniently determined by quantitative PCR technology. ZFP64 blood levels were rapidly reduced approx. 5-fold in comparison to baseline levels within 2-5 hours after drug intake, presumably reflecting a similar response at the patients' tumour site, also suggested by similar results obtained in vitro in a variety of cancer cell lines of different tumour origins.
Moreover, baseline expression of ZFP64 in HCC patients before the start of treatment proved to correlate in a statistically significant manner (p=0.04) with the achieved clinical outcome, i.e. higher baseline expression was indicative of a longer overall survival than lower baseline expression of ZFP64. High ZFP64 expression was observed in about 2/3 of the patients, resulting in a doubling of the median OS value in comparison to the 1/3 of patients with low baseline ZFP64 expression. Importantly, this observation in advanced HCC patients of the SHELTER study treated with either resminostat monotherapy or in combination with sorafenib (Nexavar(R)) was confirmed in a second Phase II study (SAPHIRE) in advanced Hodgkin Lymphoma (HL) patients treated with resminostat monotherapy, indicating a potential predictive character of this biomarker for response to resminostat treatment and suggesting a common underlying biological background in certain tumours that might be more responsive to treatment with resminostat.
Details of the Presentation
Abstract No.: 2.601
Poster Board P429
Abstract Title: Subgroup analysis of prognostic factors for overall survival in the SHLTER trial evaluating resminostat in advanced hepatocellular carcinoma (HCC)
Time/Place of Presentation: Monday, 30 September 2013, 2:00 PM - 4:30 PM (CEDT)
Session: Gastrointestinal Malignancies - Noncolorectal
Authors: Michael Bitzer1, Anna Mais2, Bernhard Hauns2, Julia Asche2, Thomas Herz2, Stefano Pegoraro2, Aldo Ammendola2, Stefan W. Henning2, Bernd Hentsch2, and SHELTER Study Group
1 Medical University Clinic, Eberhard-Karls-University, Tuebingen, Germany; 2 4SC AG, Planegg-Martinsried, Germany
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 a 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 first-line HCC towards market approval.
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.
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 March 2013. 4SC AG has been listed on the Prime Standard of the Frankfurt Stock Exchange since December 2005
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