4SC Presents Summary of Biomarker and Patient Subgroup Analysis of Prognostic Factors

4SC AG has presented 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, 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®) 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®). 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®) 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.