4SC Presents Results from Analysis of Biomarkers in Phase II SHELTER Trial in HCC

4SC AG has 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 7th 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 2nd 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®). 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: 'We are very glad that we could identify and further characterize this intriguing biomarker of ZFP64 expression. The statistical significant linkage of ZFP64-elevated expression levels before resminostat treatment start in 2/3 of the patients and patients' survival outcomes as well as the convincing suggested underlying biological mechanism of action, in our view strongly qualifies ZFP64 gene expression as a potentially predictive biomarker for clinical response to resminostat treatment to be integrated in our planned pivotal programme in advanced HCC. In addition, we have further strengthened the scientific rationale for resminostat's anti-tumour mode of action by showing that epigenetic down-regulation of ZFP64 gene expression by resminostat might result in a reduction of pro-tumorigenic NOTCH signalling and subsequently in an increased clinical response in cancer patients.'

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®). 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.