DGAP-News: Press Release: 4SC presents results from analysis of biomarkers and prognostic factors in Phase II SHELTER trial with resminostat in advanced liver cancer (HCC)
(firmenpresse) - DGAP-News: 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)
13.09.2013 / 07:30
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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 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
overallsurvival. 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:
'We are very glad that we could identify and further characterise 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(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
Abstract Title: Resminostat In Advanced Hepatocellular Carcinoma (HCC):
Overall Survival Subgroup Analysis Of Prognostic Factors In The Shelter
Trial.
Time/Place of Presentation: Sunday, 15 September 2013, 11:15 am - 11:30 am
Session: Novel and systemic therapies
Authors: Michael Bitzer1, Tom M Ganten2, Marcus A Woerns3, Jens T Siveke4,
Matthias M. Dollinger5, Max E Scheulen6, Henning Wege7, Edoardo G
Giannini8, Umberto Cillo9, Franco Trevisani10, Armando Santoro11, Vincenzo
Montesarchio12, Anna Mais13, Bernhard Hauns13, Julia Asche13, Thomas
Herz13, Stefano Pegoraro13, Aldo Ammendola13, Stefan W. Henning13, Bernd
Hentsch13, and Shelter Study Group
1 Medical University Clinic, Eberhard-Karls-University, Tuebingen, Germany;
2 Department of Internal Medicine, University of Heidelberg, Heidelberg,
Germany; 3 Medical University Clinic, Mainz, Germany; 4 Second Department
of Internal Medicine, Technical University, Munich, Germany; 5 Department
of Internal Medicine, Martin Luther University, Halle, Germany; 6 Center
for Internal Medicine, University Clinic Essen, Germany7 University
Hospital Hamburg-Eppendorf, Hamburg, Germany; 8 Gastroenterology Unit,
Department of Internal Medicine, University of Genoa, Genoa, Italy; 9
Hepatobiliary Surgery and Liver Transplant Unit, Azienda Universitàdi
Padova, Padova, Italy; 10 University of Bologna, Bologna, Italy; 11
Department of Oncology, Humanitas Cancer Center, Rozzano, Italy; 12 UO
Oncologia Ospedale Cotugno Napoli, Napoli, Italy; 13 4SC AG,
Planegg-Martinsried, Germany
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
Jochen Orlowski, Corporate Communications&Investor Relations
jochen.orlowski(at)4sc.com, Tel.: +49-89-700763-66
MC Services
Raimund Gabriel
raimund.gabriel(at)mc-services.eu , Tel.: +49-89-210228-30
The Trout Group (USA)
Chad Rubin
Crubin(at)troutgroup.com, Tel.: +1-646-378-2947
End of Corporate News
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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(at)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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