DGAP-News: 4SC AG / Key word(s): Miscellaneous
Press Release: 4SC's anti-cancer drug resminostat achieves
progression-free survival of 4.7 months in Phase II trial in advanced
liver cancer (HCC)
31.05.2012 / 07:30
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Press Release
4SC's anti-cancer drug resminostat achieves progression-free survival of
4.7 months in Phase II trial in advanced liver cancer (HCC)
- Clinical Phase II results of the SHELTER study in advanced liver cancer
(HCC) to be presented at this year's ASCO Conference in Chicago, USA,
on 4 June 2012
- Combination of resminostat and sorafenib achieves progression-free
survival of 4.7 months and thus demonstrates - to the company's best
knowledge - the highest PFS figure recorded to date by any second-line
therapy of advanced HCC in clinical Phase II/III studies
- Resminostat/sorafenib combination therapy halts disease progression for
at least 12 weeks in 70% of HCC patients (PFSR 70%)
- Preparations are underway for a registration trial in HCC
Planegg-Martinsried, Germany - 31 May 2012 - 4SC AG (Frankfurt, Prime
Standard: VSC), a discovery and development company of targeted small
molecule drugs for autoimmune diseases and cancer, today published
convincing results from its clinical Phase II SHELTER study with the cancer
drug resminostat as a second-line therapy for patients with advanced liver
cancer (hepatocellular carcinoma, HCC). The open-label, two-arm,
international SHELTER study enrolled only patients who had exhibited
radiologically proven tumour progression under first-line therapy with
sorafenib (Nexavar(R)). The study investigated the safety and efficacy of
resminostat both as a monotherapy and in combination with sorafenib for
this difficult to treat patient group, for which no approved treatment
option is currently available. The trial's lead investigator, Prof. Dr.
Michael Bitzer of Tübingen University Hospital, Germany, will present the
data in a poster at the upcoming Annual Meeting of the American Society of
Clinical Oncology (ASCO) in Chicago (USA). The poster will be available at
http://www.4sc.de/product-pipeline/publications-posters/resminostat when
the presentation begins at 8:00 a.m. CDT (3:00 p.m. CEST) on 4 June 2012.
Results of resminostat/sorafenib combination therapy
The determination of the primary trial endpoint of 'progression-free
survival after 12 weeks' has been completed for the combination group. The
study showed that resminostat in combination with sorafenib was able to
prevent progression of the disease for at least 12 weeks in 14 of the 20
evaluable patients and even considerably longer - well over a year - in
individual cases. After 12 weeks, the final progression-free survival rate
(PFSR) was 70%, which is a further slight improvement on the preliminary
trial data published at the ASCO Gastrointestinal Cancer Symposium in San
Francisco on 19 January 2012. On that date, 4SC had announced that the
primary trial endpoint had been achieved ahead of schedule with a PFSR of
66.7% based on 15 evaluable patients.
Based on the final analysis of the data, median progression-free survival
(PFS) is 4.7 months for the combination treatment group. Median PFS
describes the (median) length of time for which the progression of the
patient's disease can be halted. Thus resminostat as a combination therapy
together with Sorafenib has achieved - to 4SC's best knowledge - the
highest PFS figure recorded to date by any second-line therapy of advanced
HCC in clinical Phase II/III studies. Four patients are currently
continuing the combination therapy beyond the first 12 weeks of treatment.
The patients are being monitored continuously for the purpose of
determining the secondary trial endpoint of 'overall survival' (OS). The
median OS figure has not yet been reached in both study arms.
Results of monotherapy with resminostat
Based on the current analysis of the data, the progression-free survival
rate (PFSR) for the monotherapy group is 35.7%. This means that in this
group, five out of the 14 patients who were evaluable to date demonstrated
disease stabilisation for at least 12 weeks. Progression-free survival
(PFS) of this patient group is currently 2.2 months. Final results for the
two endpoints, PFSR and PFS, could not yet be determined because in this
patient group three patients are still undergoing treatment for whom no
evaluation after 12 weeks is yet available and one patient is continuing
treatment beyond the first 12 weeks of treatment.
Resminostat exhibits very good profiles of safety and tolerability
Resminostat has generally proven to be very safe and well tolerated during
the study. The most frequent side-effects observed were of a
gastrointestinal nature (diarrhoea, nausea). In the combination arm, in the
majority of cases the side effects were attributed to the treatment with
sorafenib. The majority of serious adverse events (SAEs) were attributed to
the patient's underlying disease; a consistent profile of SAEs which were
causally related to the study medication was not observed.
Dr. Ulrich Dauer, Chief Executive Officer of 4SC AG, commented:
'Our convincing trial results indicate that resminostat can offer a clear
clinical benefit for liver cancer patients who no longer respond to
sorafenib, the only approved cancer therapy available to them today. With a
progression-free survival (PFS) of 4.7 months, resminostat as a combination
therapy together with Sorafenib has achieved - to the best of our knowledge
- the highest PFS figure recorded to date by any second-line therapy of
advanced HCC in clinical Phase II/III studies. Therefore in our opinion
this combination therapy clearly offers a promising, new second-line
therapy option for advanced liver cancer. Accordingly, we are now aiming
for the final stage of clinical development prior to market approval of
resminostat for treating this patient group, for whom there is still no
approved drug available. Resminostat addresses an urgent medical need and
has significant commercial potential. We are doing everything in our power
to launch a registration trial in this indication, preferably together with
a partner, within the next twelve months.'
Dr. Dauer continued: 'The results presented from our SHELTER study
impressively demonstrate the growing applicability of the new epigenetic
mechanism of action offered by our compound resminostat. We believe that
the tumour cell sensitisation to other anti-cancer drugs mediated by
resminostat is highly relevant for clinical practice, since the
supplementary administration of resminostat can, for example, permit the
continued and effective treatment of patients with a cancer drug to which
patient response is no longer adequate - in the case of HCC, treatment with
the drug sorafenib. We expect resminostat to be generally capable of
effectively enhancing other existing cancer therapies in combination
treatment as a result of sensitisation.'
Increasing clinical relevance of epigenetically induced tumour cell
sensitisation
Resminostat, 4SC's lead oncology compound, is an oral
pan-histone-deacetylase (HDAC) inhibitor with an innovative, epigenetic
mechanism of action that enables this compound to be deployed as a novel,
targeted tumour therapy for a broad spectrum of oncological indications,
particularly in combination with other anti-cancer drugs. By causing
structural changes to DNA, resminostat triggers a differentiation in tumour
cells, can induce programmed cell death in cancer cells (apoptosis) and is
able to halt tumour growth. Additionally, resminostat induces what is known
as tumour cell 'sensitisation' to treatment with other anti-cancer drugs.
This process can suppress or reverse certain tolerance mechanisms that
tumour cells often develop against other cancer drugs. Supplementary
treatment with an HDAC inhibitor such as resminostat can be expected to
restore or significantly improve the efficacy of a previously administered
cancer therapy; furthermore, combining resminostat and common cancer drugs
right from the very beginning can also be expected to be effective in
enhancing the success of the treatment. This mechanism of action, i.e.
tolerance breakdown through HDAC inhibition, has previously been described
in research (1). The Phase II SHELTER trial is the first clinical study
where this mechanism has been investigated for resminostat in combination
with sorafenib, a tyrosine-kinase inhibitor (TKI), in the difficult to
treat indication of advanced liver cancer (HCC).
(1) See Sharma et al., A chromatin-mediated reversible drug-tolerant state
in cancer cell subpopulations, Cell 2010;141(1):69-80.
End of press release
Details of the Presentation:
Abstract No: (Permanent Abstract ID): 4115
Abstract Title: Efficacy, safety, tolerability and PK of the HDAC inhibitor
resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase
II SHELTER study.
Time/Place of Presentation: Monday, 4 June 2012, 8:00 a.m.-12:00 noon CDT,
S Hall A2
Poster Session: General Poster Session: Gastrointestinal (Non-colorectal)
Cancer
Authors: Michael Bitzer, Marius Horger, Tom M Ganten, Ulrich M Lauer,
Marcus A Woerns, Jens T Siveke, Matthias M. Dollinger, Max E. Scheulen,
Guido Gerken, Henning Wege, Edoardo G Giannini, Vittorina Zagonel, Umberto
Cillo, Franco Trevisani, Armando Santoro, Vincenzo Montesarchio, Bernhard
Hauns, Julia Asche, Rüdiger Jankowsky, Anna Mais, Bernd Hentsch, Shelter
Study Group
About the SHELTER Trial Design
The two-arm, international Phase II SHELTER study evaluates resminostat as
a second-line treatment of patients with advanced liver cancer (HCC), alone
or in combination with sorafenib (Nexavar(R)), the current standard of care
in the first-line treatment of advanced HCC, to see if it can prolong
progression-free survival (PFS) in patients who developed progressive
disease under first-line treatment with sorafenib. In the first study arm,
patients are being treated with the recommended dose of the combination
therapy (600 mg resminostat (OD) and 400 mg sorafenib (BID)) which was
determined through an initial dose-escalation part of the study. In the
second study arm, patients receive resminostat as monotherapy, administered
orally, once daily, over five consecutive days, followed by a nine day
treatment-free period (5+9 dosing schedule). In the combination arm,
resminostat is administered in the same 5+9 dosing schedule, while
sorafenib is administered daily throughout the cycle. In both study arms,
this 14-day-cycle is repeated until there is evidence of progressive
disease or until the patient leaves the study for other reasons. The first
two radiological tumour stagings are performed after six and 12 weeks;
after that, tumour stagings are performed every eight weeks. Patients who
experience a clinical benefit, e.g. a stabilization of their progressive
disease or tumour regression, may continue the study treatment. It was the
primary study objective to halt the further progression of this
particularly aggressive cancer disease in at least 20% of the patients
treated and for at least 12 weeks in both therapy arms. The primary
endpoint of the study is to determine the progression free survival rate
(PFSR) after 12 weeks of treatment. Secondary endpoints include the
analysis of time-to-progression (TTP), progression-free survival time
(PFS), overall survival (OS), drug safety and tolerability,
pharmacokinetics and the investigation of biomarkers.
About Liver Cancer (Hepatocellular Carcinoma, HCC)
Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer.
Liver cancer is the fifth most common cancer worldwide and, with
approximately 700,000 deaths annually, the third most deadly. The incidence
of HCC is particularly high in Pacific-Asia and Southern Europe. The
aetiology of the disease varies between different areas. In Asia, hepatitis
B virus (HBV) infection is the major risk factor for HCC, whereas in the
Western world, hepatitis C virus (HCV) infection and alcohol abuse are the
most frequent cause for liver cirrhosis, and subsequently, HCC. Even though
over the past 10 years advancements in diagnosis and treatment of HCC have
lead to certain improvements in the prognosis for HCC patients, the
treatment options for patients with advanced HCC are still very poor. With
sorafenib (Nexavar(R)), there is currently only one compound approved for
this patient group. With a five-year survival rate of less than 10%,
advanced HCC has one of the lowest overall survival rates of all cancer
diseases worldwide. Thus, particularly for these patients with advanced
HCC, there is still a high unmet medical need for novel, systemic therapy
options, especially for patients refractory or intolerant to sorafenib.
About Resminostat
Resminostat (4SC-201), 4SC's lead oncology compound, is an oral
pan-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 as a monotherapy and 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 'sensitisation' to other anti-cancer compounds.
This process can suppress or reverse certain tolerance mechanisms which
tumour cells often develop against such 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 is currently being investigated in a broad clinical Phase II
programme in the three indications liver cancer (hepatocellular carcinoma,
HCC), Hodgkin's Lymphoma (HL), and colorectal cancer (CRC). In the Phase II
SAPHIRE trial in patients with advanced Hodgkin's Lymphoma, resminostat in
monotherapy has demonstrated substantial anti-tumour activity, with an
overall response rate of 35.3% and a clinical benefit in 55.9% of the
patients in a heavily pre-treated patient population together with very
good safety and tolerability. In the Phase I/II SHORE study, which
evaluates resminostat in combination with the chemotherapeutic FOLFIRI
regimen as a second-line treatment of KRAS-mutant CRC patients, initial
results are expected in 2012. Furthermore, in the Phase II SHELTER study
resminostat is being evaluated as monotherapy and in combination with
sorafenib as a second-line treatment in advanced HCC after radiologically
proven disease progression under first-line sorafenib therapy. According to
the data presented at the ASCO-GI annual meeting in January 2012, the
primary study endpoint has been achieved ahead of schedule in both therapy
arms showing a progression-free survival rate (PFSR) after 12 weeks of
66.6% for the combination therapy group and of 33.3% for the monotherapy
group.
4SC is currently in discussions with regulatory agencies and potential
partners in order to prepare a pivotal clinical study programme for
resminostat in combination with sorafenib as a second-line treatment for
patients with advanced HCC who show tumour progression on first-line
treatment with sorafenib.
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 various autoimmune and cancer 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 balanced 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
leading pharmaceutical companies. Founded in 1997, 4SC had 90 employees at
31 March 2012. 4SC AG has been listed on the Prime Standard of the
Frankfurt Stock Exchange since December 2005.
Legal Note
This document may contain projections or estimates relating to plans and
objectives relating to our future operations, products, or services; future
financial results; or assumptions underlying or relating to any such
statements; each of which constitutes a forward-looking statement subject
to risks and uncertainties, many of which are beyond our control. Actual
results could differ materially, depending on a number of factors.
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 (0) 89 70 07 63 66
MC Services
Raimund Gabriel
raimund.gabriel(at)mc-services.eu, Tel.: +49 (0) 89 21 02 28 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@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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172111 31.05.2012
DGAP-News: Press Release: 4SC's anti-cancer drug resminostat achieves progression-free survival of 4.7 months in Phase II trial in advanced liver cancer (HCC)
| Source: EQS Group AG