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4SC's Anti-Cancer Drug Resminostat Achieves PFS of 4.7 Months in Phase II trial in HCC

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4SC AG has 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®).

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 stabilization 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 sensitization 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 sensitization.'

Increasing clinical relevance of epigenetically induced tumour cell sensitization
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 'sensitization' 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.

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).