4SC AG: Domatinostat’s mode of action in Merkel cell carcinoma

• Domatinostat (4SC-202) counteracts the immune escape of Merkel cell carcinoma cells in multiple ways
• Poster presentation at the AACR Annual Meeting, 29 March – 3 April 2019, Atlanta, USA

Planegg-Martinsried, Germany, 8 April 2019 – 4SC AG (4SC, FSE Prime Standard: VSC) today announced preclinical data at the American Association for Cancer Research (AACR) Annual Meeting 2019 that confirm domatinostat’s mode of action in Merkel cell carcinoma (MCC). The data were presented by Prof. Dr. Dr. Jürgen C. Becker, Department of Translational Skin Cancer Research at the University Hospital Essen, Germany, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. The AACR Meeting took place at the Georgia World Congress Center in Atlanta, USA, from 29 March to 3 April 2019.

Merkel cell carcinoma – tumor cells hide from the immune system

MCC is a rare, highly aggressive skin cancer often caused by either infection with Merkel cell polyomavirus or extensive UV exposure. Patients suffer from rapidly enlarging nodules that are between 0.5 and 5 cm in diameter, while the tumor aggressively spreads through the blood vessels to lymph nodes and many organs.

Although immune checkpoint inhibitors have shown compelling clinical activity in MCC, in some patients the tumor cells are very adept at evading the immune system. The tumor cells and its microenvironment prevent immune cells from entering the tumor and limit the presentation of tumor-signals on their surface. For these patients, refractory to or relapsing on checkpoint inhibitor therapy, currently no further treatment options are available.

Prof. Dr. Dr. Jürgen C. Becker explained: “In previous experiments we demonstrated that the immune escape mechanisms of MCC cells were epigenetically reversible¹. Therefore, we were highly interested in testing the effect of 4SC’s domatinostat, an orally available, epigenetically active small molecule inhibitor targeting histone deacetylases class I, on MCC cell lines.

“Our new data demonstrate that domatinostat increased the presentation of tumor signals on the cells’ surface, stopped MCC cells from dividing and even induced cell death. All these effects were specific for MCC cell lines and did not occur in healthy control cells.”

Frank Hermann, M.D., Chief Development Officer of 4SC, said: “We thank our collaborators for the dedication and energy devoted to their research with domatinostat. The fact that domatinostat counteracts the immune escape of MCC at different levels suggests that the combination of domatinostat with checkpoint inhibitors is potentially a promising therapeutic strategy in MCC and we plan to initiate a potentially pivotal clinical trial later this year.”

Abstract ID 2368: Domatinostat increases apoptosis, G2M cell-cycle arrest and immunogenicity of Merkel cell carcinoma

The poster is available on 4SC’s website.

Reference:

¹ Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma. C. Ritter, K. Fan, A. Paschen, S. Reker Hardrup, S. Ferrone, P. Nghiem, S. Ugurel, D. Schrama, and J. C. Becker. Sci Rep. 2017 May 23;7(1):2290. doi: 10.1038/s41598-017-02608-0

About 4SC

4SC AG is a clinical-stage biopharmaceutical company developing small-molecule drugs that can target key indications in cancer with high unmet medical needs. 4SC’s pipeline is protected by a comprehensive portfolio of patents and currently comprises three key drug candidates in various stages of preclinical and clinical development: resminostat, domatinostat (4SC-202) and 4SC-208.

4SC aims to generate future growth and enhance its enterprise value by entering into partnerships with pharmaceutical and biotech companies and/or the eventual marketing and sales of approved drugs in select territories by 4SC itself.

4SC is headquartered in Planegg-Martinsried near Munich, Germany. The Company had 47 employees as of 31 December 2018 and is listed on the Prime Standard of the Frankfurt Stock Exchange (FSE Prime Standard: VSC; ISIN: DE000A14KL72).

About domatinostat (4SC-202)

Domatinostat is an orally administered small molecule Class I selective HDAC inhibitor with a unique mode of action that was designed to strengthen the body’s own anti-tumor immune response. Domatinostat also influences the tumor microenvironment facilitating infiltration of immune cells into the tumor and making it more visible to the immune system.

Domatinostat has been investigated in a Phase I study with 24 heavily pretreated patients with several types of advanced hematologic cancers and was well tolerated. Positive signs of anti-tumor efficacy were also observed; with one complete remission (28 months) and one partial responder (8 months).

In addition to its therapeutic potential in cancer monotherapy, 4SC is evaluating domatinostat’s capacity as a partner in combination therapies, specifically in the immuno-oncology area. In this respect, 4SC initiated a Phase Ib/II study of domatinostat in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in patients with advanced-stage melanoma. A second Phase II study of domatinostat in combination with the anti-PD-L1 checkpoint inhibitor avelumab in patients with advanced-stage microsatellite-stable gastrointestinal cancer is conducted by Prof. David Cunningham of The Royal Marsden NHS Foundation Trust (London, UK).

As soon as results from the aforementioned trials will be available, 4SC plans to advance domatinostat into a potentially pivotal study in combination with a checkpoint inhibitor in PD-(L)1 refractory patients with advanced Merkel-cell carcinoma (MCC).

Forward-looking information

Information set forth in this press release contains forward-looking statements, which involve risks and uncertainties. The forward-looking statements contained herein represent the judgement of 4SC as of the date of this press release. Such forward-looking statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are beyond 4SC’s control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. 4SC expressly disclaims any obligation or undertaking to release any updates or revisions to any such statements to reflect any change in its expectations or any change in events, conditions or circumstances on which any such statement is based.