4SC-202 is an orally administered small molecule for the treatment of cancer. The compound has a unique mechanism of action – inhibiting the enzymes histone deacetylase (HDAC) 1, 2, 3, and lysine-specific demethylase 1 (LSD1), which are believed to play important roles in the regulation of aberrant cancer signaling.

Preclinical studies have shown that 4SC-202 is able to modulate the tumor microenvironment to make it more susceptible to anti-tumor inflammatory processes and as such 4SC-202 is potentially an excellent candidate for combination with checkpoint inhibitors that enhance the body’s immune response.

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Clinical development profile

4SC-202 has been evaluated in a Phase I clinical trial (TOPAS) in 24 heavily pre-treated patients with different types of blood cancer. 4SC-202 was well tolerated with few and/or manageable adverse events. Positive signs of anti-tumor efficacy were observed with one complete remission for 28 months and one partial responder for 8 months. Findings also exhibited disease control in 83% of the patients and long-term stabilization in 50% of patients.

In preclinical experiments, 4SC-202 exhibited an enhanced immune response to cancer. Treatment with 4SC-202 showed alteration of the tumor microenvironment and increased infiltration of immune cells into the tumor. In mouse models the combination of 4SC-202 with checkpoint inhibitors resulted in increased anti-tumor activity, suggesting a promising clinical development path for 4SC-202 in patients that are either refractory or non-responding to PD-1 or PD-L1 checkpoint inhibitors.

Clinical Trials

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Scientific background

One of the most promising therapeutic concepts in oncology drug development is the modification of chromatin. 4SC-202 is the first known dual modulator of both HDAC1, 2, 3 and LSD1.

Preclinical experiments have demonstrated that 4SC-202 has the ability to modulate the tumor microenvironment resulting in immunologically advantageous cellular differentiation patterns – for example, by increasing favorable populations of immune cells in the tumor. Specifically, 4SC-202 can drive anti-tumor immunity by increasing the expression of tumor-associated antigens (TAAs) and immunomodulatory molecules in cancer cell lines. And in animal models, the infiltration of CD8 positive cytotoxic T cells into the tumor was enhanced and the presence of myeloid-derived suppressor cells (MDSCs) was reduced. Importantly, the combination of 4SC-202 with checkpoint inhibitors had additive effects on tumor growth inhibition presumably due to a 4SC-202-mediated shift in the tumor microenvironment resulting in anti-tumor immunity.

The immune modulating effects of 4SC-202 have been shown to contribute to the anti-tumor activity of checkpoint inhibitors and as such, 4SC-202 has unique characteristics as a therapeutic partner in malignancies where the anti-tumoral T-cell response plays a role.

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