4SC-202 is an orally administered small molecule for the treatment of cancer. The compound inhibits the enzymes histone deacetylase (HDAC) 1, 2, and 3, 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.
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 addition to its therapeutic potential in cancer monotherapy, 4SC is evaluating 4SC-202’s capacity as a partner in combination therapies, specifically in the immuno-oncology area. Toward this end, 4SC initiated the Phase Ib/II study SENSITIZE of 4SC-202 in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in patients with advanced-stage melanoma. A second Phase II study of 4SC-202 in combination with the anti-PD-L1 checkpoint inhibitor avelumab, which will be conducted by an academic partner in gastrointestinal cancers, is expected to start soon.
As soon as results from the aforementioned trials will be available, 4SC plans to advance 4SC-202 into a pivotal study in combination with a checkpoint inhibitor in PD-(L)1 refractory patients with advanced Merkel cell carcinoma (MCC).
One of the most promising therapeutic concepts in oncology drug development is the modification of chromatin. 4SC-202 inhibits the enzymes histone deacetylase (HDAC) 1, 2, and 3.
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.