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Summary

Domatinostat 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 domatinostat is able to modulate the tumor microenvironment to make it more susceptible to anti-tumor inflammatory processes and as such domatinostat is potentially an excellent candidate for combination with checkpoint inhibitors that enhance the body’s immune response.

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Clinical development profile

Domatinostat is an orally administered small molecule class I selective HDAC inhibitor. It strengthens the body’s own anti-tumor immune response.  Domatinostat modulates the tumor and tumor microenvironment making it more visible to the immune system, susceptible to concomitant checkpoint inhibition, and facilitating the infiltration of immune cells into the tumor (Bretz et al., 2019).

Domatinostat has been investigated in a Phase I study in 24 heavily pretreated patients with several types of advanced hematologic cancers and was well tolerated (Tresckow et al., 2019). Signs of single-agent anti-tumor efficacy were observed; with one complete remission and one partial responder.

Besides its therapeutic potential as monotherapy, 4SC is focusing its development activities for domatinostat on 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 from which initial data was presented at ESMO 2019 (Hassel et al., abstract #5545).

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 currently being conducted by Prof. David Cunningham at The Royal Marsden NHS Foundation Trust in London, UK.

In addition, in a collaboration with the Netherlands Cancer Institute in Amsterdam, the DONIMI Study, a multicenter, investigator-sponsored phase Ib study, is conducted testing the combination of domatinostat, nivolumab and ipilimumab in high risk stage III melanoma in the neoadjuvant setting.

To advance this development program, 4SC has also signed a drug supply agreement with Merck KGaA for avelumab (anti-PD-L1 antibody) to conduct two Phase II clinical trials of domatinostat in combination with avelumab in advanced-stage Merkel cell carcinoma (MCC) patients progressing on previous anti-PD-(L)1 monotherapy (MERKLIN 2) and in metastatic treatment-naïve patients (MERKLIN 1).

Clinical Trials

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Scientific background

One of the most promising therapeutic concepts in oncology drug development is the modification of chromatin. Domatinostat inhibits the enzymes histone deacetylase (HDAC) 1, 2, and 3.

Preclinical experiments have demonstrated that domatinostat 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, domatinostat 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 domatinostat with checkpoint inhibitors had additive effects on tumor growth inhibition presumably due to a domatinostat-mediated shift in the tumor microenvironment resulting in anti-tumor immunity.

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

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