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4SC-205 is an anti-cancer compound that inhibits the kinesin spindle protein Eg5 (KIF11), which plays a key role in cell division and growth of tumor cells. Cell division inhibitors have been successful cancer therapies, however, they have serious side effects on the peripheral nervous system. Due to 4SC-205’s special mechanism of action, the compound does not cause such adverse side effects.
4SC-205 is the only orally administered Eg5 inhibitor currently in clinical development to the best of the Company’s knowledge. 4SC-205 is administered orally in low doses to maintain a steady bioavailability and exhibit continuous therapeutic effect. The anti-tumor efficacy of 4SC-205 was demonstrated in diverse pre-clinical models. In a Phase I clinical study (AEGIS) the drug demonstrated good safety and was well-tolerated; initial indications of efficacy were also determined.
4SC-205 is so far licensed for China, Hong Kong, Taiwan and Macao to Guangzhou Link Health Pharma Co., Ltd (Link Health).
AEGIS – First-in-human study of 4SC‑205 in solid tumors
The AEGIS study was a first-in-human, multi-center, open label, dose escalation Phase I first-in-human study of oral 4SC 205 in patients with advanced malignancies.
|Study phase||Phase I|
|30 May 2015
2015 Annual Meeting of the American Society of Clinical Oncology (ASCO)
|Overcoming the proliferation rate paradox: Clinical evaluation of a continuous dosing scheme of the novel oral Eg5 inhibitor 4SC-205|
|1 June 2014
2014 Annual Meeting of the American Society of Clinical Oncology (ASCO)
|First-in-human study of 4SC-205 (AEGIS), a novel oral inhibitor of Eg5 kinesin spindle protein|
Kv1.3 is a voltage-gated ion channel which has diverse functions in various cell types and cellular mechanisms but plays an essential role in the activation and proliferation of T-cells. 4SC’s family of Kv1.3 ion channel inhibitors are designed to act on chronically stimulated cell populations whilst sparing “normal” immune cells, thus addressing an underlying pathogenic principle in a multitude of autoimmune diseases.
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.
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 focused 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 conducted 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 was 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, was conducted testing the combination of domatinostat, nivolumab and ipilimumab in high risk stage III melanoma in the neoadjuvant setting.
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.