4SC (Frankfurt, Prime Standard: VSC), a drug discovery and development company, today announced that the first patient has been treated in the Phase I TOPAS study with 4SC-202, a selective histone deacetylase (HDAC) inhibitor which is also characterized by an anti-mitotic mechanism of action. The study will evaluate the safety, pharmacokinetics and clinical efficacy of orally administered 4SC-202 in patients with advanced hematological indications, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS) and lymphomas. This is the second HDAC-inhibitor in 4SC's oncology portfolio, in addition to resminostat, a pan-HDAC inhibitor.

TOPAS is a mono-centric, single arm, open-label dose escalation Phase I study designed to evaluate daily doses between 25 and 400mg of 4SC-202 in six dose cohorts. Patients will be given 4SC-202 tablets once daily for 14 consecutive days (d1-14) in a 21-day treatment cycle (14+7 scheme). The main study phase will consist of two treatment cycles and patients benefiting from treatment at the end of the main study phase may remain on therapy in a subsequent follow-up phase. Stepwise escalation of the initial starting dose (25mg) will occur according to a standard 3+3 design. Each dose cohort will include up to 6 patients and the study is currently planned to enroll up to 36 patients in total. Depending on the observed pharmacokinetic profile and the tolerability of once daily doses of 4SC-202, alternative dosing schedules such as twice daily administration will also be evaluated.

The primary objective of the TOPAS study is to investigate the safety, tolerability and pharmacokinetics of 4SC-202 and the associated determination of optimal doses and dosing regimens for patients with advanced hematological malignancies. Secondary objectives include the assessment of the clinical anti-tumour activity with respect to tumour response, duration of response (DOR) and progression-free survival (PFS) of the patients. Additional exploratory objectives include the evaluation of relevant biomarkers such as histone deacetylase (HDAC) enzymatic inhibition and induction of increased histone acetylation by 4SC-202 in peripheral mononuclear cells (PBMC) of patients as well as the analysis of altered gene expression profiles in patient blood. The study will be performed in one centre in Germany and is expected to report results in 2012.

Inhibition of histone deacetylases (HDAC) is believed to offer a promising therapeutic option in oncology drug development. Selected hematological malignancies which were described to be particularly sensitive to HDAC inhibition, are currently targeted by two marketed compounds of this class which have been approved for cutaneous T-cell lymphoma (CTCL). In contrast to 4SC's pan-HDAC inhibitor resminostat, 4SC-202 represents a selective inhibitor of class I HDAC enzymes and has shown potent anti-tumour activity in a variety of in vitro and in vivo preclinical models associated with good pharmacokinetic characteristics and good overall tolerability. The compound has also demonstrated a particularly effective anti-mitotic effect, which inhibits the process of cell division and introduces tumour cell death (apoptosis).

'With the commencement of the TOPAS study we have now advanced the second HDAC inhibitor to the clinical development stage and extended our oncology pipeline to a total of four compounds. Due to its selective inhibition profile on class I HDACs, as well as its pronounced pharmacological effect on the cell cycle, we anticipate to see a significant clinical efficacy of 4SC-202 in patients with advanced hematological malignancies combined with an acceptable side effect profile,' commented Dr. Bernd Hentsch, Chief Development Officer at 4SC.

About 4SC-202

4SC-202 is a benzamide type selective inhibitor of human class I HDAC isoenzymes 1, 2 and 3. HDAC inhibitors modify the DNA structure of tumour cells to cause their differentiation and programmed cell death (apoptosis) and are therefore considered to offer a mechanism of action that has the particular potential to halt tumour progression and induce tumour regression.

4SC-202 was extensively studied in preclinical development where it has shown anti-proliferative activity against a broad spectrum of human tumour cell lines in vitro as well as in various in vivo tumour models representing different cancer indications. 4SC-202 additionally provides a potent anti-mitotic activity by arresting the cell cycle and disrupting the mitotic spindle apparatus, which are both essential for the orderly division and proliferation of cells, thereby introducing apoptotic cell death. This specific pharmacological mode of action might be responsible for the enhanced anti-proliferative effect of 4SC-202 observed in preclinical studies which may translate into significant additional anti-tumour activity in the clinic.

Source:
4SC AG