4SC Presents Final Results from Phase I AEGIS Trial at ASCO

4SC AG has published clinical data on safety, pharmacokinetics and efficacy for the 4SC-205 cancer compound at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The data has been obtained from the clinical Phase I AEGIS trial examining 4SC-205 in various dosing schemes in 59 patients with advanced solid tumours.

4SC-205 inhibits specifically the human kinesin spindle protein Eg5 (Kif 11), which has been shown to play a crucial role in mitosis (cell division) and, therefore, in tumour growth. To 4SC's knowledge, 4SC-205 is the only orally available Eg5 inhibitor in clinical development worldwide. The ASCO poster can be downloaded from the 4SC website at http://www.4sc.de/product-pipeline/publikationen-poster/4SC-205.

Since the Eg5 target molecule is present in the cell only during mitosis, and since mitoses in humans - in contrast to preclinical models - are very rare events of limited duration (approx. 30 minutes per mitosis), it is necessary to ensure continuous exposure of 4SC-205. This means that potentially efficacious and tolerable levels of the compound must be permanently available in patients in order to become effective immediately as soon as mitosis occurs.

Conducted at two study centres in Germany, the first-in-man, open-label AEGIS dose escalation and dose-schedule finding study investigated the oral administration of 4SC-205 in patients with advanced solid tumours. Initially, the compound was tested in a conventional, intermittent dosing scheme (consisting of higher single doses and longer breaks between treatments).

Given its oral availability and its mechanism of action as a potential inhibitor of mitosis (cell division), 4SC-205 was subsequently examined in a daily (continuous) dosing scheme consisting of smaller single daily doses without breaks between treatments. The objective of the study was to evaluate safety, tolerability and pharmacokinetics, and to determine a recommended Phase II dose. The trial ended when treatment of the last patient was completed in the first quarter of 2015.

The data in detail: Good profiles of safety and tolerability, linear pharmacokinetic parameters, 20 mg daily dose of 4SC-205 recommended as Phase II dose
• A comprehensive safety and tolerability profile of 4SC-205 was established. Specifically, no peripheral neuropathies were observed. This side effect is typically observed in connection with conventional chemotherapeutic agents such as taxanes. This means that the approach of a targeted, anti-mitotic therapy, during which these side effects should not occur, was confirmed.
• The main side effects were neutropenia in the intermittent dosing scheme. At a daily dose of 20 mg the neutropenia development was well manageable.
• The oral compound demonstrated very good linear pharmacokinetic parameters, which is an ideal prerequisite for daily dosage.
• A pharmacodynamic biomarker is regulated in a dose-dependent manner, even at a low daily dose.
• The daily dose of 20 mg is recommended as the dose for further Phase II development of the compound. This dose was safe and well-tolerated by patients and furthermore demonstrated initial signs of clinical efficacy.
• An additional, positive result of the daily dose of 20 mg of 4SC-205 was the median time on treatment of 162 days, thus being four times longer than the time on treatment seen in the intermittent treatment regime (42 days). Moreover, 67% of patients in the 20 mg daily cohort showed disease stabilisation for more than 100 days.

Enno Spillner, CEO of 4SC AG, commented: "We are pleased with the successful completion of the AEGIS trial. 4SC-205 very specifically inhibits an interesting therapeutic target in anti-cancer treatment, the Eg5 protein, which plays an important role in cell mitosis and tumour growth. Since 4SC-205 is orally available, we were able to evaluate this compound as the first of its kind in a clinically promising continuous dosing scheme. In this process we identified a safe and potentially effective dose for possible future Phase II trials. We are currently reviewing scenarios of further clinical development and will intensify discussions with clinical experts and potential academic and industry partners."