4SC AG has announced clinical data of the Phase I 'AEGIS' trial with the anti-cancer compound 4SC-205 in tumour patients. All primary study objectives were achieved. A comprehensive safety and tolerability profile of 4SC-205 was established.
As well as ascertaining the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), an excellent pharmacokinetic profile of the oral compound was established. In addition, the analysis of pharmacodynamic biomarkers demonstrated the intended mode of action.
The study data and new preclinical findings about the therapeutic target warrant further clinical evaluation of 4SC-205 in cancer patients. The Company, therefore, has decided on a study amendment, which will evaluate a new, adapted dosing scheme.
The first patient has now been treated according to the new scheme. 4SC-205 inhibits specifically the human kinesin spindle protein Eg5 which has been shown to play a crucial role in cell division (mitosis) and, therefore, in tumour growth.
To the Company's best knowledge, 4SC-205 is the only orally available Eg5 inhibitor in clinical development, worldwide.
Study design and positive results
The 'first-in-man', two-centre, dose-escalating Phase I study ('AEGIS' study) investigated safety, tolerability, pharmacokinetics, and pharmacodynamics of 4SC-205 in 46 patients with advanced solid tumours.
In two treatment cycles, each over three weeks, patients were treated with ascending oral doses of 4SC-205 in order to establish the MTD and potential DLTs.
Patients were treated in two different dose schedules: in the first dose schedule, patients received once-weekly dosing on days 1 and 8 of each cycle; in a second dose schedule patients received twice-weekly dosing on days 1, 4, 8 and 11 of each cycle.
In patients receiving once-weekly dosing, the MTD was established at the 150 mg dose level; in patients receiving a twice-weekly dosing, an MTD of 75 mg was established.
DLTs were reached at the treatment doses of 200 mg with once-weekly dosing and of 100 mg with twice-weekly dosing. Main side effects at DLT level were neutropenia and stomatitis of grade 3-4.
Moreover, 4SC-205 showed an excellent pharmacokinetic profile with a dose proportional increase of exposure and an elimination half-life of about 10 hours providing the basis for effective dosing schedules since the biological activity of the compound could be demonstrated via biomarker analysis of patients' skin biopsy samples.
Here, a dose dependent accumulation of cells arrested in cell division could be observed. Thus, 4SC-205 effectively exhibits the anticipated mode of action - inhibition of cell division (mitosis) - at clinically tolerated doses.
AEGIS study amendment
The clinical findings generated to date from this trial as well as new preclinical data about the therapeutic target and distribution of 4SC-205 in tissue, strongly support further clinical investigation of the compound applying an additional treatment schedule. The study has, therefore, been amended in order to investigate a new and innovative dosing scheme of 4SC-205 for the first time in cancer patients.
According to the amendment, another 9 to 12 eligible patients are expected to be enrolled in the trial. Following recent approval of the amendment by authorities, the first patient has now been treated. The results of the amended AEGIS study protocol are expected for mid 2013.
Dr Ulrich Dauer, Chief Executive Officer of 4SC, commented: 'We are pleased that in our AEGIS trial we have achieved all primary endpoints so far. 4SC-205 inhibits with high specificity an intriguingly interesting therapeutic target in anti-cancer treatment, the Eg5 protein, which plays a central role in cell mitosis and tumour growth. The encouraging biomarker response to 4SC-205 as shown in the study and new preclinical findings regarding the therapeutic target, make a strong case to further study our drug candidate in a new, highly innovative dosing scheme. This is expected to form a basis for the further evaluation of the compound in Phase II development. The fact that 4SC-205 is the only oral Eg5 inhibitor in clinical development is a strategic strength that facilitates the possibility to further explore alternative and enhanced dosing schemes.'