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4SC Reports Positive Topline Data from Clinical Phase I Trial with 4SC-205

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4SC AG has announced positive topline data from the clinical Phase I AEGIS trial with the anti-cancer compound 4SC-205 in cancer patients. 4SC-205 inhibits specifically the human kinesin spindle protein Eg5 which has been shown to play a crucial role in cell division and, therefore, in tumour growth. To 4SC's knowledge, 4SC-205 is the only orally available Eg5 inhibitor in clinical development worldwide.

Conducted at two trial centres in Germany, the open-label AEGIS dose-finding study for the first time investigated the innovative 4SC-205 compound in 59 patients with advanced solid tumours. This involved the testing of two separate dosing schemes. As previously reported, the first part of the study, treating 46 patients with 4SC-205 in a conventional dosing scheme (i.e. with single, larger doses and longer breaks between treatment days), had delivered promising initial results for pharmacokinetics, the tolerability profile and biomarkers.

The second part of the study has been completed now. In this study amendment, 4SC-205 was evaluated in 13 patients with advanced solid tumours using a "metronomic", or continuous, dosing scheme. In this regimen, patients received the compound, in smaller single doses, daily and continuously (= no breaks between treatment days). This regimen aims to achieve and maintain permanent therapeutically active levels of the drug in patients while keeping side effects tolerable at the same time.

The oral availability of 4SC-205 and its mechanism of action as a potential cell division inhibitor make this dosing scheme promising from a scientific and clinical perspective. To the knowledge of the company, 4SC-205 is the first Eg5 inhibitor that has been clinically evaluated in patients in this dosing scheme to date.

All primary objectives of the study amendment have been achieved. Alongside very good linear pharmacokinetic parameters, a comprehensive safety and tolerability profile was established for 4SC-205. The continuous daily dosage of 20 mg of the compound showed promising initial signs of efficacy and is recommended as the dosage regimen for potential Phase II development.

Currently one patient whose previously strongly pronounced and highly aggressive cancer has been stabilized for eight months now is still continuing study treatment. 4SC will now proceed to discuss the results with external clinical key opinion leaders and potential partners, so as to assess further development options for 4SC-205 - such as a clinical Phase II trial.

Detailed results of the study amendment: extensive safety profile established; dosage regimen proposed for Phase II development showing promising efficacy signals

In the metronomic dosing scheme investigated in the study amendment, the patients were continuously treated (i.e. without breaks between treatment days) in three separate dosage groups that received daily doses of 10 mg, 20 mg or 30 mg of 4SC-205 respectively. The main study objective was to identify the maximum tolerated dose (MTD) for the treatment and potential dose-limiting toxicities (DLTs). The main study phase to be completed by all patients according to the study protocol was six weeks, i.e. two continuous treatment cycles, each of 21 days. After completion of this main phase, the follow-up phase then allowed patients benefiting from the treatment - in the form of a stabilization of their previously progressive cancers - to continue the treatment.

In these patients, the MTD was established as a daily dose of continuous 20 mg. The DLT was determined at a continuous daily dose of 30 mg of 4SC-205. Primary side effects at DLT level were neutropenia (level 3-4). Moreover, 4SC-205 showed a very good pharmacokinetic profile with a dose proportional increase of exposure and an elimination half-life of about ten hours providing the basis for effective dosing schedules.

4SC recommends the daily dose of 20 mg in the metronomic treatment regimen as a well tolerable and potentially effective dose (Recommended Phase 2 Dose, RP2D) for a possible Phase II development of the compound. Compared with the other doses examined in this trial, the six patients in this 20 mg daily metronomic group exhibited markedly superior indications for treatment efficacy, both in terms of a higher stabilization rate and a longer time on study.

Accordingly, in a total of 50% of patients receiving this metronomic dose of 20 mg per day, the previously progressive cancer disease could be stabilized beyond the study's main phase into the follow-up phase. In comparison, the average stabilization rate of all patients was 30% in the metronomic dosing scheme and 20% in the conventional dosing scheme. The median time on study of the patients receiving the daily metronomic dose of 20 mg was 128 days. In comparison, the median time on study for all patients in the metronomic dosing scheme was 44 days and 40.5 days for all patients under the conventional dosing scheme.

Currently one patient, whose previously strongly pronounced and highly aggressive cancer disease (malignant melanoma with pulmonary metastases) has been stabilized for eight months under the continuous daily dose of 20 mg 4SC-205, is still continuing study treatment.

The company expects to publish the final study data, including findings from the biomarker analysis at a scientific conference next year after completing the study report.

Enno Spillner, CEO of 4SC AG, commented: "Following the promising initial results from the AEGIS study, we are pleased to have achieved all of our primary goals in the evaluation of this innovative metronomic dosing scheme as well. In particular, our evaluation of this scheme has identified a safe, tolerable and potentially efficacious dose for use in possible clinical Phase II development of the compound. 4SC-205 inhibits with high specificity an interesting therapeutic target in anti-cancer treatment, the Eg5 protein, which plays an important role in cell mitosis and tumour growth. As 4SC-205 is orally available, we were able to evaluate the drug in a continuous dosing scheme. This approach offers some appealing options for clinical development - such as in combination therapy with proteasome inhibitors. We will proceed to review these scenarios and pursue initial discussions with external clinical experts and potential partners."