4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for autoimmune diseases and cancer, today announced an update on substantial progress in the clinical development of its lead oncology drug resminostat.
Results from the completed Phase I part of the SHORE study in advanced CRC
Positive Phase I results on safety, tolerability and pharmacokinetics from its SHORE study with resminostat in combination with FOLFIRI chemotherapy in patients with advanced colorectal cancer (CRC) will be presented at the upcoming 2013 meeting of the American Society of Clinical Oncology (ASCO) in Chicago on 2 June 2013. The SHORE study has been designed to investigate the combination of resminostat and FOLFIRI as a new second-line treatment option for patients with advanced, KRAS-mutant CRC.
Resminostat proved to be safe and well-tolerated in all doses tested, applying its standard 5+9 dosing regimen up to a daily dosage of 600 mg (once daily (OD)) or 800 mg (400 mg twice daily (BID)) in combination with the recommended standard dosage of FOLFIRI, a multi-component chemotherapy regimen that includes e.g. 5-fluorouracil (5-FU) and irinotecan. This again confirmed the clean safety profile of resminostat when applied in combination with established cancer therapies. Observed side effects were generally mild to moderate and occurred, as expected, primarily as gastrointestinal and hematological effects.
No dose-limiting toxicities (DLT) occurred and no formal maximum tolerated dose (MTD) of the combination regimen was determined up to the highest dose level of 800 mg (400 mg BID) resminostat. The known side-effect profile of the FOLFIRI regimen did not change as a result of the additional administration of resminostat. The study further confirmed the favorable pharmacokinetic profile of resminostat already observed in other studies, reflected for instance in the dose proportionality of resminostat blood levels. No pharmacological interactions between resminostat and any of the FOLFIRI components were observed.
In addition, the treatment – already in the Phase I part of the study – showed encouraging signs of clinical activity. Patients frequently experienced disease stabilisation as clinical benefit and, accordingly, could be treated with the combination of resminostat and FOLFIRI for several months: 7 of 15 evaluable patients were treated for at least 12 weeks with a maximum of 33 weeks.
Enno Spillner, Chief Executive Officer of 4SC AG, comments: “We have successfully achieved the study objective of the Phase I part of our SHORE trial. The data have once again confirmed the clean safety profile of resminostat when applied in combination with established cancer therapies. In addition, the resminostat FOLFIRI combination therapy has shown encouraging signs of clinical benefit in colorectal cancer (CRC). After having shown convincing Phase II data in our main indication liver cancer (HCC) last year, these new Phase I results in CRC once again illustrate the great clinical potential of our key compound resminostat.”
As previously communicated, 4SC will primarily focus on the further development of resminostat toward market approval as a first-line drug for treatment of advanced liver cancer (HCC). 4SC is currently working on the clinical development plan for resminostat, used in combination with sorafenib as a first-line therapy of HCC, and will then discuss the further development steps with potential partners and regulatory authorities in the EU and the US.
Identification of ZFP64 gene expression as a biomarker indicative of survival in clinical trials with resminostat in both liver cancer (HCC) and Hodgkin lymphoma (HL)
4SC also reports promising biomarker data from two Phase II clinical trials with resminostat in advanced liver cancer (hepatocellular carcinoma, HCC) (SHELTER study) and advanced Hodgkin lymphoma (HL) (SAPHIRE study). These observations in both HCC and HL patients point to a role of the gene expression levels of a certain gene, called Zinc Finger Protein 64 (ZFP64), as a potential biomarker suitable to indicate the clinical outcome of cancer diseases when treated with resminostat.
A promising positive correlation between expression levels of ZFP64 in peripheral blood cells of HCC and HL patients at baseline, i.e. before the start of resminostat treatment, and the achieved clinical outcome, was observed. High baseline ZFP64 expression levels were linked to an increased clinical benefit, i.e. patients were more likely to achieve clinical stable disease (SD). More importantly, patients displaying higher ZFP64 baseline levels also experienced a significantly longer overall survival (OS) compared to patients with lower ZFP64 baseline levels.
These findings were observed in patient cohorts from Phase II studies with resminostat in two different advanced cancer indications, liver cancer (hepatocellular carcinoma, HCC) and Hodgkin´s Lymphoma (HL). This may suggest a common underlying biological cancer cell background in both tumors types, which might be more responsive to treatment with resminostat. A patent application has been filed in order to provide adequate IP protection for these findings. ZFP64 has been described in the scientific literature as a transcription factor and co-activator of Notch, a protein controlling one of the central signaling pathways involved in the regulation of cancer.
Data were derived from the analysis of changes in gene expression patterns in response to both resminostat monotherapy (SAPHIRE study in HL and SHELTER study in HCC) and in combination with sorafenib (Nexavar®) (SHELTER study in HCC). The initial goal of the biomarker analysis was to investigate whether changes in expression levels of these genes in peripheral blood cells may serve as further pharmacodynamic markers for the pharmacological activity of resminostat.
Dr Bernd Hentsch, Chief Development Officer of 4SC AG; comments: “4SC will now conduct further studies to confirm these positive findings. It is our goal to develop resminostat, ideally in conjunction with the use of biomarkers as a personalized cancer medicine, towards market approval. As a part of this strategy, 4SC will integrate these new findings about ZFP64 in a biomarker program for the further development of resminostat in first-line HCC. Therefore, going forward, 4SC will discuss the resulting options with potential partners and regulatory authorities.”