Public Release: 

Novel therapeutic candidate targets key driver of HCC in genomically defined subset of patients

Preclinical data demonstrate that BLU-554 is first potent and selective FGFR4 inhibitor

European Association for the Study of the Liver

April 24, 2015, Vienna, Austria: Findings were presented today at The International Liver CongressTM 2015 on a novel therapeutic candidate for a genomically defined subset of hepatocellular carcinoma (HCC) patients with an aberrant fibroblast growth factor receptor 4 (FGFR4) pathway. BLU-554, a small molecule inhibitor of FGFR4, has been identified as a potential treatment option for up to 30% of HCC patients. In preclinical studies, the investigational drug was shown to be potent and 'exquisitely selective' for FGFR4 compared to other kinases targeting the FGFR family.

Overexpression of fibroblast growth factor 19 (FGF19), the ligand for FGFR4, can promote liver tumour formation (as observed in genetically-engineered mice), a process that can be blocked by knocking out the FGFR4 gene. This suggests that FGFR4 inhibition might be an effective treatment strategy in HCC patients whose tumours have an active FGF19/FGFR4 signalling axis.

The study authors found that BLU-554 had significant anti-tumour activity in liver cancer models that are dependent on FGFR4 signalling pathway and was well tolerated at the highest dose level.

Klaus Hoeflich, PhD, Director of Biology at Blueprint Medicines, explains: "HCC is a disease with a high unmet need and no approved genomically targeted therapies. These findings support the investigation of BLU-554 in clinical studies of patients with hepatocellular carcinoma driven by aberrant FGFR4 signalling. By identifying patients most likely to respond to therapy based on the molecular profile of their cancer, we hope to make a meaningful difference for HCC patients."

With limited treatment options available to patients with HCC, these findings provide a new avenue of hope; Phase I clinical trials with BLU-554 are planned to start in mid-2015.

"Most people are diagnosed with hepatocellular carcinoma once the cancer is at an advanced stage and the outlook is poor. Median survival from time of diagnosis is about six months. Finding new disease drivers and treatment options for patients with hepatocellular carcinoma is critical to make strides against this devastating disease" said Dr Laurent Castera, Vice-Secretary, European Association for the Study of the Liver.

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About The International Liver Congress™

This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Specialists share research studies and findings, and discuss the hottest topics related to liver disease. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. 2015 is a very special year for EASL and the hepatology community as they will celebrate the 50th annual meeting. The International Liver Congress™ takes place from April 22-26, 2015, Vienna, Austria.

About EASL

Since EASL's foundation in 1966, this not-for-profit organisation has grown to over 4,000 members from more than 100 countries around the world. EASL is the leading liver association in Europe, it attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Contact

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FIRST SELECTIVE SMALL MOLECULE INHIBITOR OF FGFR4 FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMAS WITH AN ACTIVATED FGFR4 SIGNALING PATHWAY Klaus Hoeflich* 1, Margit Hagel1, Chandra Miduturu1, Michael Sheets1, Nooreen Rubin1, Weifan Weng1, Nicolas Stransky1, Neil Bifulco1, Joseph Kim1, Brian Hodous1, Natasja Brooijmans1, Adam Shutes1, Christopher Winter2, Christoph Lengauer1, Nancy Kohl1, Timothy Guzi1 1Blueprint Medicines, 2Sanofi, Cambridge, United States

Introduction: Limited treatment options are available to patients with hepatocellular carcinoma (HCC) and the multi-kinase inhibitor sorafenib remains the only approved drug for this devastating disease. However, molecularly-stratified treatment schemes are beginning to be developed for HCC.

Material and Methods: Fibroblast growth factor 19 (FGF19), the ligand for fibroblast growth factor receptor 4 (FGFR4), is not expressed in normal liver, but is made in the ileum and delivered to the liver via portal circulation. However, a subset of human HCCs (6-12%) harbor amplification of FGF19 and up to one-fourth of tumors overexpress FGF19 . In the presence of FGFR4 and its co-receptor klotho β (KLB), FGF19 overexpression can promote liver tumor formation in mice, a process which can be blocked by inhibiting FGFR4 signaling. This suggests that FGFR4 inhibition might be an effective treatment strategy in HCC patients whose tumors have an active FGF19/FGFR4 signaling axis.

Results: Here, we report the discovery of BLU-554, a potent and irreversible small molecule inhibitor of FGFR4. BLU-554 is exquisitely selective for FGFR4 versus other kinases, including FGFR family members. HCC cell lines with an activated FGFR4 signaling pathway were sensitive to FGFR4 inhibition and BLU-554 treatment decreased proliferation and induced apoptosis. BLU-554 also showed remarkable antitumor activity towards HCC tumor xenografts expressing FGFR4/KLB and harboring amplified FGF19. Furthermore, similar antitumor activity was observed in liver tumor xenografts which express detectable levels of FGF19 mRNA and whose FGFR4 pathway remains intact, but lack FGF19 amplification.

Conclusions: Taken together, these findings demonstrate a novel therapeutic strategy that targets a defined subset of HCC patients with a selective FGFR4 inhibitor and clinical trials to test this hypothesis are underway.

Disclosure of Interest: K. Hoeflich: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, M. Hagel: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, C. Miduturu: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, M. Sheets: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, N. Rubin: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, W. Weng: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, N. Stransky: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, N. Bifulco: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, J. Kim: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, B. Hodous: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, N. Brooijmans: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, A. Shutes: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, C. Winter: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, C. Lengauer: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, N. Kohl: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicines, T. Guzi: Stockholder: Conflict with: Blueprint Medicines, Employee: Conflict with: Blueprint Medicine

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