Biomarker Studies Demonstrate On-Target Effects of Tarextumab Against Notch Pathway and Cancer Stem Cells in Patients With Pancreatic Cancer
Patient-Derived Preclinical and Clinical Data Support the Phase 2 Development of Demcizumab With Abraxane and Gemcitabine in Pancreatic Cancer
BARCELONA, Spain and REDWOOD CITY, Calif., Nov. 21, 2014 (GLOBE NEWSWIRE) -- OncoMed Pharmaceuticals, Inc. (Nasdaq:OMED), a clinical-stage company developing novel therapeutics that target cancer stem cells (CSCs), or tumor-initiating cells, presented data in two posters highlighting the company's translational research and biomarker efforts for its tarextumab (anti-Notch2/3, OMP-59R5) and demcizumab (anti-DLL4, OMP-21M18) clinical programs. These data were presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.
"The data from the Phase 1b clinical trials of tarextumab and demcizumab demonstrate that our preclinical understanding of on-target drug activity and predictive biomarkers is being validated in the clinic as we study actual patient tumor samples," said Jakob Dupont, M.D., OncoMed's Chief Medical Officer. "In the ALPINE Phase 1b study in advanced pancreatic cancer, we see clear evidence that tarextumab modulates the Notch cancer stem cell pathway in patient samples and that there is a potential association between tumors that show higher levels of Notch3 gene expression and best responses to tarextumab treatment. In the demcizumab poster presentation, a case study is described from our Phase 1b trial in pancreatic cancer in which the tumor response to treatment that occurred in the clinic correlates with what we observe using patient-derived xenograft models. This may provide insights into the development of potential biomarkers of response to demcizumab treatment in that program."
OncoMed researchers analyzed tissue samples including serial tumor biopsies from patients with metastatic pancreatic cancer in the Phase 1b ALPINE clinical trial of tarextumab in combination with gemcitabine plus Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound). Pharmacodynamic biomarkers showed that tarextumab at doses of 7.5mg/kg and above had marked inhibitory effects on genes associated with Notch signaling and stem cell cells in hair follicles and blood cells. Genes indicating stem cell differentiation were up-regulated at the same doses in these samples. In four paired serial tumor biopsies, Notch3 protein levels were significantly reduced by the combination of tarextumab-gemcitabine-Abraxane. Importantly, gene signatures reflective of Notch signaling, tumor metastasis, and cancer stem cells were all markedly down-regulated following treatment with tarextumab-gemcitabine-Abraxane relative to baseline tumors. These data are consistent with the proposed mechanism of action of tarextumab to inhibit Notch signaling and to reduce cancer stem cells in tumors. The dose of tarextumab in the ongoing Phase 2 portion of the ALPINE study is 15mg/kg every 2 weeks.
Using OncoMed's proprietary Notch3 gene expression assay for predictive biomarkers, OncoMed researchers observed an emerging trend suggesting that patients with higher levels of tumor-derived Notch3 gene expression at baseline exhibit improved response to tarextumab treatment. Notch3 gene expression was evaluable in pancreatic tumor samples from 80 percent of the patients enrolled in the Phase 1b trial. Notch3 gene expression is now being evaluated as a predictive biomarker for tarextumab in the Phase 2 portion of the ALPINE clinical trial.
These data were presented today by lead author Ann M. Kapoun, Ph.D., OncoMed's Vice President, Translational Medicine, in a poster titled: Biomarker analysis in Phase 1b study of anti-cancer stem cell antibody Tarextumab (TRXT) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) demonstrates pharmacodynamic (PD) modulation of the Notch pathway in patients (pts) with untreated metastatic pancreatic cancer (mPC) (abstract# 465).
In the demcizumab presentation, a patient tumor sample from the Phase 1b clinical trial of demcizumab combined with standard of care was evaluated using OncoMed's proprietary patient-derived xenograft models and the anti-tumor response was compared between the clinical and preclinical studies. The Phase 1b patient progressed rapidly on treatment with a combination of demcizumab and gemcitabine. When a tumor derived from the Phase 1b patient was grown in a xenograft model, the new tumor was also insensitive to gemcitabine and the combination of demcizumab plus gemcitabine. This tumor was significantly more sensitive to the triple combination using demcizumab-gemcitabine-Abraxane. These data suggest that OncoMed's patient-derived xenograft models can mirror activity in the clinic. Analysis of key characteristics of responsive tumors relative to non-responsive tumors may provide insights into potential biomarkers of sensitivity to demcizumab treatment.
Data from this study were presented during the Preclinical Models poster session on Wednesday, November 19, 2014 by Manuel Hidalgo, M.D., Ph.D., CNIO-CIOCC-START, a lead clinical investigator for the demcizumab Phase 1b study, in a poster titled: Preclinical and Clinical Activity of Anti-DLL4 (Demcizumab) in Combination with Gemcitabine Plus nab-Paclitaxel in Pancreatic Cancer (abstract #166).
"The biomarker programs associated with each of our clinical candidates directly informs and guides predictive biomarker efforts in randomized Phase 2 clinical trials and beyond," said Paul J. Hastings, OncoMed's Chairman and Chief Executive Officer. "This approach makes for smarter, more strategic drug development that we believe will translate into improved patient care and outcomes."
About OncoMed Pharmaceuticals
OncoMed Pharmaceuticals is a clinical-stage company focused on discovering and developing novel therapeutics targeting cancer stem cells (CSCs). OncoMed has five anti-cancer product candidates in clinical development, including demcizumab (anti-DLL4, OMP-21M18), tarextumab (anti-Notch2/3, OMP-59R5), anti-Notch1 (OMP-52M51), vantictumab (anti-FZD7, OMP-18R5), and ipafricept (FZD8-Fc, OMP-54F28), which target key cancer stem cell signaling pathways including Notch and Wnt. In addition, OncoMed has filed an Investigational New Drug (IND) application for its anti-DLL4/anti-VEGF bispecific antibody (OMP-305B83) and plans to file an IND application for anti-RSPO3 (OMP-131R10) in early 2015. OncoMed is also pursuing discovery of additional novel anti-CSC and cancer immunotherapy product candidates. OncoMed has formed strategic alliances with Celgene Corporation, Bayer Pharma AG and
GlaxoSmithKline (GSK). Additional information can be found at the company's website:
To the extent that statements contained in this press release are not descriptions of historical facts regarding OncoMed Pharmaceuticals, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including OncoMed's expectations regarding the potential for Notch3 gene expression to be useful as a predictive biomarker for tarextumab in pancreatic cancer; the validation of OncoMed's preclinical understanding of on-target drug activity and predictive biomarkers in the clinic; the ability of OncoMed's patient-derived xenograft models to mirror activity in the clinic; OncoMed's ability to gain insights into potential biomarkers of sensitivity to demcizumab treatment; the potential for OncoMed's biomarker and drug development strategies to translate into improved patient care and outcomes; and the timing of an Investigational New Drug application filing for OncoMed's anti-RSPO3 antibody. Such forward-looking statements involve substantial risks and uncertainties that could cause OncoMed's clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the preclinical and clinical development process; the risks and uncertainties of the regulatory approval process; OncoMed's dependence on its collaboration partners, including Celgene, GSK and Bayer, for the funding of its partnered programs; OncoMed's ability to raise additional capital to support the development of its unpartnered programs; OncoMed's dependence on the development and marketing efforts of its partners for the commercial success of its partnered product candidates; OncoMed's reliance on third parties to conduct certain preclinical studies and all of its clinical trials; OncoMed's reliance on single source third-party contract manufacturing organizations to manufacture and supply its product candidates; OncoMed's ability to validate, develop and obtain regulatory approval for companion diagnostics; OncoMed's ability to achieve market acceptance and commercial success of its product candidates once regulatory approval is achieved; OncoMed's ability to discover, develop and commercialize additional product candidates; the ability of competitors to discover, develop or commercialize competing products more quickly or more successfully; OncoMed's dependence on its Chairman and Chief Executive Officer, its Chief Scientific Officer, its Chief Medical Officer and other key executives; risk of third party claims alleging infringement of patents and proprietary rights or seeking to invalidate OncoMed's patents or proprietary rights; and the ability of OncoMed's proprietary rights to protect its technologies and product candidates. OncoMed undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to OncoMed's business in general, see OncoMed's Annual Report on Form 10-K for the fiscal year ended December 31, 2013, filed with the Securities and Exchange Commission (SEC) on March 18, 2014, OncoMed's Quarterly Report on Form 10-Q for the fiscal quarter ended March 31, 2014, filed with the SEC on May 8, 2014, OncoMed's Quarterly Report on Form 10-Q for the fiscal quarter ended June 30, 2014, filed with the SEC on August 7, 2014, and OncoMed's Quarterly Report on Form 10-Q for the fiscal quarter ended September 30, 2014, filed with the SEC on November 4, 2014.
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