Birgit Schoeberl, Ph.D. is an internationally recognized leader in the application of Systems Biology to biology and drug development. At Merrimack, she leads the Discovery division which focuses on development of therapeutic and diagnostic programs from early stage discovery through clinical proof of concept. Currently, she also serves on the Board of Directors and Scientific Advisory Board of Silver Creek Pharmaceuticals. She joined Merrimack Pharmaceuticals in 2003 after doing postdoctoral training at MIT where she built some of the earliest computational models of signaling networks. Dr. Schoeberl holds an M.S. in chemical engineering from the University of Karlsruhe, Germany, and a Ph.D. from the Max-Planck-Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.
“A Systems Biology Approach to Drug Development”
Using a Systems Biology approach we identified ErbB3 as the most critical activator of phosphoinositide 3-kinase (PI3K) signaling within the ErbB signaling network. Based on this insight Merrimack Pharmaceuticals designed a monoclonal antibody, MM-121, which blocks HRG (heregulin) and BTC (betacellulin) induced signaling.(Schoeberl et al., 2010)
In order to understand which patients would respond to MM-121, we identified a set of five preclinically defined biomarkers (EGFR, ErbB2, ErbB3, HRG and BTC) that allowed us to distinguish responding vs. non-responding cancer cell lines. Recently, MM-121 completed three Phase 2 clinical trials to determine if patients with advanced malignancies would derive benefit from the addition of MM-121 to their standard therapy. Here we will describe the result of translating the preclinical biomarkers into the clinical development of MM-121.
Among 464 patients (220 ovarian, 115 breast, 129 lung), RNA-ISH data were available from 224 patients (157 ovarian, 67 lung), qIHC from 252 (174 ovarian, 78 lung), and RT-PCR from 175 (105 ovarian, 57 breast, 13 lung). Of the five biomarkers, the most predictive of response was HRG mRNA: patients with detectable HRG in pre-treatment biopsies or high HRG in archived tissue blocksresponded poorly to SOC therapy and benefited most from MM-121. In addition, benefit was largely restricted to patients with low ErbB2 (<200,000 receptors per cell). Across the different trials we found that heregulin is a potential biomarker for poor response to standard of care therapy in HER2 low tumors and a potential predictor of clinical benefit from MM-121 in late-stage ovarian, lung, and breast cancers in accordance to our preclinical studies.