Biomarker with promise
CAMBRIDGE, Mass.—Merrimack Pharmaceuticals Inc. recently reported that expression of heregulin (HRG), the principal ligand that binds to and activates the ErbB3 receptor, is associated with poor response to standard-of-care therapy for patients with platinum-resistant ovarian cancer, ER/PR+ HER2- breast cancer and EGFR wild-type non-small cell lung cancer. Heregulin-driven drug resistance pathways were found to be active in approximately 30 to 50 percent of patients tested.
MM-121, Merrimack’s novel antibody developed using the company’s systems biology approach, was specifically shown to restore sensitivity to conventional cancer therapies in HRG-positive tumor populations, providing additional options for patients failing on current treatments. Using proprietary assays, Merrimack found that patients with solid tumors most at risk for disease progression may benefit from MM-121.
MM-121 is a fully human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin-driven ErbB3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and antiendocrine therapies. When used in the combination setting, MM-121 is designed to block ErbB3 signaling in order to restore or enhance the antitumor effect of a combination therapy partner.
“These are landmark studies, because they show the value of systems biology, determine a significant molecule that shows resistance to standard-of-care therapies for all solid tumors and point to a way to get patients to respond to the therapy,” says Dr. Gavin MacBeath, co-founder and senior vice president at Merrimack.
Merrimack partnered with Sanofi in 2009 to develop a broad Phase 2 program to demonstrate that HRG was driving resistance to therapy for breast, lung and ovarian cancers. When HRG was expressed, patients across the board did not respond well to therapy and had rapid progression of their disease.
Results from three Phase 2 studies were finished at about the same time. They showed that patients with heregulin-positive tumors experienced a statistically significant reduction in their risk of progression when they received a combination of MM-121 with their standard-of-care therapy as compared to patients who received the standard-of-care therapy alone. It works because the MM-121 is specifically designed to block heregulin binding to ErbB3, according to MacBeath.
Top-line data from these trials had previously been released. Detailed biomarker data for all three studies were presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 30 to June 3 at McCormick Place in Chicago.
“The consistency of these findings across three different cancer indications and the benefit achieved with MM-121 in these studies is evidence of the importance of ErbB3 signaling in cancer,” asserts MacBeath. “It also strengthens our confidence in systems biology and its applicability to drug discovery and development.”
MacBeath adds, “With these findings, we are now preparing our diagnostic assays for use in future clinical studies for MM-121 as well as for use in the clinical development of our other ErbB3-targeted therapies. These data lay the foundation for the development of ErbB3 inhibitors in oncology.”
The three Phase 2 studies that were presented at ASCO enrolled a total of 473 patients and evaluated whether MM-121 in combination with a standard-of-care therapy was more effective than the standard-of-care therapy alone in prolonging progression-free survival. As ErbB3 signaling was expected to be active in only a subset of patients, pretreatment biopsies were collected from patients in the lung and ovarian studies and archived tumor tissue in all three studies to assess heregulin, along with four other pre-specified biomarkers. Secondary analyses included evaluation of the pre-specified biomarkers, as well as overall survival and safety data.
Systems biology was useful in understanding the signaling pathway at a quantitative level to develop a computer model to design the drug in the first place to block HRG signaling, to determine what the biomarkers would be and to identify the most likely biomarkers, according to MacBeath. All three of the indications were potentially promising, with breast cancer having the most striking result in the near term, he says.
Merrimack currently has six oncology therapeutics in clinical development and three additional candidates in late-stage preclinical development.