Nov 24 2014
Merrimack Pharmaceuticals, Inc. today announced data from multiple presentations at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics. Data presented includes the first public presentation on the preclinical activity and potency of MM-131, and preclinical and clinical data on MM-151.
An additional abstract details Phase 1 results from a clinical pilot study evaluating the feasibility of using ferumoxytol*, an iron oxide nanoparticle, as a proxy to determine tumor responses to MM-398, nanoliposomal irinotecan.
"We are thrilled to present our clinical and preclinical data across three of Merrimack's programs, which includes the first public presentation of MM-131, the newest asset in our clinical pipeline," said Ulrik Nielsen, Ph.D., Chief Scientific Officer and Co-Founder of Merrimack. "MM-131 was designed, using a systems biology computational approach, as a novel bispecific antibody to potently inhibit the c-Met pathway, an important driver of tumor growth and survival. Our preclinical studies of MM-131 have supported our computational efforts and shown the molecule's activity across a broad range of c-Met driven tumor types."
Methodology and Results
MM-131: A bispecific antibody that inhibits c-Met signaling through avid binding to the EpCAM tumor antigen (Abstract #438)
To access the MM-131 poster presented at the EORTC-NCI-AACR Symposium, click here.
MM-131 is a bispecific antibody designed to block hepatocyte growth factor receptor, HGF-R (c-Met), signaling. The c-Met signaling pathway is involved in cancer cell growth, survival, and metastatic spread of disease. MM-131 concurrently binds to c-Met and epithelial cell adhesion molecule (EpCAM), a highly expressed protein on the cell surface in certain cancer types. MM-131 is designed to selectively bind to and inhibit the c-Met receptor without activating the c-Met signaling pathway.
- Computational modeling predicted that MM-131 would block HGF from binding to c-Met with higher potency through concurrent binding to epithelial cell adhesion molecule (EpCAM), an abundant protein on the cell surface of many cancer types. The models also suggested that the potency of MM-131 would increase with higher levels of EpCAM, as binding to EpCAM enables MM-131 to concentrate at the cell surface and effectively compete with HGF binding to c-Met.
- Preclinical studies validated this prediction and MM-131 was shown to inhibit HGF-mediated pathway activation and both the growth and migration of tumor cells across a panel of cell lines in vitro. Additionally, MM-131 inhibits tumor growth in models of c-Met-driven cancer in vivo.
- MM-131 potently inhibits both HGF-dependent signaling (HGF binding to c-Met) and HGF-independent signaling (gene amplification, mutation, and overexpression of c-Met) with no associated agonistic activity.
- Quantitative assays measuring EpCAM, HGF, and c-Met in patient tumor samples showed that EpCAM is expressed at high levels in a wide range of c-Met-driven tumor types. EpCAM, c-Met, and HGF were found to be co-expressed in lung (16%, 15 out of 92 evaluable tumor samples), colorectal (35%, 32/91), and gastroesophageal (33%, 32/97) cancers, suggesting a broad opportunity for the clinical development of MM-131.
Lesion characterization with ferumoxytol MRI in patients with advanced solid tumors and correlation with treatment response to MM-398, nanoliposomal irinotecan (nal-IRI) (Abstract #261)
To access the MM-398 poster presented at the EORTC-NCI-AACR Symposium, click here.
- To evaluate the feasibility and safety of using ferumoxytol as a proxy to predict response to MM-398, 15 eligible patients with refractory solid tumors in multiple indications were enrolled. Eleven out of 13 patients who received nal-IRI were evaluated for response with 1 (7%) partial response, 5 (38%) stable disease and 5 (38%) progressive disease.
- The relationship between ferumoxytol levels in tumor lesions and nal-IRI activity suggests that lesion permeability to ferumoxytol may be a useful biomarker for tumor response to nal-IRI in patients with solid tumors.
- Data from this study also suggest strong local conversion activity of nal-IRI in the tumor and concurred with pharmacokinetic modeling expectations.
- Overall, ferumoxytol was well tolerated. Adverse events of MM-398 therapy were consistent with previous studies, and no adverse events were directly attributable to ferumoxytol.
A first-in-human study evaluating the safety and pharmacology of MM-151, a novel oligoclonal anti-EGFR antibody combination, in patients with refractory solid tumors (Abstract #329)
To access the MM-151 clinical poster presented at the EORTC-NCI-AACR Symposium, click here.
MM-151 is a novel oligoclonal anti-EGFR antibody combination designed to target EGFR-driven tumor growth. These preliminary results are from updated data as of November 4, 2014, from a Phase 1 study in patients with refractory solid tumors show that MM-151 alone and MM-151 in combination with irinotecan. Preliminary data has shown an acceptable safety profile and clinical activity in colorectal cancer, head and neck cancer and non-small cell lung cancer.
- Monotherapy safety is consistent with known EGFR toxicities and combination safety is consistent with known EGFR and irinotecan toxicities.
- Prolonged stable disease and radiographic responses (3 monotherapy and 3 combination therapy partial responses) were observed in heavily pre-treated solid tumor patients, including those with prior cetuximab therapy. Initial biomarker data suggests clinical benefit in EGFR-ligand positive CRC patients.
Preclinical characterization of MM-151, an oligoclonal antibody therapeutic that targets EGFR by three distinct mechanisms of action (Abstract #152)
To access the MM-151 preclinical poster presented at EORTC-NCI-AACR Symposium, click here.
- In vitro studies demonstrate that MM-151 has enhanced activity relative to cetuximab for three mechanisms of action: ligand antagonism, receptor down-regulation, and activation of immune effector function.
- In vivo studies also show that MM-151 inhibits tumor growth and overcomes acquired resistance to cetuximab.
Source: http://www.merrimackpharma.com/