French pharmaceutical company Sanofi-aventis (Paris, France) and Merrimack Pharmaceuticals Inc., a privately-held biotechnology company based in Cambridge, Massachusetts focusing on the discovery and development of novel treatments for cancer and autoimmune diseases, have entered in an exclusive global collaboration and licensing agreement on MM-121, a first-in-class, fully human monoclonal antibody designed to block signaling of the ErbB3 (also known as HER3) receptor, for the management of solid malignancies. MM-121 is currently in Phase I clinical testing.[1,2]The ErbB3 receptor is a novel target known to be a key mediator of signaling in the ErbB pathway (also known as the EGFR or HER pathway) ? a signaling network that impacts a broad array of cancers. ErbB3 and its ligands are expressed and often upregulated in different solid tumors (breast [3] and ovarian cancer) and are associated with metastasis formation and decrease in survival. Importantly, ErbB3 is also involved in the mechanism of resistance to certain treatments such as gefinitib in lung cancer, cetuximab in colon and head & neck cancer, and trastuzumab in breast cancer.The ErbB receptor family has been known for years to have an impact on cancer signaling. In 2003, scientists at Merrimack gained insight into the critical role of the ErbB3 receptor in cancer biology through the use of their core technology, the Network Biology platform that led to novel design of MM-121. The Network Biology discovery platform, developed with the help of leading scientists from MIT and Harvard, enables the high-throughput profiling of protein networks as a basis for improved validation, lead identification and speed in the development of innovative, effective and well tolerated therapeutics.?Merrimack?s expertise along with their knowledge of biologics development has allowed them to successfully identify ErbB3 as a promising target and rapidly bring MM-121 into clinical development?, declared Marc Cluzel, Senior Vice-President R&D, Sanofi-aventis. ?MM-121 is a pioneering monoclonal antibody which brings a new innovative approach to sanofi-aventis? oncology portfolio. We are very excited to collaborate with Merrimack on the development of MM-121, which we believe is a very promising compound that will address a significant gap in treating cancer patients?.MM-121 is a monoclonal antibody designed to block signaling of the ErbB3 receptor, a member of the epidermal growth factor (EGF) receptor family (also known as ErbB family) which plays a crucial role in the development and evolution of cancer. MM-121 is the first selective ErbB3 antagonist to have entered human clinical development.Preclinical data has demonstrated that MM-121 causes dose-dependent inhibition of tumor growth on multiple cancer models (including lung, ovarian, breast, prostate and renal) as both a monotherapy and a combination therapy. Furthermore, pharmacodynamic analysis of samples from a number of studies showed that regular MM-121 administration resulted in inhibition of ErbB3 activity which correlated with efficacy.Using Merrimack Pharmaceutical?s Network Biology platform, potentially beneficial drug combinations of MM121 with other ErbB therapies have been identified. In particular, researchers simulated the effect of MM-121 in combination with erlotinib, cetuximab, lapatinib, and PI3K inhibitors. These simulations predicted optimal drug combinations for the inhibition of pErbB3 and pAKT in a wide range of cancer cell lines. Based on these simulations, a subset of cancer cell lines were treated with the drug combination in short term signaling assays and the pErbB3 and pAKT levels were measured.Posters demonstrating the potential of MM-121were presented at the annual meeting of the Annual Meeting of the American Association for Cancer Research (AACR) held April 18-22, 2009 in Denver, CO. [4, 5]As a result of preliminary results a Phase I trial is being conducted at 3 clinical centers in the United States. This study, expected to be completed by February 2010, is a pharmacologic open-labeled dose-escalation trial using a “3+3” design. Successive cohorts of three or more patients will be treated at escalating doses until a maximum tolerated dose is identified. The study will initially explore a dosing schedule every 7-days, which may be modified to longer intervals under certain circumstances. Once the maximum tolerated dose or recommended Phase II dose is identified, an Expansion Cohort will be enrolled at that dose to further characterize safety and to explore pharmacodynamic endpoints.MM-121 in NSCLCA new trial designed to determine the recommended Phase II dose of the MM-121 in combination with erlotinib based upon either the maximum tolerated dose (MTD) or the maximum feasible dose of the combination in patients with Non-Small Cell Lung Cancer (NSCLC) is expected to start soon?Commercial developmentUnder this agreement, Sanofi-aventis will receive an exclusive worldwide license to develop, manufacture and commercialize MM-121. Merrimack will retain potential co-promotion rights in the United States. Based on the agreement, Sanofi-aventis will pay Merrimack an upfront cash payment of $60M for the research, development, manufacturing and commercialization rights. Merrimack is eligible for development and regulatory milestone payments up to $410M on MM-121, royalties on the worldwide product sales and will receive additional performance milestones of up to $60M on worldwide sales. Merrimack will participate in the development of MM-121.The license agreement is subject to antitrust clearance under the Hart-Scott-Rodino Antitrust Improvements Act.For more about MM-121 in clinical trials[1] Phase I Safety Study of the Drug MM-121 in Patients With Advanced Solid Tumors Resisting Ordinary Treatment[2] A Study of MM-121 Combination Therapy in Patients With Advanced Non-Small Cell Lung CancerAlso read[3] Xue C, Liang F, Mahmood R, Vuolo M, Wyckoff J, et al. ErbB3-Dependent Motility and Intravasation in Breast Cancer Metastasis Cancer Res. 2006 66: 1418-1426.Posters presented during the 2009 AACR[4] Burenkova O, Fulgham A, Kalra A, Onsum M, Linggi B, et al. In-vivo effect of combination therapy: An anti-ErbB3 antibody, MM121, plus selected cancer therapies. Session: Antib
ody and Antibody Targets; Poster: 1243 (Date/Time: Sunday April 19, 1-5pm; Location: Hall B-F, poster section 12)[5] Onsum M, Linggi B, Karla A, Latimer H, Garcia G, et al. Computational modeling guided the identification of beneficial combinations of MM121 and other targeted therapies. Session: Immunotoxins, Immunoconjugates, and Antibody Combinations. Poster: 3244 (Date/Time: Tuesday, Apr 21, 2009, 8:00 AM; Location: Hall B-F, Poster Section 12)
