REDWOOD CITY, Calif.—OncoMed Pharmaceuticals Inc. has announced the publication of preclinical data for OMP-59R5, its anti-Notch2/3 antibody. The results appeared in the May 1 edition of Clinical Cancer Research, in an article titled “Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor initiating cell frequency.”
Tarextumab demonstrated efficacy in inhibiting growth of preclinical patient-derived xenografts from various tumor types, including lung, breast, ovarian and pancreatic cancers. In addition, inhibiting Notch signaling in tumor cells was associated with a reduction in cancer stem cell frequency, promotion of tumor cell differentiation and a delay in tumor recurrence after chemotherapy. Notch3 gene expression was also identified as a potential predictive biomarker for tarextumab.
OMP-59R5 (tarextumab) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. Based on preclinical studies, it is thought that the compound operates through two mechanisms of action: one, by downregulating Notch pathway signaling, which seems to offer anti-cancer stem cell effects; and two, by affecting pericytes, which impacts the stromal and tumor microenvironment. In Phase 1a and 1b clinical trials of tarextumab, the drug proved to be well tolerated and showed on-target modulation of the Notch signaling pathway as well as signs of anti-tumor activity.
"In this paper, we show that the blockade of Notch signaling with tarextumab sensitizes tumors to chemotherapy and reduces cancer stem frequency, delaying cancer recurrence as compared to chemotherapy alone," Dr. Tim Hoey, senior vice president of Cancer Biology and a co-author of the paper, said in a press release. "Preclinical data for tarextumab, particularly as part of a combination regimen, provide a strong rationale for the utility of targeting Notch2 and Notch3 for cancer treatment, and suggest that this therapeutic approach may improve clinical outcomes. We are currently exploring the impact of this targeted anti-cancer stem cell agent in our Phase 2 clinical trials."
OncoMed is investigating tarextumab in a pair of randomized Phase 2 clinical trials. In the ALPINE study, tarextumab is being evaluated in combination with Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in first-line advanced pancreatic cancer patients. In the PINNACLE study, the compound is being investigated in combination with etoposide and cisplain and etoposide and carboplatin in first-line extensive-stage small cell lung cancer patients.
Tarextumab is part of OncoMed's ongoing collaboration with GlaxoSmithKline. The companies struck a strategic alliance in December 2007 for the development of cancer stem cell antibody therapeutics that target the Notch signaling pathway. The agreement was amended in 2011, and is now focused solely on OMP-59R5 and OMP-52M51 (anti-Notch1). OncoMed stands to receive aggregate payments of up to $344.5 million with relation to tarextumab, as well as royalties in the low double-digit percentages to high teens on net sales, and aggregate payments of up to $349.5 million with regards to anti-Notch1, with the same rights for royalties as with tarextumab. On its part, GlaxoSmithKline has an option to obtain an exclusive license to tarextumab during certain time periods through the completion of proof-of-concept Phase 2 trials.
