OncoMed is advancing six first-in-class anti-cancer stem cell product candidates in clinical trials. All of these product candidates were discovered at OncoMed using our in-depth knowledge of cancer biology and proprietary platform discovery technologies.
OncoMed's product candidates are in clinical development in a variety of indications. For each cancer stem cell pathway, there exist multiple potential therapeutic opportunities. Four of our clinical-stage novel product candidates target the Notch cancer stem cell pathway and two product candidates target the key Wnt cancer stem cell pathway. Another product candidate targeting the RSPO-LGR pathway will enter clinical testing in 2015. We utilize biomarkers throughout our clinical development efforts to enhance our understanding of how our drugs work and help identify the patients most likely to derive greater benefit from a given OncoMed product candidate.
Demcizumab (anti-DLL4, OMP-21M18)
One of OncoMed's first anti-cancer stem cell product candidates in the clinic, demcizumab (anti-DLL4, OMP-21M18), is a monoclonal antibody that selectively targets Delta-like ligand 4 (DLL4), an activator of the Notch signaling pathway. The Notch pathway is known to be important in cancer stem cells and cancer.
Blocking DLL4 has been shown in preclinical studies to result in anti-tumor activity via multiple mechanisms, including disrupting angiogenesis, inhibiting cancer stem cell growth, and promoting cell differentiation, and potentially immune activation.
In Phase 1a clinical studies, demcizumab has demonstrated initial single-agent activity, including early evidence of durable anti-tumor responses. Results from Phase 1b studies of demcizumab plus standard-of-care chemotherapy in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) and pancreatic cancer demonstrate the safety of our truncated dosing approach, anti-tumor responses and promising signals of prolonged survival benefit. These results are being confirmed in ongoing randomized Phase 2 trials of demcizumab. The YOSEMITE trial is evaluating demcizumab and gemcitabine plus Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) in patients with first-line metastatic pancreatic cancers. The DENALI trial will assess the efficacy of demcizumab with carboplatin and pemetrexed in first-line non-squamous NSCLC. A Phase 1b/2 trial of demcizumab and paclitaxel in patients with platinum-resistant ovarian cancer is also ongoing.
Demcizumab is part of OncoMed’s collaboration with Celgene Corporation.
The most recent public presentations of the demcizumab clinical studies include:
Tarextumab (anti-Notch2/3, OMP-59R5)
Tarextumab (anti-Notch2/3, OMP-59R5) is a novel anti-cancer stem cell antibody that prevents signaling through both the Notch2 and Notch3 receptors. Tarextumab has been shown in preclinical models to inhibit cancer stem cell growth, and promote cell differentiation, as well as disrupt tumor angiogenesis by inhibiting vascular pericytes.
Tarextumab is currently being studied in two randomized Phase 2 clinical trials. The ALPINE trial is assessing tarextumab with Abraxane plus gemcitabine in first-line advanced pancreatic cancer patients. The PINNACLE trial is testing tarextumab in combination with etoposide and cisplatin and etoposide and carboplatin in first-line extensive stage small cell lung cancer patients. The Phase 1b portions of the ALPINE and PINNACLE clinical trials demonstrated that tarextumab is well tolerated in combination with standard of care chemotherapies. In small cell lung cancer, tarextumab has demonstrated dose-dependent and biomarker driven activity. In pancreatic cancer, anti-tumor responses and prolonged survival rates versus standard of care were observed, particularly in patients whose tumors were identified as high in Notch3 gene expression using OncoMed’s biomarker assay. Randomized Phase 2 clinical trials of tarextumab are ongoing: In Phase 1a clinical studies, tarextumab was well tolerated as a single agent, with evidence of Notch pathway modulation. Single-agent activity manifested by prolonged stable disease has also been observed.
Tarextumab is part of OncoMed's collaboration with GlaxoSmithKline (GSK). Public presentations of the tarextumab data include:
Vantictumab (anti-Fzd7, OMP-18R5)
OncoMed has completed enrollment in a Phase 1a clinical study of vantictumab in advanced solid tumor patients. Vantictumab demonstrates evidence of Wnt pathway modulation and potential early single-agent activity manifested by prolonged stable disease has been observed. Three Phase 1b clinical trials of vantictumab in combination with standard-of-care chemotherapy in distinct solid tumor indications were initiated in 2013. The three trials include a Phase 1b trial in HER2-negative breast cancer (vantictumab + paclitaxel), a Phase 1b trial in advanced non-small cell lung cancer (vantictumab + docetaxel), and a Phase 1b trial in advanced pancreatic cancer (vantictumab + gemcitabine + Abraxane). Vantictumab is part of OncoMed’s collaboration with Bayer Pharma AG.
Public presentations of the vantictumab clinical studies include:
Ipafricept (FZD8-Fc, OMP-54F28)
Ipafricept (FZD8-FC, OMP-54F28) is a fusion protein that consists of a portion of the Frizzled 8 receptor from the Wnt pathway fused to the Fc domain of a human IgG1. Ipafricept selectively binds Wnt ligands that are activators of Wnt signaling. FZD8-Fc has shown potent anti-cancer stem cell effects and induces tumor cell differentiation in preclinical studies. In a Phase 1a clinical trial, ipafricept was well tolerated as a single agent and demonstrated evidence of Wnt pathway modulation and potential early single-agent activity manifested by prolonged stable disease. Three Phase 1b clinical trials of ipafricept are ongoing: one in pancreatic cancer (gemcitabine/nab-paclitaxel + ipafricept), one in hepatocellular carcinoma (sorafenib + ipafricept), and one in ovarian cancer (carboplatin/paclitaxel + ipafricept).
Ipafricept is part of OncoMed’s collaboration with Bayer. Public presentations of ipafricept data include:
Brontictuzumab (Anti-Notch1, OMP-52M51)
Bronticuzumab (anti-Notch1, OMP-52M51) is a novel anti-cancer stem cell antibody that binds the Notch1 receptor. Blocking Notch1 has been shown in preclinical models to inhibit cancer stem cell growth, and promote cell differentiation, as well as to disrupt tumor angiogenesis. Brontictuzumab is being studied as a single agent in two ongoing Phase 1a clinical trials among patients with advanced solid tumors or hematologic malignancies. In early 2015 enrollment of patients whose tumors demonstrate over expression of the activated form of Notch1 began in the Phase 1a solid tumor trial. Patients' tumors are pre-screened using OncoMed's proprietary immunohistochemistry (IHC) test to determine eligibility.
Brontictuzumab is part of OncoMed’s collaboration with GSK. Public presentations of data from brontictuzumab studies include:
Anti-DLL4/VEGF bispecific (OMP-305B83)
OncoMed’s anti-DLL4/VEGF bispecific targets both DLL4 on the Notch cancer stem cell pathway and the VEGF receptor. This antibody is intended to have both anti-cancer stem cell and anti-angiogenic activity. The bispecific antibody was discovered using OncoMed’s proprietary MAbTrap™ antibody display technology, which enables the rapid identification of monoclonal antibodies that bind targets with high affinity and specificity. The antibody is also the first program based on OncoMed’s BiMAb™ bispecific platform technology, which enables bispecific antibodies with traditional antibody shape, to enter clinical testing. OncoMed is currently enrolling patients with advanced refractory solid tumors in a Phase 1a clinical trial. This program is part of OncoMed’s collaboration with Celgene Corporation.
Wnt Small Molecules
OncoMed and Bayer Pharma AG are jointly working to discover small molecules targeting the Wnt Pathway as part of the strategic collaboration announced in June 2010.
OncoMed has filed an Investigational New Drug (IND) application with the US Food and Drug Administration on its first antibody targeting the RSPO-LGR pathway, anti-RSPO3 (OMP-131R10), and a Phase 1a clinical trial is expected to commence in summer 2015. A proprietary biomarker to screen prospectively screen patients for expression of RSPO is being developed in conjunction with this clinical program. Anti-RSPO3 has demonstrated activity in preclinical models against a variety of major tumor types, including colon, lung and ovarian cancers. The RSPO-LGR pathway is believed to be an important cancer stem cell pathway. Human R-spondin (RSPO) proteins signal through the leucine-rich repeat-containing G-coupled receptors (LGRs). Antibodies that disrupt binding of RSPO proteins to LGRs, or that disrupt RSPO activation of LGR signaling, are potential anti-cancer agents. OncoMed has identified multiple antibodies targeting the RSPO-LGR pathway.
This program is part of OncoMed’s collaboration with Celgene Corporation.
Emerging Pipeline in Immunotherapy
OncoMed has multiple new discovery and preclinical efforts advancing internally. These programs are emerging from the company's focused efforts in elucidating cancer stem cell and cancer biology, expertise in monoclonal antibody and protein therapeutics and expertise in translational/predictive medicine. Among several novel discoveries in preclinical testing are HIPPO pathway leads with immunotherapy potential and robust T cell activating agents utilizing fully human single-gene GITR trimeric ligand (GITRL) attached to an antibody framework.