Date: 2015-04-02
Type of information: Clinical research agreement
Compound: demcizumab, Alimta® (pemetrexed for injection)
Company: Eli Lilly (USA - IN) OncoMed Pharmaceuticals (USA - CA)
Therapeutic area: Cancer - Oncology
Type agreement: clinical research
Action mechanism: monoclonal antibody/enzyme inhibitor/thymidilate synthetase inhibitor/antifolate Demcizumab is a humanized monoclonal antibody that inhibits Delta-Like Ligand 4 (DLL4) in the Notch signaling pathway. Based on preclinical studies, demcizumab appears to have a multi-pronged mechanism of action: halting cancer stem cell growth and reducing CSC frequency, disrupting angiogenesis in the tumor and potentially augmenting anti-tumor immune response. Pemetrexed is folate analog metabolic inhibitor containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides.Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folypolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Disease: first-line advanced non-small cell lung cancer (NSCLC)
Details: * On April 2, 2015, OncoMed Pharmaceuticals, a clinical-stage company developing novel therapeutics that target cancer stem cells (CSCs), or tumor-initiating cells, announced that it has entered into an agreement with Eli Lilly and Company. Demcizumab, OncoMed\'s anti-DLL4 antibody, is being tested in combination with Lilly\'s Alimta® (pemetrexed for injection) and carboplatin for the treatment of first-line advanced non-small cell lung cancer (NSCLC). Under the terms of this agreement, Lilly will provide clinical supply of Alimta® for OncoMed\'s ongoing Phase 2 DENALI trial. OncoMed initiated enrollment in the randomized Phase 2 DENALI trial in January 2015 to test the efficacy and safety of demcizumab in combination with Alimta and carboplatin. Alimta is approved as an initial treatment in combination with cisplatin for locally advanced or metastatic NSCLC for patients with non-squamous histology. The DENALI trial is expected to enroll approximately 200 patients with first-line metastatic Stage IV non-squamous NSCLC whose tumors do not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation.
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