Date: 2015-10-22
Type of information: Clinical research agreement
Compound: MEDI4736 (durvalumab), Cyramza® (ramucirumab), galunisertib, CXCR4 peptide antagonist, anti-CSF-1R monoclonal antibody, tremelimumab, abemaciclib, necitumumab, AZD9291
Company: AstraZeneca (UK) Eli Lilly (USA - IN)
Therapeutic area: Cancer - Oncology
Type agreement: clinical research
Action mechanism: monoclonal antibody/immune checkpoint inhibitor/cyclin dependant kinase inhibitor/serine/threonine kinase inhibitor/kinase inhibitor/CXCR4 peptide antagonist. MEDI4736 (durvalumab) is an investigational immune checkpoint inhibitor directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. MEDI4736 blocks these signals, countering the tumour’s immune-evading tactics.This antibody is directed against B7-H1, have been shown to block the interaction between B7-H1 and its receptors, PD-1 and CD80 (B7-1). This blockade may help to overcome the immunosuppressive effects of B7-H1 on anti-tumor T cells. Cyramza® (ramucirumab) is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. In an in vivo animal model, ramucirumab inhibited angiogenesis. The molecule was acquired when BMS purchased ImClone Systems in 2008. Galunisertib (LY2157299) is a TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumors growth, suppresses the immune system, and increases the ability of tumors to spread in the body. Immune function is suppressed in cancer patients, and TGF beta worsens immunosuppression by enhancing the activity of immune cells called T regulatory cells. TGF beta also reduces immune proteins, further decreasing immune activity in patients Galunisertib is currently under investigation as an oral treatment for advanced/metastatic malignancies, including Phase 2 evaluation in hepatocellular carcinoma, myelodysplastic syndromes (MDS), glioblastoma, and pancreatic cancer. CXCR4 peptide antagonist (LY2510924) blocks stromal cell-derived factor-1 (SDF1) from CXCR4 binding. Overexpression of C-X-C motif receptor 4 (CXCR4) is implicated in tumor progression. Tremelimumab is a fully human monoclonal antibody, which stimulates the immune system to destroy cancer cells through binding to the protein CTLA-4, expressed on the surface of activated T-lymphocytes. Abemaciclib (LY2835219) is a cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting CDK 4 and 6. Although abemaciclib inhibits both CDK 4 and CDK 6, the results from the cell-free enzymatic assays have shown that it was most active against Cyclin D 1 and CDK 4. Necitumumab is a human monoclonal antibody designed to bind and block the ligand binding site of EGFR. AZD9291 is a once daily, selective, irreversible EGFR tyrosine kinase inhibitor (TKI) designed to target both the activating sensitising mutation, EGFRm, and T790M, the genetic mutation responsible for EGFR TKI treatment resistance in up to approximately two-thirds of cases of EGFRm advanced NSCLC.
Disease: advanced solid tumors
Details: * On May 29, 2015, Eli Lilly and AstraZeneca announced that they have entered into a clinical trial collaboration to evaluate the safety and preliminary efficacy of AstraZeneca's investigational anti-PD-L1 immune checkpoint inhibitor, MEDI4736, in combination with Cyramza® (ramucirumab), Lilly's VEGF Receptor 2 antiangiogenic cancer medicine. The planned study will assess the combination as a treatment for patients with advanced solid tumors. The Phase I study is expected to establish the safety and a recommended dosing regimen - with the potential to open expansion cohorts in various tumors of interest - for the combination of MEDI4736 and ramucirumab. Under the terms of the agreement, the trial will be sponsored by Lilly. Additional details of the collaboration, including tumors to be studied and financial terms, were not disclosed.
Financial terms:
Latest news: * On October 22, 2015, AstraZeneca and Eli Lilly announced an extension to their existing immuno-oncology collaboration exploring novel combination therapies for the treatment of patients with solid tumours. Under the terms of the expanded agreement, AstraZeneca and Lilly will evaluate the safety and efficacy of a range of additional combinations across the companies’ complementary portfolios. Lilly will lead the execution of the studies, while both companies will contribute resources. Additional details of the collaboration, including tumours to be studied and financial terms, were not disclosed. AstraZeneca’s anti-PD-L1 immune checkpoint inhibitor, durvalumab (MEDI4736), will be combined with Lilly molecules that target the immune system, including TGF-beta kinase inhibitor, galunisertib; CXCR4 peptide antagonist; an anti-CSF-1R monoclonal antibody, which will be assessed additionally with AstraZeneca’s anti-CTLA-4 monoclonal antibody, tremelimumab. The companies will also explore other combinations targeting tumour drivers and resistance mechanisms, including: Lilly’s abemaciclib (CDK4 and 6 small molecule inhibitor) with Faslodex, AstraZeneca’s marketed selective oestrogen receptor down regulator (SERD); Both Cyramza® (ramucirumab) and necitumumab, Lilly’s anti-VEGFR and anti-EGFR monoclonal antibodies respectively, with AZD9291, AstraZeneca’s investigational third generation EGFR inhibitor.
