On January 12, 2021 Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of cancer, metabolic, autoimmune and other major diseases, reported that the National Medical Products Administration (NMPA) of China has accepted the supplemental New Drug Application (sNDA) for TYVYT (sintilimab injection) in combination with BYVASDA (bevacizumab injection) as first-line therapy for patients with hepatocellular carcinoma (HCC) (Press release, Innovent Biologics, JAN 12, 2021, View Source [SID1234573925]). This is the fifth NDA application of TYVYT that has been accepted for review by NMPA. Meanwhile, this application also seeks the fourth indication for BYVASDA.
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TYVYT was approved by the NMPA in December 2018 for the treatment of relapsed or refractory classical Hodgkin’s lymphoma. In April 2020, the NMPA accepted the sNDA for TYVYT in combination with platinum-containing chemotherapy as first-line therapy in nonsquamous non-small cell lung cancer (NSCLC). In August 2020, the NMPA accepted the sNDA for TYVYT in combination with platinum-containing chemotherapy as first-line therapy for squamous NSCLC (NSCLC). In January 2021, the NMPA accepted the sNDA for TYVYT as second-line therapy in squamous NSCLC. Meanwhile, BYVASDA was previously approved by NMPA for the indications of advanced non-small cell lung cancer, metastatic colorectal cancer and adult recurrent glioblastoma.
The sNDA application was based on the pre-specified interim analysis of a randomized, open-label, Phase 3 clinical trial (ORIENT-32)—TYVYT in combination with BYVASDA as first-line therapy for unresectable HCC. Based on the interim analysis conducted by the Independent Data Monitoring Committee (iDMC), TYVYT in combination with BYVASDA demonstrated a statistically significant improvement in overall survival (OS) and progression-free survival (PFS) as assessed by Independent Radiographic Review Committee (IRRC) compared with sorafenib, which met the pre-defined efficacy criteria.
The principal investigator of the ORIENT-32 study, Professor Fan Jia from Zhongshan Hospital of Fudan University, stated: "We are very pleased to see that TYVYT plus BYVASDA can significantly improve the overall survival and progression-free survival compared to Sorafenib, which meet the pre-defined statistical superiority criteria. ORIENT-32 study was released in a late-breaking proffered oral presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia ("ESMO Asia") Virtual Congress 2020. This is the first randomized controlled trial using PD-1 inhibitor-based combination therapy that has improve the overall survival and progression-free survival in the first-line treatment of advanced HCC，which represents great significance."
Dr. Hui ZHOU, Vice President of Medical Science and Strategy Oncology of Innovent, stated: "HCC is the fourth most common malignancy with the second highest mortality rate in China. Despite treatment advancements, there remains significant unmet need for additional effective treatment options for HCC patients. The acceptance of this sNDA by the NMPA represents an important milestone in demonstrating the potential value of TYVYT in combination with BYVASDA in HCC. We look forward to working with the China regulatory authorities on the sNDA review and we hope to bring this therapy as a first-line treatment option to patients with unresectable HCC as early as possible."
About the ORIENT-32 Trial
ORIENT-32 is a Phase 3 randomized, open-label，multi-center study in China to evaluate the efficacy and safety of TYVYT (sintilimab injection) in combination with BYVASDA (bevacizumab biosimilar injection) compared to sorafenib in the first-line treatment of patients with advanced hepatocellular carcinoma（ClinicalTrials.gov, NCT 03794440）. The primary endpoints of the trial are overall survival (OS) and progression-free survival (PFS) as assessed by Independent Radiographic Review Committee (IRRC) based on RECIST v1.1.
A total of 571 subjects were enrolled in the ORIENT-32 Phase 3 study. Enrolled patients were randomly assigned 2:1 to receive TYVYT (sintilimab injection) combination with BYVASDA (bevacizumab biosimilar injection) or sorafenib, until disease progression, unacceptable toxicity, withdrawal of consent, death, or other reasons stated in the protocol, whichever occurs first.
About HCC
Primary liver cancer（PLC）is a common malignancy of the digestive system worldwide, among which about half new cases and deaths occur in China. The main pathological types of liver cancer are hepatocellular carcinoma (HCC), accounting for 85 to 90 percent, and a small number of cases of intrahepatic cholangiocarcinoma（ICC） and HCC-ICC mixed liver cancer. In China, HCC is primarily caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection.
About TYVYT (Sintilimab Injection)
TYVYT (sintilimab injection), an innovative drug with global quality standards jointly developed in China by Innovent and Lilly, has been granted marketing approval by the NMPA for the treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy, and is included in the 2019 Guidelines of Chinese Society of Clinical Oncology for Lymphoid Malignancies. TYVYT was included in the National Reimbursement Drug List (NRDL) in November 2019 as the historically first PD-1 inhibitor entering in NRDL and the only PD-1 included in the list in that year.
In April 2020, the NMPA accepted the sNDA for TYVYT in combination with ALIMTA (pemetrexed) and platinum chemotherapy as first-line therapy for the treatment of patients with non-squamous non-small cell lung cancer (NSCLC). In May 2020, TYVYT monotherapy met the primary endpoint of overall survival in the Phase 2 ORIENT-2 study as second-line therapy in patients with advanced or metastatic esophageal squamous cell carcinoma. In August 2020, the NMPA accepted the sNDA for TYVYT in combination with GEMZAR (gemcitabine for injection) and platinum chemotherapy as first-line therapy in squamous NSCLC. In January 2021, the NMPA accepted the sNDA for TYVYT as second-line therapy for squamous NSCLC and the sNDA for TYVYT in combination with BYVASDA as first-line therapy in HCC.
TYVYT, is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, block the PD-1 / PD-Ligand 1 (PD-L1) pathway and reactivate T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies with TYVYT to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials. Meanwhile, Innovent is conducting clinical research studies on TYVYT worldwide.
About BYVASDA (Bevacizumab Injection)
BYVASDA is a bevacizumab biosimilar and a recombinant humanized anti-VEGF monoclonal antibody drug. Vascular endothelial growth factor (VEGF) is an important factor in angiogenesis that is highly expressed by the endothelial cells in most human tumors. An anti-VEGF antibody binds VEGF selectively with high affinity and blocks its binding to VEGF receptors on the surface of vascular endothelial cells, thereby inhibiting signaling pathways such as PI3K-Akt/PKB and Ras-Raf-MEK-ERK. BYVASDA produces anti-tumor effects by inhibiting the growth, proliferation and migration of vascular endothelial cells, blocking angiogenesis, reducing vascular permeability, blocking blood supply to tumor tissues, inhibiting the proliferation and metastasis of tumor cells and inducing apoptosis in tumor cells. Since the launch of bevacizumab, it has been approved for the treatment of patients with multiple malignant tumors globally, including non-small cell lung cancer, metastatic colorectal cancer, glioblastoma, renal cell carcinoma, cervical cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer. The efficacy and safety of bevacizumab have been well recognized worldwide.