This pharmaceutical field ushered in a R&D boom
May 17, 2021
On May 7, Eimerizumab was approved for the second indication-routine preventive treatment for adults and children with hemophilia A without inhibitors of coagulation factor VIII. The approval of this indication is expected to greatly broaden the clinical use of eimexizumab, and sales are expected to rise further. However, at present, the domestic price of iimerizumab is still high, especially for hemophilia patients, which can be described as "a lot of pressure", which limits the promotion of the drug to a certain extent. In addition to iimerizumab, Bonatumumab will also be launched in China at the end of 2020. This article analyzes the market performance of two dual-antibody drugs to provide a reference for the development of dual-antibody drugs.
Imicizumab-FX and FIX
Hemlibra is the first dual-antibody drug approved for marketing in China. On December 4, 2018, Hemlibra was approved by the NMPA for the routine preventive treatment of adult and pediatric patients with hemophilia A who have coagulation factor VIII inhibitors. Hemophilia is a hereditary coagulopathy disease, mainly divided into two types: A and B. Among them, hemophilia A is the most common, accounting for about 80%-85% of all hemophilia, and about 1 in 5000 newborn male babies is a patient with hemophilia A. The lack of coagulation factor Ⅷ in the plasma of patients with hemophilia A makes it difficult for blood to coagulate after a vascular rupture, and the bleeding time is prolonged. Clinically, hemophilia A mainly takes factor Ⅷ replacement therapy, but about 15%-25% of hemophilia A patients undergo factor Ⅷ replacement therapy, coagulation factor Ⅷ inhibitors appear in the body, and conventional treatment is ineffective. Increased risk of bleeding. Aimed at the patients whose factor Ⅷ therapy is ineffective, eimexizumab provides them with a new treatment path. Immexizumab is a recombinant humanized IgG4 bispecific monoclonal antibody. By bridging FIXa and FX, it promotes the production of thrombin, restores the coagulation process of patients with hemophilia A, and makes FⅧ dysfunction or Patients with hemophilia A who lack FⅧ completely stop bleeding at the bleeding site. After iimerizumab was launched in China in 2018, its sales are not optimistic. On the one hand, the approved indication for eimerizumab is "Haemophilia A adults and children with coagulation factor Ⅷ inhibitors." Routine preventive treatment of patients”, this indication has a narrow scope of application. In clinical practice, only 15%-25% of hemophilia type A patients will have coagulation factor Ⅷ inhibitors; The price is high, and the cost of treatment is a huge obstacle for hemophilia patients. With the approval of the new indications, patients with hemophilia can use eimerizumab regardless of the presence of factor Ⅷ inhibitors. In view of this, the sales volume of iimerizumab is expected to rise rapidly. Compared with the U.S. market, in April 2018, after imicelizumab was approved for the indication of the "preventive treatment of hemophilia A without factor Ⅷ inhibitors", sales have increased rapidly, and Hemlibra's global sales in 2020 will reach 2.19 billion Swiss francs, becoming the first bispecific antibody drug with sales to enter the global TOP100.
Hemlibra global sales
Data source: Roche financial report
Bonatumumab-CD3×CD19
Bonatumumab (Blincyto) is an innovative bispecific antibody. One end can bind to CD19 expressed on the surface of B cells, and the other end can bind to CD3 expressed on the surface of T cells. By connecting CD19 malignant B lymphocytes and CD3+ T lymphocytes, Blincyto can mediate the lysis of tumor cells by T cells.
Bonatumumab structure
Data source: Amgen
Bonatumumab is a dual antibody drug developed based on Amgen's bispecific T cell adapter system (BiTE platform). BiTE is a tandem scFv. Its advantages are that it does not contain an Fc structure, has a small molecular weight, and has high permeability. It can reach parts that are difficult for macromolecular antibodies to bind to the antigen. But the disadvantage is that because there is no Fc-terminal-mediated FcRN recycling mechanism, the half-life is short. Blincyto has a half-life of approximately 2 hours and requires more frequent administration. Blincyto is expensive, which limits its scope of use. In 2014, Bonatumumab was approved by the FDA for use in adults and children with relapsed or refractory precursor B-cell ALL patients. Blincyto was approved in 2018 for the treatment of adults and children with minimal residual disease (MRD)-positive precursor B-cell acute lymphoblastic leukemia. From the perspective of global market performance, after Blincyto went public, sales have increased rapidly, with sales reaching 379 million U.S. dollars in 2020. As an innovative drug, the price of Blincyto is as high as Hemlibra. It is priced at US$178,000 for every two rounds of treatment in the US market. Excessive pricing also limits the widespread use of the drug.
Blincyto global sales
Data source: Amgen's financial report
In the domestic market, in December 2020, NMPA conditionally approved Blincyto for the treatment of adult relapsed or refractory precursor B-cell acute lymphoblastic leukemia (ALL). BeiGene has the rights and interests of Blincyto in China.
CD3×CD19 layout of domestic pharmaceutical companies
Against the backdrop of global anti-biological research and development, there has also been an upsurge in the development of anti-biological drugs in China. There are currently close to 50 anti-biological drugs in the clinical stage. Among them, Kangfang Bio's AK104 (PD-1×CTLA-4) and Kangning Jerry's KN046 (PD-1×CTLA-4) are in the leading research and development progress, and both are in clinical phase III. Hengrui Medicine’s SHR-1701 (PD-L1×TGF-β) and Innovent’s IBI318 (PD-1×PD-L1) are in clinical phase II. For the CD3×CD19 target (Blincyto), which has performed well in the market, pharmaceutical companies such as Green Bamboo, Generon, and AisMed are intensively working in this field. Among them, Lvzhu Bio-K193 and Generon-Long's A319 are in the clinical phase I, and the dual-antibody drugs of Asmil and Yanyi Bio are in the pre-clinical stage. Green Bamboo's K193 is a dual-antibody drug developed based on the Fabite platform. In 2019, it obtained clinical approval and entered phase I clinical research. The indication is relapsed/refractory B-cell lymphoma. The K193 molecular structure is in the form of Fab-ScFv structure, which avoids the situation that single-chain antibody molecules are easy to form polymerization and lead to decreased activity. Generon's A319 is a bispecific antibody molecule designed and produced based on the ITabTM platform that targets the tumor-associated antigen (TAA) CD19 and activates human T cells through CD3. In November 2018, A319 was approved by NMPA for clinical trials, and its indications are B-cell leukemia and B-cell lymphoma. It is currently in phase I clinical trials. ExMed’s EX102 is a dual-antibody drug based on the four-chain bispecific antibody platform ExMab®, which can simultaneously target CD19 on the surface of B cells and CD3 on the surface of T cells. Refractory B-cell acute lymphoblastic leukemia is currently in the preclinical stage.
