Event:
On April 11, 2022, in order to further guide and standardize the clinical research and development of bispecific antibody antitumor drugs, the drug examination center (CDE) of the State Food and Drug Administration issued a notice to solicit the opinions of the guiding principles for clinical research and development of bispecific antibody antitumor drugs.
Comments:
This exposure draft clearly points out that double antibodies need to reflect their advantages over the same target monoclonal antibodies and combined treatment schemes in clinical trials. This guiding principle will further standardize the competition of different treatment schemes with the same target and effectively reduce the disordered competition between the combination scheme with the same target and the double antibody.
Compared with monoclonal antibody or combination, double antibody has better curative effect, better safety and differential advantages
Double antibodies can recognize and combine two different epitopes, so as to bridge tumor cells and effector cells and mediate their targeted killing to tumors; Or bridge two different receptors, which may activate new biological signals. Compared with monoclonal antibody monotherapy, double antibody can block multiple signal pathways at the same time, prevent drug resistance and improve the curative effect; Compared with monoclonal antibody combination therapy, the specificity and targeting of double antibodies are stronger and the safety is better. The development of dual antibody needs to solve the problem that the monoclonal antibody does not meet the clinical needs, and the trial design must be head-to-head compared with the SOC. This exposure draft focuses on that the development purpose of dual antibody drugs should be to solve the clinical needs that the monoclonal antibody fails to meet, such as solving the primary / secondary drug resistance, improving the clinical efficacy or safety, and the clinical trial should also reflect the relevant confirmation. Therefore, the opinion draft clearly points out that in principle, the key research trials of double antibodies should be compared with the current optimal standard therapy (SOC) design. Moreover, if the SOC of the proposed subject corresponding to the indication has included the McAb variety of any target of the dual antibody or its combination, the trial design shall be head-to-head compared with the treatment regimen containing the McAb or its combination.
Several innovative drug companies’ double anti clinical programs comply with the guiding principles and are progressing smoothly
Compared with the combination of PD-1 and CTLA-4, kangfang biological’s PD-1 / CTLA-4 dual antibody ak104 has significantly improved the curative effect on the indications of cervical cancer. The listing application of ak104 for the treatment of recurrent or metastatic cervical cancer has been accepted by nmpa and given priority to review. The clinical trial results of ak104 in the treatment of cervical cancer disclosed by the company show that among 100 evaluable patients, the orr is 33%, and the Dor rates at 6 and 12 months are 77.6% and 52.9% respectively; In 64 patients with PD-L1 positive (CPS ≥ 1), the orr was 43.8%, the median PFS was 6.34 months, and the median OS was not reached. The clinical results of PD-1 combined with CTLA-4 published by agenus based on 125 patients showed that the orr was 25.6%, and the orr was 32.8% in 86 patients with PD-L1 positive (CPS ≥ 1). In addition, ak104 has actively expanded to the field of first-line treatment of cervical cancer, and has been approved by CDE to carry out phase III clinical trial of combined concurrent radiotherapy and chemotherapy in the treatment of locally advanced cervical cancer; Gastric cancer, liver cancer and other cancers have advanced to the key / phase III clinical research stage. Phase III trial of Corning Jerry PD-L1 / CTLA-4 double antibody kn046 combined with chemotherapy in the treatment of first-line advanced squamous non-small cell lung cancer. The interim analysis of enreach-lung-01 reached the preset end point in March this year. Compared with standard chemotherapy, PFS was significantly prolonged. In phase II data, Orr was 57.6% and dcr84.5% 8%, patients with PD-L1 ≥ 1% had MPFs for 10.8 months and OS was not reached; Another phase III trial of combined chemotherapy for first-line treatment of advanced pancreatic cancer was also completed by KN046303, and the II phase data ORR reached 50%, DCR95. 5% is effective. Both trials used a control design with chemotherapy SOC, which met the requirements of the guidance. In addition, kn046 has also carried out registered clinical trials for the treatment of thymic cancer and combined treatment of second-line non-small cell lung cancer with lenvatinib, and the progress of dual antibody research and development is leading.
Investment suggestion: the release of public solicitation of opinions on the guiding principles indicates that CDE will further standardize the research and development of dual antibody: support the development of dual antibody therapy based on clinical value and using clinical data to show better efficacy than the same target monoclonal antibody and combination regimen. We suggest to pay attention to the research and development pipeline of differentiated clinical value, and the innovative drug companies that have carried out the research and development pipeline of double antibodies in line with the guiding principles and specifications: Baiji Shenzhou, kangfang biology, Betta Pharmaceuticals Co.Ltd(300558) , Jiangsu Hengrui Medicine Co.Ltd(600276) , Xinda biology, Shanghai Junshi Biosciences Co.Ltd(688180) and Corning Jerry.
Risk tips: policy change risk, innovative drug R & D risk, and increased competition of innovative drugs
