Three inspirations from the CDE double antibody R&D guidelines for the industry

Bispecific antibody (BsAb, hereinafter referred to as "double antibody") is one of the hot spots in the research and development of new anti-tumor drugs.

On April 11, the Center for Drug Evaluation (CDE) of the State Drug Administration issued the "Technical Guidelines for Clinical Research and Development of Bispecific Antibody Antitumor Drugs (Draft for Comment)" and its drafting instructions (referred to as "Draft for Comments")

It's time for the principle

The concept of double antibody was first proposed in 1960, and the world's first BsAb drug was approved by the European Medicines Agency (EMA) 50 years later

China is closely following the trend and the R&D progress of leading companies has emerged

Under the global outbreak of double antibody, the introduction of the technical guidelines for double antibody clinical research and development means that the regulatory authorities fully recognize and encourage the value or significance of double antibody clinical development

The development threshold is further raised

The draft requires that the development of new dual-antibody drugs should be based on clinical needs, which is also in line with the "Clinical Value-Oriented Clinical Research and Development Guidelines for Anti-tumor Drugs" previously issued by CDE

The development of any new tumor drug should be based on a fully rational and scientific anti-tumor mechanism, especially the double antibody with a more complex structure than the monoclonal antibody, rather than the concept of a simple arrangement and combination.

The document proposes to determine a reasonable R&D project, emphasizes the need to consider the efficacy and safety of double-antibody drugs as a whole new whole, and clearly proposes to "guide antibody design with clinical needs", focusing on target selection, structure Design and optimization provides guidelines for requirements

The document also proposes to "achieve mechanism innovation through scientific design", which clarifies that the development of double antibody can generate new drug effects through spatial rearrangement and/or realize innovation in the mechanism of action such as carrying and transporting functions through the time dimension, so as to solve the problem of monoclonal antibody.

At the same time, the exposure draft emphasizes the impact of the research and development of the drug itself on the clinical value

In addition, solid non-clinical pharmacodynamic studies should be carried out to support the theoretical mechanism and goals of dual antibodies

The guiding principles put forward guidance requirements for a series of key links in the preclinical and clinical development of double antibodies, which not only put forward implementation guidelines for the clinical development of double antibodies, standardize the development order, reduce blind behavior, and further raise the development threshold of double antibodies

Encourage in-depth exploration of clinical advantages

Solicitation of opinions In the issues that need attention in clinical research and development, it is explained that in the process of clinical research and development, double antibody is different from monoclonal antibody products in clinical trial risk control, determination of optimal drug administration strategy, clinical trial design, immunogenicity , biomarker development and other issues requiring special attention

These directional guidance requirements for key aspects of double-antibody clinical research, on the one hand, can help developers to conduct clinical trial preparations and plans more clearly, and on the other hand, still focus on clinical research from the perspective of patient benefit and clinical value.

In addition to the relevant technical requirements, the requirements for the design of the control group are one of the important concerns of the industry and the market

The industry is most concerned about the head-to-head study of double antibody and monoclonal antibody

According to public statistics, PD-1/PD-L1 accounts for 61.
5% of the targets involved in domestic double antibodies, and CD3 accounts for 27%.
CD3 mAbs have not yet been established as drugs in the world.
Therefore, the comparison between double antibodies and mAbs is expected to be different.
Mainly focus on PD-1/PD-L1-related double antibody and monoclonal antibody
.
The first situation is proposed: the optimal SOC includes the constituent target monoclonal antibody or combination drug of the double antibody, which requires head-to-head
.

Generally speaking, it is approved in China and recommended by guidelines, and there is no major problem in drug accessibility, that is, it is defined as SOC
.
Several domestic PD-1/PD-L1 inhibitors combined with chemotherapy have been approved for the first-line treatment of advanced driver gene-negative NSCLC.
Therefore, future research in such indications needs to be considered head-to-head with PD-1/PD-L1 inhibitors Controlled study
.
However, for EGFR-mutated advanced NSCLC that has failed EGFR TKI treatment, the current SOC is chemotherapy, and PD-1/PD-L1 inhibitors have not been approved.
Therefore, in the future, to conduct research in such indications, it is only necessary to carry out head-to-head comparison with chemotherapy.
research
.

It needs to be seen that head-to-head research with monoclonal antibodies will not bring resistance to the development of dual-antibodies, but will greatly increase the value of leading companies
.
Products with a successful PK will be marketed, setting a new standard of care, and will also facilitate the investment of resources into the development of new target drugs
.

At present, the leading companies have entered the development stage of double antibody.
According to the information that the author understands and the preclinical research results of related products, developers should have strong confidence in the head-to-head PK monoclonal antibody
.
And for example, the domestic Kangfang Bio Cardonilide treatment of R/M cervical cancer has more than doubled the data of the market application of PD-1 monoclonal antibody, and the combination therapy of this drug is also far better than the combination therapy of PD-1 in gastric cancer, liver cancer and other aspects.
In addition, the results of Kangfang AK112 monotherapy and combination chemotherapy in multiple lung cancer phase II fields are also encouraging, and multiple phase III registration studies have been carried out
.

Of course, the research cost will definitely increase, but once the monoclonal antibody is defeated, the dual antibody becomes a new SOC and it will become a huge moat for the enterprise
.
However, there are precedents for the failure of the double antibody to challenge the PK of the monoclonal antibody.
For example, the study of Merck's PD-L1/TGFβ control K drug has been terminated
.
The description of the remaining two cases is clear and straightforward, and no further comment is made
.

3 lessons for practitioners

As the official cognition and attitude of CDE, the consultation draft will also have a long-term impact on enterprises
.
For enterprises that focus on the development of double antibodies, they can start from the following aspects:

The first is to enhance the R&D strength of independent innovation and continue to innovate at the source
.
The draft for comments guides developers to form a capability system that starts with target research and extends to the back end for product development
.
For example, if the two target mAbs of the company are independently developed, the so-called "children of their own family know best", it will be much easier to develop double-antibody on this basis, and it will be able to provide more and more for the regulatory authorities.
Convincing preclinical research evidence to show that the double antibody may be superior to the related target monoclonal antibody in mechanism, and then support the double antibody to enter the clinical research stage
.

If the developer's research on the double antibody itself is not sufficient, the product may not even be able to obtain clinical approval.
The large number of supporting materials involved in the clinical trial plan and the marketing application process may pose a great challenge to those companies that rely too much on license in
.
Therefore, the company will extend forward and improve the upstream capabilities of drug development, including systems such as double-antibody platforms, which will become the basic capabilities
.
Correspondingly, the strength of the basic conditions such as the team ability and financial strength of developers will also need to become higher
.

Second, product development thinking needs to undergo a profound change
.
Product development should strive for commercial value from the perspective of creating clinical value
.
The consultation draft proposes that the double antibody should solve the problem that the monoclonal antibody cannot solve.
In the current environment, it mainly refers to the problem that cannot be solved by PD-1/PD-L1
.
Specifically, you can find development ideas from the following aspects:

Market opportunities for primary/secondary resistance to monoclonal antibodies
.
There are still many diseases/types that are not covered by PD-1/PD-L1 mAbs
.
Clinical experience shows that even if some specific patients (such as high PD-L1 expression) respond to PD-1/PD-L1 monoclonal antibody, there are still >50% of patients who do not respond to it
.
In addition, the resistance rate of PD-1/PD-L1 monoclonal antibody is relatively high.
According to the existing data, the secondary resistance rate of its treatment of GC, SCCHN, NSCLC, and melanoma is as high as 71%, 54%, 55%, and 60%, respectively.
%! These related fields are the important areas where the double-antibody drug can exert its value
.

There is still room for further refinement in the areas of indications that PD-1/PD-L1 has been approved to cover, and it is worthy of in-depth research to create a market and fill the gap
.

There is also huge room for development in the exploration and challenge of combination therapy based on double antibody
.
As more and more anti-tumor mechanisms and targets are discovered, it is impossible for the drugs for combination therapy to be superimposed indefinitely.
Therefore, the development of dual antibodies provides space and opportunities for more combination therapy strategies in the future; once approved for marketing, Bispecific antibodies are generally safer than the combination of two mechanism drugs, and also have natural advantages in clinical application
.

On the basis of solid drug mechanism research, challenge the SOC of monoclonal antibodies with strong confidence as soon as possible.
Once the double-antibody-based therapy becomes a new SOC, relying on the advantages of the double-antibody product itself, it will establish a short-term difficult for developers to establish.
Shaking the moat
.

Avoid popular targets and develop non-PD-1-based double antibodies
.
For platforms with existing PD-1 products, priority can be given to the deployment of dual-target antibodies that can be used in combination with PD-1; to avoid homogeneous competition, and to cooperate with existing PD-1 products in the pipeline to rapidly improve existing PD-1 indications barriers
.

The third is to advance the double antibody to Phase III clinical stage as soon as possible
.
Before the official implementation of the guiding principles, the dual-antibody treatment plan that can enter the Phase III clinical trial will become an important asset of the company
.

In general, on the basis of guiding and regulating the development of the industry, it is obviously beneficial to the leading companies that have a complete self-development system, in-depth research on targets, and stronger combination capabilities, and more products/indications enter Phase III clinical trials.
The business development model brings greater challenges
.
However, the development of double resistance has just emerged, and the cake of market development must be prepared for enterprises with strong strength and cognitive ability, rapid thinking change and high execution efficiency
.