Check out over 100 antibody drugs approved by the FDA! Double antibody, ADC...Where is the new flashpoint?
May 20, 2021
Since the US FDA approved the first monoclonal antibody OKT3 (muromonab-CD3) in 1986, it has a history of 35 years. Today, antibody drugs account for one-fifth of new drugs approved by the FDA each year. Up to now, the US FDA has approved more than 100 antibody drugs. Corresponding to the continuous increase in the number of approvals is the steadily increasing global antibody drug market. The market size in 2020 has exceeded 150 billion U.S. dollars. Recently, Nature Reviews Drug Discvoery published a review article analyzing the overall pattern of 100 antibody drugs approved by the US FDA.
Antibody drugs enter the outbreak period
Although the development of antibody drugs has a history of 35 years, 50 of the 100 approved antibody drugs were approved between 2015 and 2021. The picture below shows the FDA approval of antibody drugs over the years.
Figure 1 Antibody drugs approved by the US FDA each year
Source: Reference 1
According to statistics, in the 2020 list of top 20 drug sales, antibody drugs occupy 8 seats, and the cumulative income of these 8 antibodies is 69.3 billion US dollars. Among them, the sales of Xiumile reached 20.39 billion U.S. dollars in 2020, about 132 billion yuan, an increase of 3.4% compared to 19.73 billion U.S. dollars in 2019. Merck’s PD1-1 inhibitor "K drug" has a sales revenue of US$14.38 billion in 2020. It is the monoclonal antibody drug that has the most potential to surpass Xiumira and become the new generation of drug king.
Table 1 Ranking of antibody drug sales in 2020
Data source: Fierce Pharma, data compilation of Yaozhi
Monoclonal antibodies have attracted much attention from drug developers because of their excellent specificity and affinity for cell surface target antigens. And compared to the past that medicinal chemists may have to spend years searching for small molecules that are active on specific targets, the discovery of antibodies may only take a few months. According to Reichert's analysis of 569 antibodies that entered the clinic between 2005 and 2014, from phase I clinical to approval, the overall success rate was 22%, and the probability of antibody success in trials is twice that of small molecules.
Figure 2 The form of the antibody
Source: Reference 1
Hot targets are highly competitive
Although the number of antibody drugs has exceeded 100, the targets covered are still very limited, and 10 targets account for 42% of the approved number. At the top of the list are PD1/PDL1 immune checkpoint inhibitors, 7 drugs have been approved; and CD20 monoclonal antibodies have also been approved for 6 drugs.
Table 2 Distribution of approved targets
Source: Reference 1
There are hundreds of antibodies in clinical development, but there is still a large concentration of popular targets.The article points out that this trend is partly driven by Chinese companies developing antibodies for the Chinese market. According to incomplete statistics from Yaozhi data, in 2020, CDE will accept a total of 208 antibody drug clinical trial applications (173 monoclonal antibodies, 27 dual antibodies, and 8 ADC drugs).
Figure 3 Distribution of antibody drug targets declared for clinical use in China in 2020
As can be seen from the above figure, the competition for target drugs such as PD1/PDL1, HER2, CTLA4 is still very fierce, but some newer targets, such as 4-1BB, LAG3, CD47, etc., have emerged.
ADC, bi-antis...the rapid rise
In recent years, antibody technology has been continuously updated and iterated, and more and more other antibody drug forms have been derived from the initial monoclonal antibodies, such as ADCs, double antibodies, and so on. Antibody-drug conjugate (ADC) is a new molecule formed by combining traditional small-molecule anti-cancer drugs with recombinant monoclonal antibody (mAb) molecules through a linker through a chemical reaction. Generally speaking, these mAbs can specifically recognize tumor-specific antigens, so they are known as "biological missiles." The FDA approved the first ADC drug in 2000, Pfizer's CD33-targeted gemtuzumab ozogamicin, for acute myeloid leukemia (AML). The FDA has approved 11 ADC drugs so far. The bispecific antibody has also become a late-stage show in the antibody field. So far, the FDA has approved two dual-antibody drugs. Although my country's double-antibody and ADC drugs started late, they still have achieved good results in terms of the number of clinical studies. According to statistics from Yaozhi data, in 2020, CDE will handle 27 double-antibody clinical applications with acceptance numbers, and ADC drug clinical applications will include 8 with acceptance numbers. Rongchang Biotech's ADC drug injection Vidicuzumab has submitted a marketing application. Although rapid follow-up is still the main theme of China's innovation, the differentiated innovation achievements of domestic companies have gradually emerged. In the combination of some popular targets, Chinese companies have made more advanced progress. For example, Corning Jereh’s KN046 is the world’s first dual antibody that targets both PD-L1 and CTLA-4. At present, KN046 combined with platinum-containing chemotherapy is effective for stage IV Phase III clinical trials on the efficacy and safety of squamous non-small cell lung cancer have been launched in China. TJC4's CD47 monoclonal antibody TJC4 has a unique antigen-binding epitope, which can minimize the combination with normal red blood cells and reduce the impact on red blood cells. It has the potential to be the best in class; in classic Hodgkin's lymphoma, BeiGene's tislelizumab has the highest complete remission rate (CR) among all PD-1 that has been marketed in China. Corning Jerry's subcutaneous injection of PD-L1 monoclonal antibody KN035 (Envolimab) is the first subcutaneous injection of PD-1/L1 monoclonal antibody to submit an NDA in China. In addition, there are innovative pharmaceutical companies dedicated to the development of brand-new target drugs. For example, Dr. Yuelei Shen, founder/chairman of Biocytometer, said that he hopes to find new targets and new monoclonal antibodies through the "Thousand Rats" plan.
Conclusion
Antibody drug research and development may have just started, and the next 100 antibodies are estimated to take less time. The article points out that although many therapeutic antibodies can block the interaction between receptors and ligands, agonist antibodies that mimic natural ligands to activate cell signaling are still out of reach. In addition, drug developers are still involved in antibody-protein fusion biologics, and some antibodies fused with cytokines, receptor ligands, peptides, etc. may also open up new possibilities. For the research and development of antibody drugs in my country, the speed of domestic multi-target new drugs is close to that of global research and development, and a number of global original new drugs have emerged. Although the current domestic hot target track is crowded, differentiated innovation is gradually emerging. I believe that with the continuous advancement of technology, more excellent antibody drugs will appear, bringing more treatment options to patients.
Reference materials:
1.https://www.nature.com/articles/d41573-021-00079-7
