ADC circuit ushered in a new era of "flying wings.

Previously, Bailey Tianheng authorized the BL-B01D1 of dual-antibody ADC products to Bristome Squibb with a potential total transaction volume of up to US $8.4 billion, which not only set a new record for a single project of domestic innovative drugs, but also was an important milestone for domestic dual-antibody ADC to go abroad for the first time.

coincidentally, FDA approved Mercadon k drug (pembrolizumab, Keytruda) combined with Padcev(Nectin-4 ADC) for first-line treatment of locally advanced or metastatic urothelial cancer. due to its excellent curative effect (OS and PFS almost doubled), it was approved nearly 5 months earlier than the original PDUFA date of may 9, 2024.

while opening up a unique path of dual anti-ADC, while strongly combining with PD-1 monoclonal antibody, the gears of ADC drug fate began to turn.

01

unique path,

Step into a new era of dual-resistance ADC

ADC drugs, known as "biological missiles", have become a hot research and development topic due to the high targeting of monoclonal antibodies and the strong lethality of chemotherapy drugs, leading a new era of targeted tumor therapy.

In recent years, the amount of transactions authorized by domestic ADC has repeatedly reached new highs. For example, when Baili Tianheng double BL-B01D1 goes to sea, BMS just takes a fancy to the potential of double anti-ADC.

ADC drugs are composed of three parts: antibody, small molecule cytotoxin and linker. Different modular design will produce different curative effects. Among them, the antibody part is mainly monoclonal antibody, which is responsible for selective recognition of cancer cell surface antigen.

now, pharmaceutical companies have adopted different development strategies to replace the original monoclonal antibody ADC antibody part with double antibody, which has played a greater advantage: double target can block two different signaling pathways, enhance cell killing toxicity, overcome drug resistance, improve endocytosis efficiency and enhance killing effect.

Image source: GF Securities

According to different targets, dual antibody ADCs can be divided into two types.

One type is aimed at different targets, characterized by stronger specificity, better therapeutic effect and increased drug safety. For example, Bailey Tianheng BL-B01D1 (target EGFR/HER3) and Tongyi Pharmaceutical CBP-1008 (target FRα/TRPV6) belong to this category of drugs.

in the phase I study of treating non-small cell lung cancer patients who have undergone a large number of front-line treatments, the BL-B01D1 has shown excellent curative effect and can effectively solve the long-standing EGFR-TKI drug resistance problem: the median PFS for EGFR mutant patients is 6.9 months, ORR is 63.2, DCR is 89.5; The median PFS of EGFR wild-type patients is 5.2 months, ORR is 44.0, the DCR is 94.0 percent.

The other is a dual epitope for the same target. By combining antigens with poor internalization and good internalization at the same time, the internalization efficiency is improved, and the drug resistance caused by the decline of corresponding receptor expression can be overcome. Typical such as HER2 dual-bit dual-anti-ADC, including Corning Jerry, Baiji Shenzhou and Xuan Bamboo Biology, etc. have a layout.

For example, the JSKN003 modified and designed by Corning Jerry on the basis of KN026 has stronger endocytic activity and bystander effect and better serum stability than similar drugs, effectively expanding the therapeutic window. showed a favorable safety profile and efficacy similar to DS-8201 in both high and low HER2 expressing cells (CDX + PDX model).

according to the phase I clinical results of JSKN003 treatment of HER2 expression advanced solid tumors, the ORR for HER2 high expression breast cancer patients is 75%, and the ORR for HER2 low expression breast cancer patients is 40%. This data and ADC "drug king" DS-8201 and other competing products, the efficacy of non-inferior, and has a safety advantage.

it can be seen that both the huge BD deal reached between Baili Tianheng and BMS and the excellent curative effect announced by the existing dual-antibody ADC, all indicate that the dual-antibody ADC research and development boom will be detonated in the near future and lead the ADC track into a new era.

02

strong combination,

Opening a new chapter of "PD-1 + ADC"

The second new era of the ADC circuit was unveiled by Merck's "PD-1 + ADC" combination therapy.

recently, FDA approved Mercadon k drug combined with Padcev for first-line treatment of locally advanced or metastatic urothelial cancer (mUC), nearly 5 months earlier than the original PDUFA date of may 9, 2024.

according to the EV-302 results of phase iii clinical study released by 2023 ESMO conference, the median OS of k drug combined with Padcev group compared with platinum chemotherapy group was 31.5 months vs16.1 months, the median PFS was 12.5 months vs6.3 months, and both OS and PFS achieved double benefits.

The FDA approved the combination therapy nearly five months in advance based on its excellent efficacy.

Image source: Guolian Securities

In fact, before PD-(L)1 + ADC combination therapy entered the historical stage, "PD-1 + chemotherapy" was once a hot topic in the research and development of tumor combination therapy.

however, in the first-line treatment of mUC indications, there have been a number of PD-1 failed, including atrizumab + chemotherapy, k + chemotherapy, duvalizumab + Imjudo(CTLA-4) double immunotherapy all ended in failure.

Instead, K-drug combined with targeted Nectin-4 of ADC drug Padcev took the lead in hitting the line with the efficacy of "1-1-2", becoming the world's first approved PD-1-ADC combination therapy.

Why does PD-(L)1 + ADC combination therapy become a drug and exert higher efficacy than monotherapy?

According to the Debang Securities Research Report, ADC combination therapy mainly includes chemotherapy, targeted therapy, anti-angiogenic agents and immunotherapy four categories. From the perspective of mechanism of action, the simultaneous use of ADC and molecular targeted drugs can lead to the simultaneous blockade of multiple oncogenic pathways or the dual blockade of a specific pathway, thereby more effectively inhibiting downstream signaling.

ADCs can be used in combination with immunotherapy due to the different mechanisms of ADCs with cytotoxic payloads, which facilitate immune monitoring rather than immune tolerance, thereby increasing the efficacy of PD-1/PD-L1 mAbs.

after tasting the benefits of PD-1 + ADC combination therapy, mershadon has accelerated the introduction of ADC pipelines in the past two years. for example, it has made a lot of big moves such as betting heavily on various ADC projects in columbo and spending 22 billion us dollars to cooperate with the first three co-development of three ADC.

"The heart of Mercadon is well known", while building the "ADC empire", by carrying out clinical trials of the core product K drug combined with ADC, to extend the life cycle of K drug and consolidate the market advantage.

Image source: Minsheng Securities

coincidentally, roche and AstraZeneca are currently carrying out a number of clinical trials of PD-(L)1 + ADC combination therapy in China. the former has carried out a trial of atrizumab combined with HER2 ADC drug Kadcyla treatment of breast cancer, while the latter has carried out a DS-1062 of duvalizumab combined with DS-8201.

the reason why BMS bet heavily on Baili Tianheng BL-B01D1 is not only to take a fancy to the market potential of dual anti-ADC, but also to carry out BL-B01D1 combination with its pillar product o drug.

After all, for the PD-1 monoclonal antibody market, the patents for drug K and drug O will both expire in a few years, which means facing competition from biosimilars. What's more, the special mechanism of ADC can be combined with PD-(L)1 monoclonal antibody in many large indications to play a huge therapeutic potential, the market space is broad.

03

pharmaceutical companies compete,

Vidicetuzumab is a "hot item"

in the face of the huge market space shown by PD-(L)1 + ADC combination therapy, domestic pharmaceutical companies will certainly not let it go easily.

especially those pharmaceutical companies that have commercialized PD-(L)1, PD-1 the "four little dragons" (junshi biology, cinda biology, hengrui medicine, baiji shenzhou), as well as yuheng biology and fuhong hanlin, are carrying out clinical trials of combined ADC drugs. many pharmaceutical companies have chosen to combine with rongchang biology's vidicetuzumab.

Although Vidicetuzumab is a popular HER2 ADC, it has been differentiated and approved for gastric cancer and urothelial cancer indications. This makes the indications targeted by PD-1 pharmaceutical companies in combination with Vidicetuzumab, mainly urothelial cancer, including Junshi Treprizumab, Henricarilizumab and Basilizumab.

At present, the more advanced research and development progress is treprozumab combined with vidicetuzumab in the treatment of urothelial cancer, has been in the clinical phase III stage, and showed good efficacy and safety. The results of phase Ib/II study showed that cORR was 73.2. In HER2 IHC 3 +/2 + and IHC 1 + subgroups, ORR was 83.3 and 64.3, respectively, PFS was 9.2 months, and 2-year overall survival rate was 63.2.

Image source: Minsheng Securities

Of course, there are some differentiated clinical trials of combination therapies. for example, the main indications for yuheng biology's seperizumab combined with vedicetuzumab are biliary tract cancer and cervical cancer, of which HER2 expression cervical cancer treated in PD-1/PD-L1 with failure of at least first-line platinum-containing standard treatment has been approved to carry out phase ii clinical treatment in July 2023.

The active participation of ADC pharmaceutical companies is naturally indispensable for the layout of PD-(L)1 + ADC combination therapy.

For example, Koren Pharmaceuticals has developed PD-L1 inhibitor KL-A167 in combination with Korenbotai TROP2-ADCClinical trials of the drug SKB264 for the treatment of breast cancer (TNBC) and non-small cell lung cancer, in which phase I studies showed that the ORR of first-line treatment of TNBC patients was 86% and DCR was 100.

in addition, baiotai has carried out a clinical trial of PD-1 monoclonal antibody BAT1306 combined with its own HER2 ADC drug BAT8001 in the treatment of HER2 positive solid tumors; Rongchang Biology has also carried out a clinical trial of its own drug PD-L1 monoclonal antibody RC98 combined with vedicetuzumab in the treatment of gastric cancer.

04

Conclusion

it is understandable that the ADC field has ushered in a new era of "two wings flying together" in the combination therapy of dual anti-ADC and PD-(L)1 + ADC.

to keep up with the participants of this era, there are PD-1 pharmaceutical companies, there are new generation of pharmaceutical companies focusing on ADC new drug research and development, but also take advantage of the opportunity to enter the ADC track of the pharmaceutical companies, can be described as a variety.

But no matter what type of pharmaceutical companies, they are developing new drugs with better efficacy and better quality based on solving unmet clinical needs. And urothelial cancer indications, seems to have become two new era "stepping stone".

Reference:

1. the company's financial report, announcement, official website

2. "20230130-Baili Tianheng -688506-Potential Global Large Variety B01D1, Multiple Differentiated Research Projects", Guangfa Securities

3. "20230614-PD-1PD-L1 special study on pharmaceutical and biological industry: domestic and foreign sales continue to grow, perioperative and combined ADC may open up new space", Minsheng securities

4. Guolian Securities, Debang Securities Research Report