The next bombshell: 'PD-1 + ADC', Kelun, Hengrui are going to win numbness?

For a long time, the market has had big questions and differences about Merck's continuous investment in the injection of Colognet Patai ADC, in addition to recognizing the company's technology platform and pipeline, is there any deeper reason?

On February 2, Kelun Pharmaceutical's latest exchange minutes said the most concerned issues in the market. Management mentioned: "Merck values Colombert ADC and, to a large extent, the potential of combining with K drugs, which can further extend the life cycle of K drugs and continue to maintain the status of K drugs."

This answer also leads us to think about the domestic ADC competition pattern and even the layout of some PD-1 pharmaceutical companies.

01

ADC fundamentals, there are obvious differences between different ADCs

At present, ADC drugs have broad prospects in the treatment of solid tumors and hematological tumors, and they are essentially "precision amplified" chemotherapy.

Since 2019-2020, the ADC drug R&D boom has risen, and the number of domestic R&D pipelines has experienced explosive growth in 2021-2022. Up to now, NMPA has accepted more than 80 new ADC drugs.

From the perspective of the scale of the number of pipelines under development, the ADC field gives a very involuted feeling, but it is not.

As we all know, ADC drugs are formed by linking highly specific monoclonal antibodies (antibodies) and highly active small molecule toxic drugs (payloads) through linkers.

The structure seems simple, but the design is relatively difficult. The use of different antibodies, different linkers, and different toxin drugs will affect the efficacy of ADC drugs.

Although the antibody parts of Kadcyla (TDM1) and Enhertu (DS-8201) are the same anti-Her2-targeted drug trastuzumab, the clinical trial data of the two are very different due to the differences in small molecules, linkers, conjugation methods, DAR values and many other designs.

According to the Southwest Securities Research Report, Kadcyla is formed by trastuzumab and the chemotherapy drug metatancin (DM1), which inhibits microtubule aggregation, connected by a thioether bond, with a DAR value of about 4; Enhertu uses a tetrapeptide linker, which can be cleaved by proteases in cells, and the small molecule DXd, a novel DNA topoisomerase I inhibitor exatecan (esartecan derivative), with a DAR value of about 8.

Enhertu, as a latecomer, not only replaced Kadcyla as the preferred regimen for second-line therapy for HER2-positive breast cancer in the United States, but also some institutions predict that the peak sales of the two will more than double.

Therefore, the core competitiveness of innovative drug companies in the ADC field depends to a large extent on their own technology platforms and clinical development strategies.

It is worth noting that ADCs are also resistant to drugs, and many studies have failed to replace standard chemotherapy with ADCs.

Actively exploring combination drugs has become the core way to extend the drug treatment window of ADC and expand indications.

02

The endowment of PD1+ADC: first-line therapy for major cancers

Tumors also have "hot and cold", and the two can be distinguished by the content of immune cells in tumor tissues (the degree of confrontation between tumor cells and immune cells, where the core indicator is the degree of invasion of tumor by T cells).

Because hot tumors highly express PD-L1 protein binds to PD-1 receptors and inhibits T cells, immunotherapy led by PD-1 inhibitors can play a better role; Cold tumors are called "immune deserts" due to the lack or absence of T lymphocytes, and immunotherapy naturally does not work as it should.

For example, "cold tumors" mainly include tumors such as glioblastoma, ovarian cancer, prostate cancer and pancreatic cancer; Hot tumors mainly include breast cancer, pancreatic head cancer, etc.

This also explains to a certain extent why PD-1 monotherapy has an immune response in only about 30% of patients with most cancers, so from the perspective of PD-1 combination strategy, to improve the response rate of patients' tumor cells, the best combination is drugs that can "heat" tumors.

ADCs have the ability to "heat" tumors. According to the data of a clinical trial in which TDM1 was combined with PD-1 and CTLA-4, the agonists in ADC can trigger innate immunity and acquired immunity, so that a large number of T cells infiltrate tumors, thereby improving the effect of immunotherapy.

At present, clinical trial data in a number of cancer types show that PD-1 combined with ADC has shown excellent efficacy, and even has the strength to impact the first-line treatment standard in some cancers.

Among the global MNC, Merck Sharp & Dohme has the most powerful layout "PD-1+ADC", which not only acquired Seattle Gene at a premium of $400 billion earlier, but also launched a number of cooperation with Kelun, all in order to consolidate the status of its K drug "new drug king".

Merck and AstraZeneca have made positive progress in exploring the "PD-1+ADC" treatment regimen, and the two parties have initiated the phase III clinical trial of DS-1062 (Trop2 ADC) in combination with K drug (PD-1) in the first-line treatment of PD-L1-positive advanced/metastatic NSCLC to replace the existing standard therapy of chemotherapy.

The Phase III clinical trial of this combination was carried out thanks to excellent data in Phase Ib: the remission rate (ORR) was 37%, and the ORR for platinum-based chemotherapy was 41%; It is particularly effective as first-line therapy, with a disease control rate (DCR) of 100%.

In addition, Merck has chosen to cooperate with Gilead in the field of triple-negative breast cancer to impact the first-line treatment of triple-negative breast cancer through the clinical exploration of K drug and Trodelvy combination (Trodelvy has been approved as a second-line therapy).

Looking back at China, the "PD-1+ADC" combination of the two domestic innovative pharmaceutical companies is also quite interesting.

In 2022, Remegen released a preliminary stage Ib/II result (48 subjects) of RC-2 (HER-1 ADC) combined with Junshi Biologics teripulimab (PD-41 monoclonal antibody) for locally advanced or metastatic urothelial carcinoma (UC): ORR up to 71.8% and CR of 7.69%.

Clinical data showed that RC-48 and teripulimab monotherapy in advanced UC had ORRs of 50.5% and 26%, respectively,

RC-48 monotherapy ≥ grade 3 TRAE was 54.2%.

The combination therapy of the two showed the effect of "1+1>2", which not only significantly improved at the ORR data level, but also improved the safety (the incidence of TRAE grade 3 was 36.59% in ≥)

03

Players who have already been approved for PD-1 cannot be taken lightly

In 2022, the PD-(L)1 of Akeso, Yuheng Pharmaceutical, and CStone Pharmaceuticals directly abandoned medical insurance negotiations.

Although the latecomers of PD-1 missed the opportunity to earn the dividends of the times, they were still able to smooth their initial R&D expenses from "PD-1 combined with XXX".

For example, Akeso's péamplimab, through the combination promotion strategy of Chia Tai Tianqing's strong commercialization ability & "anlotinib +", the product sales amount in the first half of the year was nearly 2 million yuan, once catching up with Junshi Biologics' 97 million.

From some enterprises with leading ADC pipeline layout in China, it seems that it is not difficult to see the space for the future existence of the "ADC+PD-1" strategy.

Hengrui Pharmaceutical is not only the domestic leader in PD-1 commercialization, but also the company with the largest clinical ADC pipeline, including HER2, cMET, Trop2, etc. If the above-mentioned Merck K drugs are combined with AstraZeneca and Gilead Trop2 ADC as a reference, it is not ruled out that Hengrui Pharmaceutical will continue this idea in the future. However, Hengrui Pharmaceutical has carried out SHR-A1811 (HER2 ADC) and SHR-1701 (PD-L1/TGF-β fusion protein) in clinical trials, and there are already signs of exploration.

Biotech companies Lepu Biotech (Meiyake) and Kelunbotai featuring ADC pipelines have PD-1 pipelines in the commercial stage, among which the combination of KL-A167 injection (PD-1) and SKB264 (Trop2 ADC) for injection for the treatment of non-small cell lung cancer has been approved for clinical trials.

Duoxi Biologics and Remegen Biologics have cooperated with Junshi Biologics, the rights of Trop2 ADC in Asia except Japan and South Korea have been introduced by Junshi Biologics, and Remegen Biologics' RC48 and Junshi Biologics' teripulimab have been jointly explored.

The other two PD-1 tigers are also not to be outdone, Innovent has two ADCs in the clinical stage, namely IBI-343 (CDN18.2 ADC) and IBI-354 (HER2 ADC); BeiGene introduced Ambrx's fixed-site coupling technology while tracking the development of immunostimulatory ADCs.

Conclusion: Merck can consolidate the position of K drugs through joint use, can't domestic biotech companies "drive" PD-1 pipelines through their core ADC products to recover R&D costs or even make a profit?

The rise of ADC is the trend of the times, and at present, it may be a good thing that ADC new drugs have their own PD-1.