How to become the overlord in the field of oncology? In the past few years, Johnson & Johnson has taught the market a lesson in the field of myeloma.

From monoclonal antibodies to CAR-T and then to bispecific antibodies, the number of treatment lines has been extended from the first line to the last line: through the progressive and broad and precise layout, Johnson & Johnson has sought a higher moat for itself and also given latecomers a smaller breakthrough gap.

The growth of the overlord of multiple myeloma is in progress. At present, Johnson & Johnson's layered handover is taking shape, and the revenue of related products in 2023 has exceeded the 10 billion US dollar mark.

But such a story is destined not to belong only to Johnson & Johnson. Any powerful pharmaceutical company has its own unique core capabilities, corresponding to a smooth product portfolio echelon management system and "playing style".

It can be seen that many powerful pharmaceutical companies are also telling such stories, such as BeiGene, which is well known in the market.

In the field of hematological tumors, with BTK inhibitor zabutinib as the basic base, BeiGene's BCL2 inhibitors, BTK CDAC and other pipelines are accelerating, and a larger map has emerged.

This may also indicate that the competition for tumor drugs has reached a new height without knowing it.

In the era of technological exploration, new drug combinations emerge in an endless stream, which puts higher demands on the defenders; "defenders" will naturally not sit and wait for death, but will make arrangements in advance and actively adapt to changes in demand.

Under this logic, the competition for tumor drugs continues to rise. BeiGene's layout of hematological tumors also allows us to see this trend more clearly.

Especially in the field of CLL, as the largest indication for BTK inhibitor drugs, competition is surging. At this year's ASH Annual Meeting, the AMPLIFY Phase 3 study evaluated the combination of "acalabrutinib (acotinib) + venetoclax" as a fixed course of treatment for newly diagnosed CLL, which attracted much attention.

Although the logic of the "A+V" combination has yet to be verified, at the same time, BeiGene is telling the market that new variables have emerged.

At the ASH Annual Meeting, BeiGene released Phase 1/1b study data showing that the "BCL-2 inhibitor sonrotoclax + zabutinib" (hereinafter referred to as ZS) combination has the characteristics of "fast onset" and "deep and lasting relief".

Specifically:

The combination regimen did not detect a high incidence of minimal residual disease (uMRD) and appeared earlier. The uMRD4 rate reached 78% at 24 weeks of treatment, and the degree of relief continued to deepen over time to 48 weeks (91%). As of the data cutoff date (median follow-up time was 19.4 months), no patient turned from MRD4 negative to MRD4 positive.

Since the uMRD4 rate is closely related to the patient's progression-free survival (PFS) and overall survival (OS), it is an important parameter for evaluating treatment effect and prognosis. Therefore, the above data reflects the combat effectiveness of the "ZS" combination and also indicates that it may have higher dominance in the future.

In contrast, at a similar time point, patients treated with ZS achieved a more favorable uMRD4 than those treated with AV/AVO/chemotherapy. Although not head-to-head data, it is relatively convincing considering that the Phase 1/1b study is one of the most high-risk characteristic groups included in the world.

The outstanding safety data further guarantees this. In the Phase 1/1b study, most TEAEs of the ZS combination were low-grade, and the most common ≥3 TEAEs were mostly transient.

In addition, the ZS combination registration clinical trial for TN CLL is the only Phase 3 trial in the world aimed at proving PFS superiority over the standard treatment of venetoclax+obinutuzumab, so it is expected to consolidate BeiGene's position in the TN CLL market in the future.

The logic of driving industry competition to a high degree is also reflected in BeiGene's BTK CDAC BGB-16673.

In the past few years, the biggest disruptor in the BTKi market is undoubtedly the emergence of the non-covalent BTK inhibitor Pitobutinib, which not only solves the needs of drug-resistant patients and achieves dislocation competition; it is also likely to subvert the pattern of covalent inhibitors.

Based on this, BeiGene has played the BGB-16673 card in a targeted manner. At this year's ASH annual meeting, BGB-16673 also showed its edge.

Specifically, BGB-16673 still showed outstanding safety and tolerability in the R/R CLL/SLL patient population who had previously received multiple lines of treatment. No cardiac toxicity and side effects of traditional BTK inhibitors have been seen, and the proportion of bleeding is also relatively low.

At the same time, BGB-16673 has outstanding anti-tumor activity. In the cohort of CLL/SLL patients (median number of previous treatment lines: 4), BGB-16673 achieved an ORR of 94% at a dose of 200mg, and its PFS estimate is more favorable than that of Pitobutinib.

In the more difficult-to-treat Richter’s transformation patients, it also showed good activity, with an ORR rate of 58.3%, which is potentially better than Pitobrutinib. Also at this year’s ASH Annual Meeting, Pitobrutinib announced an ORR of about 50% for this group of patients. Based on the data from related studies, BeiGene has planned to conduct a head-to-head study of BGB-16673 and Pitobrutinib in 2025.

Obviously, the emergence of BGB-16673 has given more answers to the direction of the BTKi dynasty change. As for BeiGene itself, through the layout of three core products, it has covered the entire treatment process of CLL patients.

In the game of the BTKi market, with the subtle conversion of "offensive" and "defensive", the complexity and difficulty of competition have increased significantly.

In fact, for the leading oncology pharmaceutical companies, the focus is not just a single pipeline, but their ability to work together. Because these pharmaceutical companies can often maximize the potential of each pipeline through a combination of strong and strong combinations. This is also the core of the extensive and precise layout of the leading tumor pharmaceutical companies.

The same is true for BeiGene. It can be seen that the three cards launched by the company, zabutinib, sonrotoclax, and BGB-16673, are not only for defense, but also for "offense" to achieve more "enclosure" plans in the field of hematological tumors.

The core idea is to meet the treatment needs of various lines on the one hand, and expand to new indications with significant unmet medical needs on the other hand through different combinations of these three differentiated molecules.

For example, in BeiGene's conception, sonrotoclax aims to become the BCL-2 inhibitor with the widest coverage of indications:

In addition to maintaining and improving its leadership in CLL and other B-cell malignancies, it will also expand to AML and may be the first BCL-2 inhibitor approved in the indication of MM carrying t(11,14).

As shown in the figure below, the current Phase 3 clinical trials of sonrotoclax for untreated CLL/SLL (TN CLL/SLL) and relapsed or refractory MCL (R/R MCL) are being accelerated, and these studies are all conducted in combination with zanubrutinib.

In addition, the Phase 3 clinical trials of sonrotoclax for indications such as TN WM and 1L AML through different combinations are also on the agenda.

In the CaDAnCe-101 clinical trial, we can also see BeiGene's high expectations for BGB-16673.

First, it is to "go back" and solve the drug resistance problem of multiple indications. In its CaDAnCe-101 clinical trial, a total of 7 cohorts were set up, covering different types of B-cell hematological tumors.

Second, it is to "go forward". The 1C cohort in the CaDAnCe-101 clinical trial has been exploring the earlier line treatment of BGB-16673 monotherapy in the BTK first-line cohort. Moreover, it is possible to go further in the future and promote the "de-chemotherapy" of B-cell tumors by combining with sonrotoclax, zabutinib and CD20xCD3 bispecific antibodies.

In other words, BeiGene aims to push the overall competition in the field of hematological tumors to a new strategic height through a carefully planned pipeline combination strategy.

Although it is still unknown whether BeiGene's ambition can be realized, in any case, it provides us with another dimension to understand the competition in hematological tumors: ecological warfare will bring a higher ceiling.

The emergence of BeiGene's sonrotoclax, BTK CDAC and other pipelines is not accidental. In previous plans, the company has clearly mentioned that the future growth of hematological tumors is a "multi-step strategy":

The first step is to consolidate the leadership position through zabutinib.
The second step is to expand the leadership position through sonrotoclax and BTK CDAC.
The third step is to expand the territory through different combinations of 3 differentiated molecules.
The fourth step is to maximize its influence in the field of hematological tumors.

Now, with the rapid rise of BeiGene, it has reached the stage of accelerating strategic advancement and embracing the next wave of products.

On the one hand, Zebutinib has performed strongly. It is the new generation of BTK inhibitor with the widest approved indications in the world and has achieved leadership in the new CLL patient market, which supports BeiGene's expansion logic;

On the other hand, its unique clinical quality and efficiency in the world ensure that it can widen the gap with competitors while making extensive layout.

A typical example is that the enrollment of patients in the key clinical trial of sonrotoclax has expanded from 800 at the end of the first quarter to more than 1,600 at present. In other words, BeiGene has guaranteed an enrollment efficiency of about 100 people per month.

This is an amazing speed. According to the McKinsey report, even for large varieties such as PD-1, the average monthly enrollment of patients is about 0.3-0.5 worldwide, while patients such as GLP-1, which are easier to enroll, have an average of about 2 per month. The blood tumors targeted by sonrotoclax have a relatively smaller patient scale and greater difficulty in enrollment.

For this reason, BeiGene's pipelines such as sonrotoclax and BTK CDAC will accelerate their appearance in the public's field of vision. Even more pipelines in the field of solid tumors, not only blood tumors.

At the recent San Antonio Breast Cancer Symposium, the CDK4 inhibitor BGB-43395 led the lineup, which showed us the comprehensiveness and advancement speed of BeiGene's layout in the field of breast cancer. So far, more than 120 patients have been enrolled in the clinical trial of BGB-43395 one year after its launch, which is enough to catch up with the pace of competitors.

This also means that the story of the continuous increase in the level of competition has appeared not only in the field of blood tumors, but also in the field of solid tumors.

This also reflects a trend of the times:

In the era of technological navigation in the biopharmaceutical industry, the iteration of technology itself is very rapid, and the ideas and heights of competition are constantly changing. With the emergence and maturity of more ambitious pharmaceutical companies like BeiGene, this process has been further accelerated.

How pharmaceutical companies can do more is driven by "certainty", which is a natural result of the advantages accumulated by companies and teams over the years. This requires more pharmaceutical companies to improve themselves more comprehensively. Only by building more core capabilities can there be more possibilities in the future.

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