RATIONALE 306 to RATIONALE 305 Operation path for Beigene

Beigene (06160.HK) announced on April 20, 2023 that global Phase 3 clinical trial RATIONALE305 had reached the primary endpoint. Regardless of the expression status of PD-L1, tirelizumab (Chinese trade name: Beigene?) was used in patients receiving chemotherapy. Overall survival (OS) was superior in patients with advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma treated with combination chemotherapy, and no new safety warnings were found.

High starting point, facing globalization

Beigene carried out RATIONALE306 research and announced on April 27, "RATIONALE306, its indigenously developed PD-1 monoclonal antibody Biozem (Tirelizumab) in combination with chemotherapy in the treatment of first-line advanced or metastatic esophageal squamous cell carcinoma (ESCC), achieved the primary endpoint of overall survival (OS) in the global Phase 3 clinical trial." It can be seen from here that Beigene has conducted a series of research and development on RATIONALE, which has been upgraded from RATIONALE306 to RATIONALE305! And this research and development time, only took about a year.

Moreover, this adaptation symptom has further expanded from the treatment of first-line advanced or metastatic esophageal squamous cell carcinoma (ESCC) to advanced unresectable or metastatic gastric or gastroesophageal conjunctive adenocarcinoma (G/GEJ), which is really rapid progress. Not only that, but it's basically a randomized, double-blind, placebo-controlled, global Phase 3 trial, which, as you can see, is starting from a pretty high base!

Why stick to such a high starting point? Esophageal cancer is a common malignant tumor, and more than 90% of esophageal cancers are esophageal squamous cell carcinoma (ESCC). In particular, China is a region with a high risk of esophageal cancer in the world. The annual number of new cases accounts for about 53.7% of the world, and the number of death cases is also quite large, accounting for about 55.7% of the world. And in the case of stomach cancer, this cancer, not only is the third most common cause of cancer death worldwide, but it's also very difficult to treat in advanced stages.

As some media outlets have noted, "Approximately 15% to 20% of advanced gastric and gastroesophageal junction cancers (especially prevalent in East Asia) are HER2-positive. Since Herceptin combined with cisplatin and fluorouracil was approved by the FDA for first-line treatment of Her2-positive metastatic gastric cancer in 2010, both Herceptin relapsed after treatment and Her2-negative patients, Treatment options are very limited." Because it is difficult to cure, it is necessary to find a new way to achieve a certain breakthrough, in order to solve the problem.

Tirelizumab, a humanized IgG4 anti-PD-1 monoclonal antibody, is specifically designed to minimize binding of the antibody to the Fc-γ (FC-γ) receptor on macrophages. And it has been shown in previous studies that PD-1 binding to FC-γ receptors on macrophages "activates antibody-dependent macrophage-mediated T-effector cell killing, thereby reducing the antitumor activity of PD-1 antibodies," which is to say, has a therapeutic positive effect.

The superior outcome of patient survival further highlights the important value of this research and development

Drug therapy and research and development are inseparable from how to expand the efficacy of patients. This is especially true for cancer patients, where it is important to find ways to further extend this overall survival (OS). On the surface, RATIONALE306 study expanded the overall survival (OS) of patients with esophageal squamous cell carcinoma (ESCC). This is a local breakthrough, but such a breakthrough is not easy!

In fact, when it is upgraded from RATIONALE306 to RATIONALE305, the indication is further expanded. At this time, it is not a small overall survival (OS) optimization problem, but a series of cumulative improvements. From a point of accumulation, will form a more benign surface, its market will become larger!

And don't underestimate the improvement in tislelizumab in combination with chemotherapy in the ITT population, because this patient trial is global! In other words, once the overall effect is more stable, it is more positive.

Nevertheless, Beigene has made significant progress in these areas, namely, Beigene has been approved in China for ten indications, but its market channel weaknesses are also obvious, as to date, Tirelizumab has not been approved outside of China. From these aspects, it is necessary to consider the problem from the strategic height of market globalization, do a good job in this aspect of layout! Therefore, its previous partnership with Novartis in 2021 to develop, manufacture and commercialize tirelizumab in multiple countries was a good strategic choice!

Because of the superior efficacy of patients' survival period, the value of this R&D strategy of pharmaceutical companies will be further highlighted, and the market development potential will become larger and smoother in the future, which can accelerate globalization.

Research and development needs to control risks, reduce costs and form its own characteristics, in order to be more likely to succeed

What can be learned from the research and development path of Beigene? Which aspects can be used for reference by similar pharmaceutical companies? In addition to the technical path, the steps and pace of this research and development, or to adapt to this stage of development. Through a series of research and development, the scattered resources are pooled, the chaotic market is reorganized and orderly, so that the professional treatment tends to a clear refinement and deep stratification. Earlier, the cancer drug Pronabrine was not approved, presumably because it had not been tested in patients in a global market like Beigene. If there is a clear breakthrough in Pronabulil, the drug's chances of getting approved will increase considerably, rather than getting stuck.

There are no more than two kinds of research and development, one is forward research and development, the other is backward research and development. Forward research and development is a kind of cumulative development. Not only accumulate popularity, accumulate market, accumulate resources, but also accumulate experience. It can see very clearly its own problem, that is, these drugs are not enough! Knowing when to go public, rather than hitting the road like a blind guy trying to get approved, is not. The success or failure of research and development depends on the details. It is very important to make clear the rules and regulations.

On the other hand, in order to achieve the success of R&D, in addition to technological innovation reserves and new discoveries, we also need to find ways to save costs, save time, and consolidate resources, so that all aspects of R&D need to cooperate more closely and control the R&D risks more clearly.

Beigene started from RATIONALE306 research to RATIONALE305, a global phase 3 clinical trial. On the surface, the two are not closely related. Actually, quite a bit. Because these cancers, especially esophageal squamous cell carcinoma (ESCC), are associated with this stomach cancer. Moreover, once cancer has spread and metastasized, it is useless to say that it is unrelated.

Therefore, from the point of view of reducing the risk of research and development, according to their own conditions and resources, to choose the most suitable for the current path of research and development, can become easier and easier to achieve success.