Edited by the e-trade medical content team
In 2012, the current oneWang Lai, Senior Vice President and Global Head of R&D at BeiGeneWhen I was looking at the project at the American Association for Cancer Research, I noticed a BTK inhibitor - ibrutinib.
Dr. Lai Wang, Senior Vice President and Head of Global R&D, BeiGene.
Source: BeiGene's official website.
At that time, ibrutinib was not yet on the market, and the study data showed that its selectivity and absorption needed to be improved. Wang Lai, who has a keen sense of business, immediately realized that this was an opportunity.
After returning to China, Wang Lai immediately set out to establish a BTK inhibitor project and proposed to make me better.
In December 2022, BeiGene's BTK inhibitor zanubrutinib won a head-to-head clinical battle with ibrutinib, not only achieving the "me better" vision, but also becoming a "best in class" product at this stage.
In its first full year as a BIC product, zanubrutinib reached $1.3 billion in sales revenue and officially became a member of the "Billion Dollar Molecule" club.
From the code name "BGB-3111".
BeiGene's early development of BTK inhibitors was carried out by:Zhiwei Wang, who is also one of the inventors of zanubrutinib, is in charge.
Zhiwei Wang is a R&D staff brought by the company's founder, Ou Leiqiang, from his previous company, BioDuro, and has now become senior vice president and head of chemical research at BeiGene.
Dr. Zhiwei Wang, Senior Vice President and Head of Chemical Research at BeiGene.
Source: BeiGene's official website.
In June 2012, BeiGene officially approved the approval of BTK inhibitors. "We made thousands of compounds. One day when we were continuing to work on compounds, a colleague reported that a certain compound was very unstable and difficult to make. It seems to have been seen, but it can't be separated, and then it becomes messy, complicated, and no longer a single product. Wang Zhiwei said in a later interview.
He also said that researchers should not abandon any "so-called" failed trial, and should always summarize some useful information from the failed trial.
It was also during this failure that the team discovered that one of the double bonds in the compound was unstable. After reducing this double bond, the product is single. This discovery provides a valid clue for the subsequent invention of the zanubrutinib molecule.
From the beginning of the project, after about half a year of hard workWang Zhiwei and his team screened out a compound that only inhibits the BTK target, namely zanubrutinib, with the internal code name BGB-3111It is the 3111th compound synthesized by the R&D team since the establishment of BeiGene, and this number also reveals the team's hard work and perseverance.
In fact, half a year is not a long time for drug discovery, the first step in the development of new drugs. BeiGene's team of scientists has adopted an emerging detection technology, that is, based on the covalent binding of the BTK inhibitor to the target, using "antibody technology" to directly analyze how many targets have not yet been occupied by the compound. This technology greatly shortens the previous preclinical animal research on a monthly basis to a daily basis.
It is reported that among the series of compounds selected by Wang Zhiwei and his team at that time, BGB-3111 exhibited the highest selectivity, and at the same time, the exposure in vivo was also the highest. This indicates that BGB-3111 will bring better efficacy and safety after becoming a drug, and reduce the risk caused by off-target
Clinical stage
After screening BGB-3111, BeiGene quickly completed patent submissions and formulation studies to accelerate the advancement of the product to the clinical stage.
In 2013, Wang Lai took the project to Australia in the southern hemisphere. There, he was introduced by local experts to Andrew Robert and Constantine Tam, doctors who had done clinical studies on ibrutinib.
Although, at that time, the project that Wang Lai brought to Australia was BGB-283,However, Constantine Tam showed great interest in BGB-3111, and eventually became the leading PI for BGB-3111 overseas.
peter maccallum cancer centre, victoria, australia
Constantine Tam, MD.
The picture comes from the Internet.
In 2014, zanubrutinib officially entered the clinical stage in Australia. In August of that year, the world's first patient dosing was completed.
In the same year, at the American Society of Hematology (ASH) annual meeting in December, zanubrutinib made its first public appearance in the world. Data from a Phase I clinical study of the drug in Australia was released, and Constantine Tam conducted an oral presentation on the clinical trial.
Source: Pharmaceutical Cube Plus
Subsequently, the clinical trial of zanubrutinib continued to advance in an orderly manner. After the domestic drug policy reform in 2015, BeiGene released zanubrutinib into Phase II clinical trials in China.
In 2016, Professor Zhu Jun, Secretary of the Party Committee and Director of the Department of Lymphoma at Peking University Cancer Hospital, and his team led the study.
Professor Zhu Jun, Secretary of the Party Committee and Director of the Department of Lymphoma, Peking University Cancer Hospital.
The picture comes from the Internet.
September 2016,BeiGene has appointed Weijuan Huang as Chief Medical Officer for Hematology-Oncology responsible for late-stage clinical development of BTK inhibitors(Retired in April 2022).
Since then, BeiGene has conducted clinical trials of zanubrutinib in multiple indications in multiple regions around the world. In 2017, the global Phase III clinical trial of BGB-3111 (ASPEN study) was initiated, which directly took zanubrutinib out a positive PK with the approved blockbuster BTK inhibitor ibrutinib. The study continued for many years until in 2022, when BeiGene published the full results of the study.
In June 2019, BeiGene announced the results of a pivotal Phase 2 clinical trial in China, which showed that zanubrutinib demonstrated high activity in MCL patients, with 84% of patients achieving objective remission and 78% of patients achieving complete remission as a result of the study.
At the same time, the results of the Phase I and II clinical trials conducted around the world have also been updated, which also showed that zanubrutinib is generally tolerated and active in MCL patients.
These two clinical trials have laid the foundation for the approval of zanubrutinib in the United States, China and other countries in the future.
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In the same year that zanubrutinib officially entered the clinical phase, zanubrutinib officially entered the clinical phaseXiaojun Yan joined BeiGene to engage in pharmaceutical administration and prepare for the clinical trial and late-stage marketing of zanubrutinib and communication with the regulatory authoritiesToday, Xiaojun Yan serves as Senior Vice President and Chief Pharmaceutical Officer at BeiGene.
Xiaojun Yan, Senior Vice President and Chief Drug Officer, BeiGene.
Source: BeiGene's official website.
Research policies have a profound effect on accelerating the R&D and marketing of new drugs and entering the market as soon as possible. Yan Xiaojun's team integrates the laws and regulations between countries.
For zanubrutinib, in view of the policy differences between countries, its innovative strategy is to support the Phase 2 clinical trials and pivotal clinical trials in China and the United States through the Phase I clinical trial data in Australia, and further support the marketing applications and approvals in the United States, China, and subsequent countries through the pivotal Phase 2 clinical trial data in China.
The ultimate goal of Yan's team is to take advantage of the U.S. policy of accelerated new drug approval and use phase II clinical trials to support zanubrutinib to complete global registration in the fastest way.
In March 2015, the drug administration team led by Yan Xiaojun had the opportunity to communicate face-to-face with the FDA for the first time, which was a pre-IND communication meeting, and it was also the first face-to-face meeting between BeiGene and the FDA. Since then, the team has been traveling between China and the United States, meeting with the FDA.
With the disclosure of more active clinical trial data, the communication between Yan's team and the FDA has become smoother. The commercialization of zanubrutinib is just around the corner.
In August 2019, BeiGene announced that the U.S. FDA has accepted and granted Priority Review status to zanubrutinib for patients with mantle cell lymphoma (MCL) who have received at least one prior treatment.
In November of the same year, zanubrutinib was approved by the FDA for priority review, which was the first drug approved by BeiGene, and the first time that an innovative drug independently developed in China was approved in the United States. At the same time, the company has also officially entered the commercialization stage from the R&D stage.
In June of the following year, zanubrutinib received another round of good news, and the marketing application in China was also approved by the Food and Drug Administration.
Yan Xiaojun said at a public event after the approval of zanubrutinib that the first indication for zanubrutinib was mantle cell lymphoma, which saved the company about $3 million in registration fees by applying for orphan drug designation (ODD).
With the globalization of zanubrutinib, BeiGene has established regulatory affairs teams in the United States, Europe, Singapore, Australia, South Korea and other regions around the world. To date, zanubrutinib has been approved for multiple indications in 70 markets worldwide.
Commercialization stage
BeiGene's truly in-house commercialization team was founded in 2018, a year before the product was approved.
This year,Wu Xiaobin, a heavyweight who was then the president of Pfizer China, joined BeiGene China as the company's president and general manager of China, responsible for the commercialization of the company's products.
Dr. Xiaobin Wu, President and Chief Operating Officer of BeiGene.
Source: BeiGene's official website.
In a press conference after the first batch of zanubrutinib, Wu Xiaobin said: "The commercial team in the United States has been established and trained, and I estimate that American patients will be able to use our drug very quickly, possibly within the year." ”
According to the official website,BeiGene's Head of Commercialization in the U.S. is Josh Neiman, who joined BeiGene in July 2018 and is currently Senior Vice President, Chief Commercial Officer for North America and Europe.
Josh Neiman, Senior Vice President, Chief Commercial Officer, North America & Europe, BeiGene
Source: BeiGene's official website.
At the same time, as the final approval time in China is approaching, the domestic commercialization team is also in full swing. In 2018,Yifei Zhu, former Vice President of Sales & Marketing of Janssen China, has been appointed Vice President of BeiGene, responsible for commercial operations, sales, access and ** affairs in China. Xin Bian, former Vice President of Janssen China's Innovative Products Division, is BeiGene's Chief Commercial Officer for Greater China.
However, before zanubrutinib was approved, Zhu Yifei and Bian Xin left BeiGene (March 2019). In June 2019, BeiGene was appointedQingyi Wu, former head of Sanofi's pharmaceutical business unit, is the chief commercial officer of Greater China(Departed in September 2021).Yan Liu, former vice president and head of Specialty Pharmaceuticals Business Unit of Takeda, is vice president and head of marketing in Greater China(Retired in 2022). This year, BeiGene's global commercialization team expanded rapidly to more than 900 people.
2020 was the first full year of sales of zanubrutinib after approval, with total sales of $41.7 million in the United States. This year, the best-selling BTK inhibitor ibrutinib sold 94US$4.2 billion, more than 200 times that of zanubrutinib.
In 2021, BeiGene's sales reached 2US$5.5 billion, a year-on-year increase of more than 500%, but it is still far from surpassing zanubrutinib.
In 2022,Yin Min, former general manager of AstraZeneca's oncology division, succeeded Wu Qingyi as BeiGene's chief commercial officer for Greater China.
Min Yin, Chief Commercial Officer, BeiGene Greater China.
Source: BeiGene's official website.
With the advancement of time, more clinical data of zanubrutinib has been disclosed, more indications have been obtained, and at the same time, new market areas are being expanded, and zanubrutinib's sales are rising.
On the other hand, ibrutinib is gradually being squeezed by similar drugs in the market, and its market share is shrinking. The gap between the annual sales of zanubrutinib and ibrutinib is getting smaller and smaller.
During the 2022 American Blood Annual Meeting, BeiGene announced results from a Phase III clinical trial of zanubrutinib head-to-head ib, which demonstrated improved safety and tolerability in addition to superior efficacy. After this battle, zanubrutinib became the first BTK inhibitor of its kind to beat ibrutinib.
In 2023, AbbVie and Johnson & Johnson jointly announced plans to voluntarily withdraw two indication approvals for accelerated ibrutinib in the U.S. for patients with mantle cell lymphoma who have received at least one prior treatment**, and patients with marginal zone lymphoma who have received at least one prior anti-CD20**.
The sales of ibrutinib, which has been hit one after another, will be halved to 35 in 2023$9.6 billion (2022: $83.6 billion.)$500 million), while zanubrutinib broke into the "billion-dollar molecule" club in one fell swoop, with sales doubling from $600 million in 2022 to $1.3 billion.
Although zanubrutinib has not yet become the best-selling BTK inhibitor, judging from the sales trend of the product, this day is not far away. Of course, zanubrutinib still needs to be wary of the competition and breakthrough of other similar products.
Summary
The success of zanubrutinib cannot be attributed simply to the executives and their teams, such as in late 2012 and early 2013, when BeiGene had financial problems, the company's founder, O'Rayson, personally flew overseas to negotiate a BD deal and get cash for the company. This is also an important reason why zanubrutinib can go to the clinic.
In addition, BeiGene is behind the investors; subjects in clinical trials; The team responsible for technical operations and the first chain; Even every employee on the zanubrutinib production line ......They all lit up the birth of the first domestic "billion-dollar molecule".
Reference**:1Jiemian News "Depth The Inside Story of the First Domestic Anti-cancer Drug Going to Sea: After Seven Years, Nine Deaths".
2.Pharmaceutical Cube "Zanubrutinib: The First Domestic Billion Dollar Molecule Apocalypse".