Zanubrutinib: China's First Homegrown Anti-Cancer Drug Approved by FDA Marks Historic Breakthrough for Domestic Innovation

On November 15, 2019, BeOne Medicines announced that its independently developed BTK inhibitor, zanubrutinib (brand name: BRUKINSA™), had received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with mantle cell lymphoma (MCL) who had previously received at least one prior therapy. This marked zanubrutinib as the first anticancer new drug entirely independently developed by a Chinese company to gain FDA approval for marketing, achieving a breakthrough in the global launch of Chinese original new drugs. Furthermore, this was the first approved independently developed product of BeOne Medicines, representing another significant milestone in the company’s development history.

Dr. Wu Xiaobin, General Manager of BeOne Medicines in China and President of the Company, stated, “We are immensely proud of the FDA approval of zanubrutinib. This historic breakthrough not only signifies international recognition of China’s new drug R&D capabilities and fulfills the aspiration for Chinese innovative drugs to ‘go global,’ but more importantly, it demonstrates that China’s innovative pharmaceutical enterprises are not only capable of benefiting domestic patients but also possess the full strength to serve a broader global patient population.”

Lymphoma is a collective term for a group of malignant tumors originating from the lymphatic and hematopoietic systems. It is one of the malignancies with the fastest-growing incidence rate worldwide. According to 2018 survey data published in The Lancet, there were approximately 450,000 new cases of lymphatic system malignancies globally in 2012 [1]. Among the more than 70 known subtypes of lymphoma, mantle cell lymphoma (MCL) is highly aggressive, with a median survival time of only three to four years [2]. Most patients are already at an advanced stage of the disease at diagnosis, facing limited treatment options and a poor prognosis.

Zanubrutinib is a novel, potent BTK inhibitor currently undergoing clinical trials as a monotherapy or in combination with other therapies for the treatment of various types of lymphoma. Data show that in clinical trials for mantle cell lymphoma, over 84% of patients treated with zanubrutinib achieved an overall response.[3]

The FDA approval of zanubrutinib was based on efficacy data from two clinical trials. In the multicenter Phase 2 trial BGB-3111-206, which enrolled patients with relapsed/refractory mantle cell lymphoma (MCL), the overall response rate (ORR) reached 84% following treatment with zanubrutinib, including a complete response (CR) rate of 59%. The median duration of response (DOR) was 19.5 months, with a median follow-up time of 18.4 months.

This pivotal Phase 2 clinical study was led by Peking University Cancer Hospital, with Professor Zhu Jun, Director of the Lymphoma Department and Director of the Department of Internal Medicine at Peking University Cancer Hospital, serving as the principal investigator. Professor Zhu stated, “In recent years, clinical treatment and drug development for lymphoma in China have entered a period of rapid growth. In the past, we could only hope for new drugs from abroad to become available in China, but the situation has changed dramatically. As a clinical oncologist, I am deeply gratified to participate in and witness the first FDA approval of a domestically developed innovative drug. This signifies international recognition of China’s innovation capabilities and research standards. We are not only developing new drugs for Chinese patients but also benefiting patients in many other countries, offering Chinese therapeutic solutions to the world. I take genuine pride in this progress.”

“With strong support from researchers both in China and abroad, zanubrutinib has gained FDA approval based on its excellent clinical data,” said Ms. Yan Xiaojun, Senior Vice President and Head of Global Regulatory Affairs at BeOne Medicines. “We are proud to see zanubrutinib receive accelerated approval through the Priority Review pathway, following earlier distinctions such as Fast Track designation and Breakthrough Therapy designation. This achievement is the result of years of concerted efforts by the BeOne Medicines team and clinical trial investigators. More importantly, we extend our heartfelt gratitude to every patient who participated in the clinical trials.”

In January 2019, zanubrutinib was granted “Breakthrough Therapy Designation” by the U.S. Food and Drug Administration (FDA), becoming the first domestically developed anti-cancer new drug to receive this designation. In August, the FDA formally accepted the New Drug Application (NDA) for zanubrutinib and granted it Priority Review status.

Zanubrutinib was developed at the BeOne Medicines R&D Center in Changping, Beijing. In July 2012, the research team officially initiated the BTK development project. After a series of screening and testing processes, the final candidate molecule was selected from more than 500 compounds and assigned the code BGB-3111, signifying it as the 3,111th compound synthesized since the establishment of BeOne Medicines.

Dr. Zhiwei Wang, Head of Chemistry R&D at BeOne Medicines and one of the principal inventors of zanubrutinib, stated, “At the outset of the project, our objective was clear: to develop a compound with high selectivity and highly specific inhibition of the target. By optimizing the molecular structure, we aimed to maximize the specific binding affinity for the BTK target while minimizing off-target effects, thereby reducing the incidence of adverse reactions. Furthermore, through a series of process improvements, we strove to enhance the drug’s absorption in vivo.”

In 2014, zanubrutinib officially entered the clinical trial phase in Australia, with the first patient dosed globally in August of that year. From initial project initiation to FDA approval for marketing, the development of zanubrutinib spanned over seven years. To date, more than 20 clinical trials have been launched worldwide, covering over 20 countries, and more than 1,600 patients globally have received treatment with zanubrutinib. Over 400 international clinical experts have participated in or led these clinical trials, including more than 60 clinical experts from China.

“From the outset of its clinical development, zanubrutinib underwent simultaneous clinical trials both overseas and in China, as our goal has been to bring independently developed novel drugs to the international market and create high-quality medicines that rival global standards and earn international recognition. To achieve this, we have maintained strict control over the quality of our clinical trials,” said Dr. Lai Wang, Senior Vice President of BeOne Medicines, Head of Global Research, Clinical Operations and Biostatistics, and Head of Asia-Pacific Clinical Development, who was one of the key leaders in the development of zanubrutinib. “We are delighted that, with the collective support of investigators, zanubrutinib has demonstrated outstanding efficacy and safety data, validating our initial hypotheses and strongly supporting its eventual successful approval by the FDA, thereby bringing hope to patients in more countries around the world.”

It is reported that BeOne Medicines is currently conducting 16 clinical studies of zanubrutinib worldwide, including nine registrational or potentially registrational clinical trials. Meanwhile, zanubrutinib is undergoing two global Phase III head-to-head comparative studies against ibrutinib for the treatment of Waldenström’s macroglobulinemia and chronic lymphocytic leukemia, marking the first time a domestically developed new drug in China has engaged in direct head-to-head research against a product developed by a foreign pharmaceutical company.

For a long time, the original anticancer drugs marketed in China have relied mainly on imports, while pharmaceutical products exported from China have mostly consisted of active pharmaceutical ingredients (APIs) or generic drugs, contributing relatively little to the global pharmaceutical innovation ecosystem. In recent years, with the deepening of reform and opening-up and the enhancement of China’s comprehensive national strength, the Chinese pharmaceutical industry has accelerated its transformation and upgrading. Driven by favorable policies related to drug regulatory and healthcare reforms, a wave of innovation has emerged in the pharmaceutical sector. A large number of scientists have returned to China to engage in new drug research and development, injecting sustainable vitality into the industry’s transition from generics to innovation and from domestic markets to the global stage.

Dr. Wu Xiaobin, General Manager of BeOne Medicines’ China Region and President of the Company, stated: “The continuous and in-depth reforms in drug review and approval systems, as well as in medical insurance payment mechanisms, have created a favorable macro environment for domestic innovative drugs to achieve historic breakthroughs in global expansion. Benefiting from national policy support, innovative pharmaceutical companies represented by BeOne Medicines have maintained sustained investment and strived to catch up, now gradually entering a period of harvest. As a Chinese enterprise, we are encouraged by the nation’s reforms and look forward to their further deepening, so that the R&D achievements of Chinese scientists and enterprises can benefit more patients at an earlier stage, continuously promote industrial upgrading, and advance our country toward the strategic goal of becoming a global ‘pharmaceutical powerhouse.’”

BeOne Medicines submitted new drug applications to the National Medical Products Administration (NMPA) of China in August and October 2018 for zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma (MCL) and relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Both applications were accepted into the priority review pathway, with the aim of making the therapy available to patients in China at an earlier date. Following domestic approval, zanubrutinib will be commercially manufactured at BeOne Medicines’ small-molecule drug production facility located in the Sangtian Island Industrial Park in Suzhou.

[1] The CONCORD-3 study was published in The Lancet in 2018

[2] Philip J. Bierman, James O. Armitage, in Goldman's Cecil Medicine (Twenty Fourth Edition), 2012

[3] BRUKINSA (zanubrutinib)

Prescribing Information. beigene.com/PDF/BRUKINSAUSPI.pdf. BeiGene, Ltd; DATE 2019.