BeiGene Announces Final Results from Head-to-Head ALPINE Trial of Zanubrutinib Published in The New England Journal of Medicine

On December 14, BeiGene (Nasdaq: BGNE; HKEX: 06160; SSE: 688235) announced that zanubrutinib (brand name: Brukinsa), a BTK inhibitor independently developed by the company,^®) final analysis results of progression-free survival (PFS) in the global Phase 3 head-to-head ALPINE trial.

On the same day, these landmark findings were presented orally in the Late-Breaking Abstracts session at the 2022 American Society of Hematology (ASH) Annual Meeting and published simultaneously in The New England Journal of Medicine, a premier international journal with an impact factor of 176. Zanubrutinib has since garnered the highest level of international academic recognition, shining on the global stage. These pivotal results robustly demonstrate its position as the global “best-in-class” Bruton’s tyrosine kinase (BTK) inhibitor, holding promise to deliver transformative new treatment options for a broader patient population.

Assessed by the Independent Review Committee (IRC) and investigators, zanubrutinib demonstrated superiority in progression-free survival (PFS) compared with ibrutinib for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (HR: 0.65 [95% CI, 0.49–0.86]; p = 0.0024). At 24 months, the IRC-assessed PFS rate was 79.5% for zanubrutinib versus 67.3% for ibrutinib. Based on the ALPINE study, zanubrutinib has become the first and only Bruton’s tyrosine kinase (BTK) inhibitor globally to demonstrate dual superiority over ibrutinib in both PFS and overall response rate (ORR).

Dr. Wu Xiaobin, President, Chief Operating Officer, and General Manager of China at BeiGene, stated, “As BeiGene’s first approved innovative drug globally, zanubrutinib has achieved a series of breakthroughs since the beginning of this year, which is truly exhilarating for us. Particularly in the important indication of chronic lymphocytic leukemia (CLL), zanubrutinib has successfully demonstrated superiority in head-to-head studies, bringing new hope for treatment to patients worldwide. With its robust product strength, zanubrutinib has rightly become BeiGene’s global pioneer. We believe and look forward to zanubrutinib having the opportunity to become another global blockbuster drug, benefiting patients around the world.”

Dr. Lai Wang, Senior Vice President and Head of Global R&D at BeiGene, stated, “The ALPINE study spanned four years, and its positive outcomes further attest to our high-quality science and global clinical development capabilities. As a differentiated BTK inhibitor, zanubrutinib has undergone ten years of relentless refinement since its internal project initiation in 2012, continuously scaling new heights. The selection of the ALPINE study data for presentation as a Late-Breaking Abstract at the ASH Annual Meeting, coupled with its publication in The New England Journal of Medicine, represents the two highest forms of academic recognition within the international pharmaceutical community. This marks another peak and breakthrough for zanubrutinib. Behind this achievement lie the efforts of countless BeiGene employees over more than a decade, embodying BeiGene’s enduring commitment to science and its pioneering spirit.”

Zanubrutinib was independently developed by BeiGene’s team of scientists. From the outset of the project, the R&D team was committed to creating a BTK inhibitor with greater specificity, enhanced efficacy, and an improved safety profile. Based on positive data from preliminary studies, BeiGene decided to conduct global, large-scale, head-to-head Phase 3 trials to validate the therapeutic advantages of zanubrutinib, thereby maximizing its international potential.

As a “latecomer” in the BTK field, conducting head-to-head trials is the best way to compete in the global market and validate that this is a superior product. However, head-to-head trials are by no means easy; they entail high risks, significant challenges, and substantial investment, requiring immense determination and confidence. Even under these circumstances, BeiGene ultimately chose to trust in science and opt for a direct head-to-head challenge.

Since its initiation in 2018, the ALPINE study has enrolled 652 patients globally across 145 clinical research centers in 15 countries, including the United States, the United Kingdom, China, and Germany, thereby ensuring the diversity and representativeness of the trial data across different ethnicities and regions. In April 2022, zanubrutinib demonstrated superiority in the study’s primary endpoint—overall response rate (ORR) as assessed by an Independent Review Committee (IRC)—and exhibited a more favorable safety and tolerability profile.

The final analysis data from the ALPINE study demonstrate that zanubrutinib significantly prolongs progression-free survival (PFS) in patients with chronic lymphocytic leukemia (CLL) compared to ibrutinib. As assessed by an independent review committee (IRC), the 24-month PFS rates were 79.5% for zanubrutinib versus 67.3% for ibrutinib. Furthermore, zanubrutinib significantly reduced the risk of disease progression by 35% (HR = 0.65), providing CLL patients with more stable and long-term therapeutic benefits. Additionally, PFS benefits were observed across all major subgroups, including the high-risk subgroup of patients harboring del(17p)/TP53 mutations.

As a “gold standard” for evaluating the treatment efficacy of chronic lymphocytic leukemia (CLL), progression-free survival (PFS) refers to the time from randomization to disease progression or death from any cause. Given that CLL patients require long-term treatment, PFS holds significant reference value in assessing the efficacy and quality of life associated with long-term therapeutic regimens.

In addition to superior efficacy, zanubrutinib also demonstrates a higher level of safety and tolerability. According to the final analysis released this time, regarding safety indicators related to cardiac function, the incidence of atrial fibrillation/atrial flutter in the zanubrutinib group was significantly lower compared to the ibrutinib group, at 5.2% vs. 13.3%, respectively. Furthermore, six fatal cardiac adverse events were reported in the ibrutinib group, whereas no such adverse events were reported in the zanubrutinib group. Compared with the ibrutinib group, the proportion of patients who discontinued treatment due to cardiac-related conditions was also significantly lower in those receiving zanubrutinib, at 0.3% vs. 4.3%, respectively.

Professor Qiu Lugui, Director of the Lymphoma Diagnosis and Treatment Center at the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, and Principal Investigator for China in the ALPINE trial, stated: “The ALPINE study confirms that zanubrutinib is the only drug in the field of chronic lymphocytic leukemia (CLL) treatment proven to be superior to the first-generation BTK inhibitor ibrutinib in both safety and efficacy. As the Principal Investigator for China in the ALPINE study, I am delighted to see that this drug, through a rigorous, high-quality, large-scale international Phase 3 head-to-head clinical trial, has been confirmed as a ‘best-in-class’ innovative therapy, delivering tangible long-term survival benefits to patients. The development of innovative drugs requires a robust industrial ecosystem, substantial upfront investment, and accumulation over a lengthy cycle. The success of the ALPINE study serves as the best testament to this, verifying that the development of a high-quality drug demands far-sighted vision and determination.”

Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia, accounting for approximately one-quarter of new leukemia cases globally, and represents the most critical therapeutic area in the competitive landscape of Bruton’s tyrosine kinase (BTK) inhibitors worldwide. As the first BTK inhibitor approved globally, ibrutinib pioneered the era of targeted therapy for CLL/small lymphocytic lymphoma (SLL). However, with accumulating clinical experience, first-generation BTK inhibitors have been shown to have certain limitations and safety risks.

Since the beginning of this year, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have successively issued warnings highlighting the cardiovascular risks associated with the use of the first-generation BTK inhibitor ibrutinib. In view of the toxicity of first-generation BTK inhibitors, the 2023 Version 1 of the National Comprehensive Cancer Network (NCCN) Guidelines for the Diagnosis and Treatment of CLL/SLL have downgraded ibrutinib from a “preferred recommendation” to an “other recommended” option for both first-line and second-line treatment of chronic lymphocytic leukemia (CLL).

Based on the ALPINE study, zanubrutinib has definitively demonstrated significant breakthroughs in therapeutic efficacy and safety compared to ibrutinib, earning repeated professional recognition from the international academic community.

As one of the medical journals with the highest impact factor globally, The New England Journal of Medicine enjoys a prestigious reputation in the global medical community. The publication of the ALPINE study results in The New England Journal of Medicine underscores the international academic community’s full recognition of the study’s design, quality control, and clinical value.

In fact, since the beginning of this year, buoyed by positive data from two global Phase III clinical trials, including ALPINE, the global research findings on zanubrutinib have been successively published in top-tier international journals, including the Journal of Clinical Oncology (JCO) and The Lancet Oncology, fully demonstrating its international academic strength and breakthrough therapeutic value. Furthermore, in the updated US NCCN Guidelines released this year, zanubrutinib has been listed as a Category 1 recommendation for CLL/SLL, underscoring the high expectations placed on it.

Professor Li Jianyong, Director of the Pukou Chronic Lymphocytic Leukemia Center at Jiangsu Province People’s Hospital and Director of the Department of Hematology at the First Affiliated Hospital of Nanjing Medical University, stated, “Chronic lymphocytic leukemia (CLL) is a hematologic malignancy with a relatively indolent progression, predominantly affecting the elderly population. These patients often present with comorbid chronic conditions such as hypertension and coronary heart disease, which significantly impact treatment tolerance and regimen selection. The long-term safety of medication can improve patient adherence, thereby further enhancing therapeutic efficacy, which holds significant importance for patients. The next-generation BTK inhibitor zanubrutinib offers more precise targeting, demonstrating superior efficacy and a more favorable toxicity profile. The research results released this time fully corroborate zanubrutinib’s ‘best-in-class’ therapeutic strength, holding the potential to deliver more stable, safer, and sustained long-term benefits for patients with CLL.”

Currently, zanubrutinib has been approved in more than 60 markets worldwide, with over 40 additional regulatory submissions under review. Notably, in addition to major developed countries in Europe and the United States, zanubrutinib has also reached multiple developing country markets, truly extending its benefits to a broader patient population.

Driven by its extensive global commercial footprint and robust clinical evidence, zanubrutinib has demonstrated strong growth in global sales revenue. By the end of the third quarter of this year, zanubrutinib’s global sales for the year had surpassed RMB 2.5 billion. Of this, sales in the United States reached RMB 1.755 billion, reflecting accelerating market uptake. In China, zanubrutinib also delivered notable performance, achieving sales of RMB 725 million and further solidifying its leading position in the domestic BTK inhibitor market.

In terms of clinical development, zanubrutinib has undertaken an extensive global clinical program, with 35 trials conducted in more than 30 countries and regions worldwide. These trials cover various B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and marginal zone lymphoma, with a total global enrollment of over 4,700 participants.

Furthermore, BeiGene’s other core in-house developed product, the anti-PD-1 antibody tislelizumab (brand name: Baizean®), has also seen a stream of positive developments, with its latest clinical study data recently presented at the 2022 European Society for Medical Oncology Immuno-Oncology (ESMO-IO) Congress. In multiple studies targeting non-small cell lung cancer and hepatocellular carcinoma, tislelizumab has demonstrated outstanding efficacy and safety advantages, characterized by prolonged survival, high response rates, and robust control of disease progression, significantly reducing the risk of disease progression. Leveraging its unique structural advantages and high-quality clinical data, tislelizumab holds the potential to deliver improved prognosis and enhanced survival outcomes for a broader patient population.

As a representative achievement of BeiGene’s global R&D and operational model, the success of zanubrutinib and tislelizumab not only validates the company’s robust global clinical development capabilities but also serves as a testament to BeiGene’s scientific excellence, global strategic layout, and determination.

Since its inception in 2010, BeiGene has established a global development strategy. Leveraging forward-looking strategic insights and a steadfast global footprint, BeiGene has secured a leading position in globalization, becoming one of the first Chinese biopharmaceutical companies to enter the international pharmaceutical arena. To date, BeiGene has initiated 110 clinical trials across more than 45 countries and regions worldwide, with over 60% being international multi-center clinical studies. The company has enrolled more than 20,000 subjects globally, approximately half of whom were enrolled outside China.

Furthermore, BeiGene has built a rich and diversified product pipeline. Currently, BeiGene has nearly 50 candidates in its development pipeline and product portfolio, with multiple independently developed projects progressing steadily. These include the highly anticipated anti-TIGIT antibody ociperlimab, the BCL-2 inhibitor BGB-11417 with differentiated potential, as well as anti-OX40 antibodies, HPK1 inhibitors, PI3Kδ inhibitors, and TYK2 inhibitors. In the preclinical stage, BeiGene is advancing more than 60 research programs, approximately half of which have the potential to be “first-in-class” or “best-in-class.”

Over the past 12 years, BeiGene has successfully advanced 16 self-developed drug candidates into clinical stages through its in-house R&D team. Starting from 2024, the company expects to advance more than 10 new molecular entities into clinical trials annually, ushering in a new wave of research and development.

After more than a decade of global R&D layout and accumulation, BeiGene has demonstrated its scientific research strength and pioneering spirit with an exploratory and pragmatic attitude, accelerating into a new phase of high-quality, internationalized development. Zanubrutinib’s journey, marked by multiple milestones, serves as a vivid testament to the company’s commitment to innovation and relentless efforts, while also providing a practical model and reference for the future globalization of the innovative drug industry.