When it comes to BeiGene's BTK, you will think of zanubrutinib without thinking, but BeiGene's BTK inhibitors are not limited to zanubrutinib. BGB-16673, which is under development in the pipeline, is another potential "sharp sword".

Recently, BeiGene's BTK PROTAC molecule BGB-16673 was granted fast track qualification by the FDA for CLL/SLL patients who have undergone at least two lines of treatment, including BTK inhibitors and Bcl-2 inhibitors.
Since the first BTK inhibitor ibrutinib was approved for marketing in 2013, 6 BTK inhibitors have been approved for marketing worldwide.

Although many BTK inhibitors have been approved for marketing and these drugs have demonstrated excellent efficacy, they still have certain limitations, namely the problem of drug resistance.

PROTAC (protein degradation) has been a very hot research and development track in recent years.

Compared with small molecule inhibitors, PROTAC degraders have many advantages: they expand the druggable targets and can target target proteins that do not have small molecule inhibitors or have poor efficacy; they have high catalytic efficiency and can work with catalytic amounts, avoiding the situation where small molecules need to be in use for a long time to exert their efficacy; they overcome drug resistance. PROTAC degraders not only inhibit protein activity, but also degrade the entire protein to destroy the protein's enzyme and non-enzyme functions (such as scaffolds) or transcription functions, overcoming the drug resistance of traditional small molecules.

Including Eli Lilly's Pirtobrutinib, the currently approved BTK drugs are all small molecule inhibitors, which are prone to drug resistance. In order to further improve drug efficacy and overcome drug resistance problems, many companies have turned their attention to the development of PROTAC drugs for BTK, and BeiGene is one of them.

As early as 2021, when Zebutinib had not yet shown its power, BeiGene began to apply PROTAC technology to BTK drug development. According to the data, the first clinical PROTAC project launched by BeiGene is BGB-16673. In August 2021, BeiGene registered for clinical trials on ClinicalTrials.gov, and launched clinical trials in China in March 2022.

BGB-16673 induces BTK degradation through ubiquitination, showing great potential in solving the problem of BTK inhibitor resistance. The application for fast track designation is mainly based on the potential of BGB-16673 to address the unmet medical needs of CLL/SLL patients with disease progression.

At the 2024 European Hematology Association Annual Meeting held in June this year, BeiGene announced the data from the ongoing Phase I/II first-in-human trial (NCT05006716) of BGB-16673, highlighting that the drug has tolerable safety and good efficacy for the treatment of R/R CLL/SLL patients who have previously received multiple lines of treatment. In addition, it has shown tolerable safety and preliminary efficacy in patients with various types of non-Hodgkin lymphoma (NHL).

To date, the BGB-16673 global clinical development program has treated more than 300 patients in 15 countries and regions. BGB-16673 is currently undergoing a dose expansion cohort study of CLL/SLL after the BTK inhibitor, and BeiGene expects to launch a Phase III clinical trial at the end of this year and early next year.

In addition to BGB-16673, Hisun's HSK29116 and Nurix Therapeutics' NX-2127 and NX-5948 are also BTK PROTAC degraders under development, with BGB-16673 making the fastest progress.

Globally, the BTK inhibitor market is growing rapidly, reaching $7.2 billion in 2020. According to Sullivan's analysis, the BTK inhibitor market size is growing at a compound annual growth rate of 22.7%, reaching US$20 billion in 2025, and will continue to expand at a compound annual growth rate of 5.5% to US$26.1 billion in 2030.

Obviously, BeiGene is bound to spare no effort to play the BTK game well. In the future, we will wait and see what kind of swords will be played by Zanubrutinib and BGB-16673.

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