The third model in the world! BeiGene BGB-16673 was approved for clinical use

According to the public information of the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA), BeiGene BTK targeted protein degrader BGB-16673 has been approved for clinical use in China, which is the second in China and the third in the world.
Clinically approved BTK-PROTAC
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 Table 1 Global approved clinical BTK-PROTAC pattern Data sources: [1][2] Tabulation: BTK inhibitor (BTKi) has become a popular target for the treatment of hematological malignancies and autoimmune disorders, rising stars and industry giants The competition is in full swing
.

(Related reading: Exploring the headlines | Up-and-coming stars are one-to-four, who can win the BTK golden track?) However, BTK inhibitors that have been marketed around the world mainly form covalent bonds with cysteine ​​residues in the active site of BTK.
Produces enzyme inhibition, and covalent binding is prone to resistance mutations (C481S mutation), resulting in the mutation of cysteine ​​to serine, making the inhibitor unable to bind to BTK
.

Protein degradation targeting chimera (PROTAC) technology utilizes hybrid bifunctional small molecule compounds to bring the target protein and intracellular E3 ubiquitin ligase closer, and then specifically degrade the target protein through the ubiquitin-proteasome protein degradation pathway in vivo
.

PROTACs can target traditional non-drugable targets and effectively overcome the resistance problems of traditional small molecule inhibitors
.

Introduction to PROTAC platform (Source: Haisco's official website) 01Technical advantages + top-notch team BeiGene was established in 2010 and is an innovative biopharmaceutical company in the commercial stage, focusing on the development and commercialization of innovative molecular targets for cancer treatment Xiang and tumor immunotherapy drugs are known by the industry as the "first brother" of China's innovative drugs
.

At present, the company has commercialized two self-developed drugs, which are sold in China and the United States respectively, the BTK inhibitor Baiyueze® (zanubrutinib capsules) and the anti-PD1 antibody drug Baizean® (tislelizumab) Anti-injection), while the company's PARP inhibitor Baihuize® (Pamidibali) was approved by China's National Medical Products Administration (NMPA) in May 2021 as the company's third commercialized drug
.

Some of BeiGene’s tumor pipelines (Source: BeiGene’s official website) BGB-16673 is BeiGene’s first project developed based on its Chimeric Degradation Activating Compound (CDAC) technology platform
.

The CDAC platform has different advantages, and the E3 ligase with broader and tissue specificity constructed by it can reduce the dose-limiting toxicity, overcome E3-related drug resistance, and broaden the range of potential substrate proteins
.

Preclinical models show that the targeted degradation of BTK by BGB-16673 can overcome C481S resistance, which is expected to overcome the problem of BTK inhibitor resistance
.

Meanwhile, BGB-16673 has favorable pharmacological properties, bioavailability, tolerability, as well as high selectivity, efficacy and long half-life
.

 The technical advantages of the CDAC platform (source: [3]) In addition, BeiGene also targets tyrosine kinase receptors (lung cancer), cyclins (hematological tumors), apoptosis-related proteins (hematological tumors and solid tumors), TLR Multi-targets such as signaling pathways (hematological tumors and tumor immunity), cytokines (hematological tumors and tumor immunotherapy), and epigenetics (hematological tumors) are deployed for CDAC project layout
.

 CDAC layout (Source: [3] ) BeiGene has successively established teams in clinical research and development, drug registration, production supply, and commercialization around the world, with an international layout covering the complete industrial chain
.

 02Generic drug transformation and innovation Haisco started with nutritional products, focusing on first generic and specialty specialty drugs, occupying an important position in the segmented market in the field of liver disease, with a number of domestic first generic drugs, and in recent years, it has turned to small molecule chemical innovative drugs and monoclonal antibodies and other fields
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Table 2 Haisco's pipeline under development (Source: Haisco's official website) HSK29116 is the world's first BTK-PROTAC to apply for clinical application, which is an oral PROTAC small molecule anti-tumor drug
.

On the one hand, HSK29116 can directly inhibit BTK activity by specifically binding to BTK; on the other hand, it can induce the BTK ubiquitination mark and degrade it through the proteasome pathway, thereby blocking the transmission of the BCR signaling pathway and inhibiting B-cell lymphoma The growth and proliferation of cells play a dual anti-tumor effect
.

HSK29116 not only has better efficacy against wild-type BTK, but also overcomes the problem of drug-resistant mutations
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 After being approved for clinical use in China in 2021, clinical trial applications in Australia and the United States are also in progress
.

If it is successfully marketed, it will bring more clinical benefits and better drug choices for patients with B-cell malignancies
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 Introduction to the Haisco PROTAC platform (Source: [6]) The Haisco PROTAC platform relies on its own innovative drug system and has deployed more than 20 early projects; the R&D team covers design synthesis, biological evaluation, intellectual property, formulation research and clinical research, etc.
Multi-faceted technical force
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Haisco has become an important player in the BTK-PROTAC field by virtue of its first-mover advantage and relatively leading R&D progress
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 Table 3 Comparison of Haisco and BeiGene BTK-PROTAC Source: [4][7] Tabulation: Bio-Exploration Editing Team -2127 is still in Phase I clinical stage, and BeiGene's R&D capabilities are obvious to all, and it has a mature R&D and commercialization team.
It also holds China's BTKi's first innovative overseas product, and can conduct targeted clinical trials independently.
It may be possible in the future development.
It came from behind, leading BTK-PROTAC
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Written by | Shan Luyao Typesetting | Mu Zijiu End References: [1] Center for Drug Evaluation, State Drug Administration of China
.

https:// Innovation pipeline for medicines
.

https:// to Host Investor Conference Call and Webcast to Discussthe Company's Early Development Pipeline and Research.
https://ir.
beigene.
com/news-events/events-presentations/[4 ] The official website of Haisco Pharmaceutical Group
.

http:// Announcement of Haisco Pharmaceutical Group Co.
, Ltd.
on the approval of the clinical trial of the innovative drug HSK29116 powder
.

http://epaper.
stcn.
com/paper/zqsb/page/1/2021-01/26/B029/20210126B029.
[6] Introduction to Haisco PROTAC platform
.

http://static.
cninfo.
com.
cn/finalpage/2021-06-15/1210237587.
PDF[7] BeiGene official website
.

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