AstraZeneca's Acalabrutinib Becomes China's Fourth BTK Inhibitor Filed for Approval, Poised to Join Blockbuster Drug Ranks

On January 5, the CDE website showed that the marketing application for AstraZeneca's new-generation BTK inhibitor "Acalabrutinib Capsules" has been accepted.

Acalabrutinib (Acalabrutinib, trade name Calquence) is a second-generation Bruton's tyrosine kinase (BTK) inhibitor that works by permanently binding to and inhibiting BTK. BTK is a key regulator of the B-cell receptor (BCR) signaling pathway, widely expressed in various types of hematologic malignancies, and is involved in the proliferation, trafficking, chemotaxis, and adhesion of B cells, making it an important target for treating hematologic malignancies. Preclinical studies have shown that acalabrutinib has minimal off-target effects.

In October 2017, Acalabrutinib was granted accelerated approval by the FDA for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least one prior therapy. In November 2019, the drug was further approved by the FDA for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Additionally, Acalabrutinib is also being developed for the treatment of various other B-cell blood cancers, such as diffuse large B-cell lymphoma (DLBCL), Waldenstrom macroglobulinemia (WM), follicular lymphoma (FL), and multiple myeloma.

Acalabrutinib was developed by Acerta, and in 2015, AstraZeneca acquired 55% of Acerta's shares for $4 billion. According to AstraZeneca's financial report, the sales of Calquence have been climbing since its launch, and it is expected that the sales in 2021 will break through the $1 billion mark, entering the ranks of blockbuster products.

In China, Acalabrutinib has registered six clinical trials (see table below), with indications covering CLL, MCL, and DLBCL. Based on the trial progress, it is currently impossible to speculate on the specific indication for this application.

Speaking of BTK inhibitors, three have been approved in China so far (see the table below), including two domestically produced and one imported. All three BTK inhibitors have been included in the 2021 National Medical Insurance Catalog. Globally, five BTK inhibitors have been approved: Johnson & Johnson's Ibrutinib (brand name Imbruvica), BeiGene's Zanubrutinib, InnoCare Pharma's Orelabrutinib, and Ono Pharmaceutical/Gilead’s Velexbru (tirabrutinib hydrochloride). Among them, Velexbru was approved in Japan in March 2020 for the treatment of recurrent or refractory primary central nervous system lymphoma (PCNSL) and was again approved in August 2020 for the treatment of Waldenström's macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL).

Among the five approved BTK inhibitors, Ibrutinib has the best market performance due to its first-mover advantage. According to public data, Ibrutinib's sales in 2020 reached $9.442 billion, while Zanubrutinib’s sales in 2020 were $41.70 million. Orelabrutinib’s sales in the first half of 2021 were 101 million yuan. Notably, after a 44% price reduction during the 2020 National Reimbursement Drug List negotiation, Zanubrutinib was further reduced by 14%. The latest reimbursement execution price is 5,440 yuan per box, with a pre-reimbursement monthly treatment cost of 10,200 yuan, making it the BTK inhibitor with the lowest monthly treatment cost in its category.

In addition to the aforementioned BTK inhibitors, according to the Insight database, there are currently multiple BTK inhibitors under development in China (see table below). Among them, Haisco's HSK29116 and BeiGene's BGB-16673 are BTK protein degraders, while the others are small-molecule drugs. Based on the current progress of BTK inhibitors, it is expected that the market will experience explosive growth in the number of approved BTK inhibitors and overall market size within the next two to three years.