Bruton tyrosine kinase (BTK) is a non-receptor tyrosine kinase which plays a critical role in the signal transduction of the B-cell antigen receptor as well as other cell surface receptors, in both health, normal, and malignant B lymphocytes.[1]

B-cell antigen receptor signaling is activated in secondary lymphatic organs and drives the proliferation of malignant B cells. Over the last decade, bruton tyrosine kinase inhibitors (BTKi) have transformed the therapeutic landscape for the treatrment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and non-Hodgkin lymphoma, replacing chemotherapy-based regimens. [1][2]

BTKi’s have led to an unprecedented improvement in outcome in CLL, in particular for high-risk subgroups. [2] But despite the current BTKi market being valued at approximately US$ 6 billion, sales specifically for chronic lymphocytic leukemia (CLL) are predicted to be nearly US$ 5 billion by 2032 in the seven major markets (US, France, Germany, Italy, Spain, UK, and Japan).

Pirtobrutinib (Jaypirca®; Eli Lilly) is forecast to become the market leader in BTK inhibitors for CLL, garnering nearly 60% share with about US$ 3 billion in sales by 2032, according to GlobalData, a leading data and analytics company.

Additionally, the generic erosion of ibrutinib (Imbruvica®; Pharmacyclics/Janssen), a first-generation BTK inhibitor and the market leader since 2013, is expected to affect sales, with its market exclusivity ending in the US by 2028 and the 5EU (France, Germany, Italy, Spain, and the UK) by 2029.

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In the price negotiations program between manufacturers and Medicare*, ibrutinib is the only cancer drug on the list that needs to slash its sale price in the US in 2026.

It is expected that second-generation BTK inhibitor acalabrutinib (Calquence®; AstraZeneca) will occupy second place in the market, with sales exceeding US $1 billion and a share of 21.7%.

Zanubrutinib (Brukinsa®; BeiGene) is predicted to attain third place with US $ 774 million in sales, representing 15.8% of the overall BTK inhibitor therapy market share by 2032.

“In the future, the role of [pirtobrutinib is expected] set to expand. Presently, 16 Phase I-III clinical trials are in progress, investigating the potential of this drug as a first-line and subsequent-line therapy for hematological malignancies. Its potential uses include maintenance therapy after CAR-T-cell therapy, in cases of CAR-T failure, as a bridging therapy before CAR-T, and in combination with other targeted immunotherapies, such as bispecific or trispecific antibodies,” noted Biswajit Podder, PhD, Oncology and Hematology Analyst at GlobalData.

Remarkably, the current landscape boasts a total of six marketed BTK drugs in the oncology sector globally. Further bolstering this optimistic outlook, there are nearly 400 ongoing Phase I-III trials worldwide, utilizing 37 distinct BTK inhibitors.

Second generation BTKi
“In addition to the success of Imbruvica, second-generation BTK inhibitors are taking a significant share of the BTK inhibitor market because of their superiority to first-generation BTK inhibitor drugs. Second-generation inhibitors pirtobrutinib, zanubrutinib, acalabrutinib, and tirabrutinib (Velexbru®; Ono Pharmaceutical/Gilead Sciences) offer fewer off-target effects, leading to less cardiotoxicity and allowing patients to maintain treatment longer, thereby increasing efficacy,” Podder said.

“In addition, if pirtobrutinib gets approval for other indications like diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone B-cell lymphoma, it will strengthen its market position,” Podder concluded.

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Note: * Following the adoption of the US Inflation Reduction Act in August 2022, the Centers for Medicare & Medicaid Services (CMS) is able to negotiate directly with drug companies to improve access to some of the costliest single-source brand-name Medicare Part B and Part D drugs.

Highlights of prescribing information
Pirtobrutinib (Jaypirca®; Eli Lilly)[Prescribing Information]
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen)[Prescribing Information]
Acalabrutinib (Calquence®; AstraZeneca)[Prescribing Information]
Zanubrutinib (Brukinsa®; BeiGene)[Prescribing Information]
Tirabrutinib (Velexbru®; Ono Pharmaceutical/Gilead Sciences)

Reference
[1] Burger JA. Bruton Tyrosine Kinase Inhibitors: Present and Future. Cancer J. 2019 Nov/Dec;25(6):386-393. doi: 10.1097/PPO.0000000000000412. PMID: 31764119; PMCID: PMC7083517.
[2] Ahn IE, Brown JR. Targeting Bruton’s Tyrosine Kinase in CLL. Front Immunol. 2021 Jun 23;12:687458. doi: 10.3389/fimmu.2021.687458. PMID: 34248972; PMCID: PMC8261291.

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