BTK-inhibitors (overview)

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that plays a central role in signal transduction of the B-cell antigen receptor and other cell surface receptors in both normal and malignant B lymphocytes. The BTK gene is located on the X chromosome at the Xq22.1 locus.

Activation of the Bruton’s tyrosine kinase (BTK) signaling pathway plays an important role in the pathophysiology of a number of lymphoproliferative B-cell disorders. Several preclinical and clinical studies have demonstrated that inhibition of Bruton’s tyrosine kinase is a mechanism for treating lymphoproliferative and autoimmune B-cell disorders (e.g., pemphigus vulgaris) (Castillo JJ et al. 2016).

A Bruton’s tyrosine kinase mutant plays a crucial role in oncogenic signaling, which is essential for the proliferation and survival of leukemic cells in many B-cell malignancies. It was originally demonstrated that BTK is involved in the primary antibody deficiency (D80.9)—a condition in which all Ig isotypes are reduced, accompanied by decreased or absent B cells (Bruton’s agammaglobulinemia, also known as XLA = X-linked agammaglobulinemia)—is mutated.

The following classification, based on pharmacological criteria, is commonly used:

• Covalent, irreversible BTK inhibitors
• Non-covalent, reversible BTK inhibitors
• Selective and less selective BTK inhibitors
• BTK-targeted protein degraders (a new class of drugs in clinical development)

BTK inhibitors (BTKis) have increasingly replaced chemotherapy for various malignant lymphomas in recent years (Liu J et al 2021). Bruton tyrosine kinase inhibitors are most effective in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but have also been approved for Waldenström macroglobulinemia, small lymphocytic lymphoma (SLL), marginal zone lymphoma, and chronic graft-versus-host disease (Brullo C et al. (2021).

The first-generation inhibitor, ibrutinib, acts by covalently irreversibly binding to BTK (irreversible BTK inhibitor), a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood) family that plays a critical role in B-cell receptor signaling (Sibaud V et al 2020). Ibrutinib also causes "off-target" inhibition of other kinases, such as epidermal growth factor receptor (EGFR), Src tyrosine kinases (Src= compound acronym of cellular and sarcoma) and other kinases of the TEC family (interleukin-2-inducible T-cell kinase also referred to as ITK as well as BMX).

Subsequently, second-generation BTKis have been developed that differ from ibrutinib, as an irreversible BTK inhibitor, by their specificity for BTK (reversible BTK inhibitors). They therefore stand out from ibrutinib in terms of side effects or efficacy (Liang C et al 2018). An example of this is acalabrutinib.

BTK inhibitors are used to treat B-cell-mediated malignant and immunological diseases. Their therapeutic significance ranges from the inhibition of malignant B-cell clones to the modulation of autoreactive B cells and Fc receptor-mediated inflammatory reactions (e.g., pemphigus vulgaris).

BTKi exhibit a number of drug-food interactions that can alter drug efficacy and/or increase toxicity (Fancher KMet al.2020). For example, zanubrutinib in humans is metabolized primarily by CYP3A. It can be assumed that with other BTKis, an influence on the active levels can also be expected with appropriate co-medication (Mu S et al. 2020).

BTK inhibitors approved to date (as of October 2026; approvals vary between the EU, the U.S., and other countries)

A. Hematologic-oncologic BTK inhibitors

• Ibrutinib (^Imbruvica®); covalent, irreversible; indication: CLL, mantle cell lymphoma (MCL), sometimes in combination therapy
• Zanubrutinib (^Brukinsa®); covalent, irreversible; Indications: CLL, Waldenström’s macroglobulinemia, marginal zone lymphoma, follicular lymphoma (in combination)
• Pirtobrutinib (^Jaypirca®); non-covalent, reversible; Indication: Previously treated B-cell malignancies, particularly MCL and CLL; exact approval varies by region and treatment line
• Tirabrutinib (^Velexbru®); covalent, irreversible; indication: primary CNS lymphoma; approved particularly in Japan
• Orelabrutinib; covalent, irreversible; indication: B-cell lymphomas; regional approval in China

B. Immunologically and dermatologically relevant BTK inhibitors

• Remibrutinib (^Rhapsido®); Indication: Chronic spontaneous urticaria (CSU); approved in the U.S. since 2025
• Rilzabrutinib (^Wayrilz®); Indication: Persistent or chronic immune thrombocytopenia (ITP); approved in the U.S. and EU (2025/2026)
• Fenebrutinib; Indication: Multiple sclerosis, CSU, autoimmune diseases; in clinical development
• Tolebrutinib; Indication: Multiple sclerosis, particularly progressive forms; in clinical development
• Branebrutinib; Indication: Systemic lupus erythematosus, Sjögren’s syndrome, atopic dermatitis; in clinical investigation
• Poseltinib; Indication: Rheumatoid arthritis and other autoimmune diseases; in clinical investigation
• TAS5315; Indication: Chronic spontaneous urticaria and immunological diseases; in early clinical development
• Note: Remibrutinib and rilzabrutinib mark an important step in development: BTK inhibitors are no longer exclusively oncological therapies but have opened up independent immunological indications (e.g., chronic spontaneous urticaria) (Metz M et al. 2025).

Current clinical practice is the continuous long-term administration of BTKi, which can be complicated by adverse effects or the development of drug resistance. Alternatives to the long-term use of BTKi are currently being developed, such as combination therapies that allow for time-limited therapy.

The 2nd generation BTK inhibitors acalabrutinib and zanubrutinib, were developed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC kinases). These drugs were recently approved by the FDA for relapsed or refractory mantle cell lymphoma.

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