Orelabrutinib: A Novel BTK inhibitor

I. Introduction to Orelabrutinib

Orelabrutinib, developed by InnoCare Pharma, is an orally bioavailable, second-generation Bruton's tyrosine kinase (BTK) inhibitor. [Dhillon, 2021] This novel drug has shown promise in treating various diseases, particularly B-cell malignancies and autoimmune diseases. [Dhillon, 2021]

Bruton's tyrosine kinase (BTK) is an enzyme that plays a crucial role in B-cell development and function within the immune system. BTK is particularly important for the maturation of B cells and their response to various signals, including those involved in the immune response. [Grassilli, 2022]

In diseases, BTK is often associated with B-cell malignancies, autoimmune disorders, and allergic conditions. For example, BTK inhibitors are used in the treatment of B-cell malignancies like chronic lymphocytic leukemia (CLL) and mantle cell lymphoma, where aberrant B-cell signaling contributes to disease progression. BTK's role in immune responses makes it a target for therapeutic intervention in various diseases. [Grassilli, 2022]

II. Understanding BTK and Its Role in B cell malignancies

BTK is a member of the TEC family of non-receptor kinases. [Dhillon, 2021] It is expressed constitutively in myeloid and lymphoid cells and plays a key role in the development, survival, and activation of B cells. [Dhillon, 2021] Dysregulation of BTK signaling has been linked to various B cell malignancies and autoimmune diseases, providing a rationale for the development of BTK inhibitors. [Dhillon, 2021]

The first-generation BTK inhibitor, ibrutinib, revolutionized the treatment of B cell malignancies. However, its use has been limited by adverse events resulting from off-target kinase inhibition.  [Dhillon, 2021] This has led to the development of highly selective, second-generation BTK inhibitors with fewer off-target effects. [Dhillon, 2021]

The following are some of the drawbacks of ibrutinib:

Bleeding Risk: Ibrutinib can increase the risk of bleeding due to its impact on platelet function.

Patients taking this medication should be cautious, especially if they have a history of bleeding problems or are undergoing surgical or dental procedures. [Ibrutinib, 2024].

Cardiovascular Effects: Some patients may experience heart rhythm problems while on ibrutinib. Individuals with existing heart conditions, high blood pressure, high cholesterol, or diabetes should be closely monitored. [Ibrutinib, 2024]

Infections: Ibrutinib can suppress the immune system, making patients more susceptible to infections. Patients with existing infections should be carefully managed while on this medication.  [Ibrutinib, 2024]

Liver Function: Liver problems can occur with ibrutinib use.Regular liver function tests are essential to monitor any adverse effects. [Ibrutinib, 2024]

Common Side Effects: These include diarrhea, fatigue, rash, nausea, and musculoskeletal pain.Thrombocytopenia (low platelet count) and neutropenia (low neutrophil count) are also common.  [Ibrutinib, 2024]

III. Understanding BTK and Its Role in multiple sclerosis

Bruton's tyrosine kinase (BTK) plays a significant role in the context of Multiple Sclerosis (MS), an autoimmune disease characterized by inflammation and demyelination in the central nervous system. While traditionally known for its involvement in B-cell signaling and function within the immune system, recent research has shed light on the broader implications of BTK in various autoimmune conditions, including MS. [Krämer, 2023]

In MS, BTK is implicated in the activation and function of B cells, which are key players in the autoimmune response that characterizes the disease. B cells are known to contribute to the pathology of MS by producing autoantibodies and promoting inflammation in the central nervous system. BTK, being a crucial component in B-cell signaling, becomes a potential target for therapeutic intervention in an effort to modulate the autoimmune response associated with MS. [Krämer, 2023]

Studies have suggested that inhibiting BTK activity may have a positive impact on the progression of MS. By targeting BTK, researchers aim to disrupt the aberrant signaling pathways that lead to the activation of autoimmune responses, ultimately mitigating the inflammatory processes and damage to the myelin sheath observed in MS patients. This has led to the exploration of BTK inhibitors as a potential treatment strategy for MS, with the goal of suppressing the autoimmune response and alleviating the symptoms of the disease. [Krämer, 2023]

While research on BTK's role in MS is still evolving, the exploration of BTK inhibitors as a therapeutic approach underscores the dynamic nature of understanding the immune system's involvement in autoimmune disorders. Further investigations into the specific mechanisms through which BTK influences the pathogenesis of MS may provide valuable insights and potentially pave the way for more targeted and effective treatment options for individuals affected by this complex autoimmune condition. [Krämer, 2023]

IV. Orelabrutinib: A Second-Generation BTK Inhibitor

Orelabrutinib is an oral small molecule that targets BTK, an enzyme important for the activation of immune cell populations implicated in multiple sclerosis (MS), namely B-cells and macrophages. [Dhillon, 2021] By preventing their activation, orelabrutinib is expected to ease inflammation and slow MS progression. [Dhillon, 2021]

Orelabrutinib seems to be more selective for BTK, with more than 90% inhibition of the enzyme and no blocking of other similar enzymes. [Dhillon, 2021] It also has a favorable pharmacological profile and seems to bind to a greater proportion of BTK enzymes in the blood than other similar inhibitors. [Dhillon, 2021] This could allow the medication to be given once per day at low doses. [Dhillon, 2021]

Moreover, orelabrutinib is able to cross the selective barrier that separates the brain from the bloodstream, and thereby enter readily into brain tissue. [Dhillon, 2021] The company believes these properties will make for a BTK inhibitor with improved safety and high efficacy. [Dhillon, 2021]

V. Conclusion:

In conclusion, the development of orelabrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor by InnoCare Pharma, represents a significant stride in addressing the limitations of first-generation BTK inhibitors, such as ibrutinib, particularly in the treatment of B-cell malignancies and autoimmune diseases. Orelabrutinib's enhanced selectivity for BTK, favorable pharmacological profile, and ability to cross the blood-brain barrier make it a promising candidate for multiple sclerosis (MS) treatment, where BTK plays a pivotal role in autoimmune responses. The potential of orelabrutinib in modulating aberrant B-cell signaling in MS opens new avenues for therapeutic intervention in this complex autoimmune condition. As research on BTK and its inhibitors advances, the hope is that such innovative treatments will contribute to more targeted and effective strategies for managing not only B-cell malignancies but also autoimmune disorders like MS, providing improved safety and higher efficacy for patients in need.

VI. Sources

Dhillon, Sohita. "Orelabrutinib: First Approval." Drugs, vol. 81, no. 4, 2021, pp. 503-507. Drugs, doi:10.1007/s40265-021-01482-5.

Grassilli, Emanuela, et al. "BTK, the New Kid on the (Oncology) Block?" Frontiers in Oncology, vol. 12, 2022, article IX3P87PZ, doi:10.3389/fonc.2022.944538."

Ibrutinib: Uses, Dosage, Side Effects, Warnings." Drugs.com, 2024, https://www.drugs.com/ibrutinib.html. Accessed 29 Feb. 2024.

Krämer, Julia, et al. "Bruton Tyrosine Kinase Inhibitors for Multiple Sclerosis." Nature Reviews Neurology, vol. 19, no. 5, 2023, pp. 289-304. Nature Publishing Group, May 2023, doi:10.1038/s41582-023-00800-7.

About the Author:

David Orchard-Webb

David  Orchard-Webb, Ph.D., is a technical writer with broad interests including health & technology writing, plus extensive training and knowledge of  biomedicine and microbiology. My Ph.D. and postdoc were in oncology and  developing cancer medicines. I provide technical medical and other writing  services for projects ranging from “knowledge automation” to pure pharma, to  food safety, to the history of science, and everything in between. I also provide white papers, ebooks, meta-analysis reviews, editing, consulting,  business, and market research-related activities in biomedicine, technology,  and health. In addition to its well-known role in the development of  medicines, I am a big believer in biotechnology’s ability to revolutionize industries such as food-tech, agtech, textiles & fashion.