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Jaypirca ® (pirtobrutinib) tablets
50 mg,100 mg
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What is the mechanism of action of Jaypirca™ (pirtobrutinib)?
Jaypirca (pirtobrutinib) is a small molecule, non-covalent (reversible) inhibitor of BTK, a signaling protein of the B-cell antigen receptor and cytokine receptor pathways.
Mechanism of Action
Pirtobrutinib is a small molecule, non-covalent (reversible) inhibitor of Bruton's tyrosine kinase (BTK), a signaling protein of the B-cell antigen receptor and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.1,2
Pirtobrutinib binds to wild-type BTK and BTK-harboring C481 mutations, leading to inhibition of BTK activity.1 Pirtobrutinib binding has been postulated to stabilize BTK in a closed, inactive conformation that may be less accessible to other cellular proteins.3
In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild-type and BTK C481S mutant mouse xenograft models.1
Pirtobrutinib Mechanism of Action Infographic
The mechanism of action is described in Pirtobrutinib Mechanism of Action .
1. BTK is a key component of the B-cell receptor pathway and plays an important role when B-cells give rise to certain cancers.
2. Pirtobrutinib is a novel, non-covalent (reversible) BTK inhibitor.
3. In preclinical studies, pirtobrutinib demonstrated single-digit nanomolar potency against wild-type and C481-mutated BTK and was over 300-fold more selective for BTK versus 98% of 370 non-BTK kinases.
4. B-cells synthesize new BTK throughout the day. Pirtobrutinib has a long half-life (approximately 19 hours) which allows significant concentrations to maintain BTK inhibition regardless of BTK protein or cell turnover.
5. As a reversible inhibitor, pirtobrutinib binds in a different way to inhibit BTK regardless of common acquired resistance mutations. Pirtobrutinib binding has been postulated to stabilize BTK in a closed, inactive conformation that may be less accessible to other cellular proteins.
Pirtobrutinib is a different kind of BTK inhibitor that continues to be investigated in global clinical studies. Pirtobrutinib is a non-covalent (reversible) BTK inhibitor, has a long half-life with sustained target coverage, is highly potent and selective, and overcomes common resistance mutations.
Abbreviation: BTK = Bruton's tyrosine kinase.
Pirtobrutinib Mechanism of Action Video
The mechanism of action is described in the following video: Pirtobrutinib Mechanism of Action.
Other BTK Inhibitors
Various B cell malignancies rely on B cell receptor signaling to initiate the survival and proliferation of malignant B cells.4,5
There are both covalent and noncovalent BTK inhibitors being studied or used for B-cell malignancies.7 Covalent BTK inhibitors bind irreversibly at the C481 residue of BTK, while noncovalent inhibitors bind reversibly to BTK and do not bind to C481.10 Pirtobrutinib is a non-covalent (reversible) BTK inhibitor.1,2
For information on other BTK inhibitors, please contact the individual manufacturers of these drugs.
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Jaypirca [package insert]. Indianapolis, IN: Eli Lilly and Company; 2024.
2Wang ML, Shah NN, Jurczak W, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed/refractory mantle cell lymphoma: additional patients and extended follow-up from the phase 1/2 BRUIN study. Poster presented at: 64th Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2022; New Orleans, Louisiana. Accessed December 10, 2022.
3Gomez EB, Ebata K, Randeria HS, et al. Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor. Blood. Published online February 16, 2023. https://doi.org/10.1182/blood.2022018674
4Gu D, Tang H, Wu J, et al. Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies. J Hematol Oncol. 2021;14(1):40. https://doi.org/10.1186/s13045-021-01049-7
5Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014;14(4):219-232. https://doi.org/10.1038/nrc3702
6Alsadhan A, Cheung J, Gulrajani M, et al. Pharmacodynamic analysis of BTK inhibition in patients with chronic lymphocytic leukemia treated with acalabrutinib. Clin Cancer Res. 2020;26(12):2800-2809. https://doi.org/10.1158/1078-0432.CCR-19-3505
7Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative analysis of BTK inhibitors and mechanisms underlying adverse effects. Front Cell Dev Biol. 2021;9:630942. https://doi.org/10.3389/fcell.2021.630942
8Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. https://doi.org/10.1016/S0140-6736(21)00224-5
9Ou YC, Tang Z, Novotny W, et al. Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma. Leuk Lymphoma. 2021;62(11):2612-2624. https://doi.org/10.1080/10428194.2021.1929961
10Profitós-Pelejà N, Santos JC, Marín-Niebla A, et al. Regulation of B-cell receptor signaling and its therapeutic relevance in aggressive B-cell lymphomas. Cancers. 2022;14(4):860. https://doi.org/10.3390/cancers14040860
Date of Last Review: January 09, 2023