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  4. What is the mechanism of action of Jaypirca™ (pirtobrutinib)?
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Jaypirca ® (pirtobrutinib) tablets

50 mg,100 mg

Full Prescribing Information

This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.

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.

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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

Various B cell malignancies rely on B cell receptor signaling to initiate the survival and proliferation of malignant B cells.4,5 

Pirtobrutinib Mechanism of Action Infographic

The mechanism of action is described in Pirtobrutinib Mechanism of Action .

Pirtobrutinib Mechanism of Action3-9 

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

JAYPIRCA® (pirtobrutinib) tablets, for oral use, Lilly

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

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