Pirtobrutinib

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Pirtobrutinib
Pirtobrutinib.svg
Clinical data
Trade names Jaypirca
Other namesLOXO-305
AHFS/Drugs.com Monograph
MedlinePlus a623012
License data
Routes of
administration 		By mouth
Drug class Protein kinase inhibitor
ATC code
Legal status
Legal status
Identifiers
  • 5-amino-3-[4-[[(5-fluoro-2-methoxybenzoyl)amino]methyl]phenyl]-1-[(2S)-1,1,1-trifluoropropan-2-yl]pyrazole-4-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
Formula C22H21F4N5O3
Molar mass 479.436 g·mol−1
3D model (JSmol)
  • COC1=C(C=C(F)C=C1)C(=O)NCC1=CC=C(C=C1)C1=NN([C@@H](C)C(F)(F)F)C(N)=C1C(N)=O
  • InChI=1S/C22H21F4N5O3/c1-11(22(24,25)26)31-19(27)17(20(28)32)18(30-31)13-5-3-12(4-6-13)10-29-21(33)15-9-14(23)7-8-16(15)34-2/h3-9,11H,10,27H2,1-2H3,(H2,28,32)(H,29,33)/t11-/m0/s1
  • Key:FWZAWAUZXYCBKZ-NSHDSACASA-N

Pirtobrutinib, sold under the brand name Jaypirca, is an anticancer medication that is used to treat mantle cell lymphoma. [1] [2] [4] It inhibits B cell lymphocyte proliferation and survival by binding and inhibiting Bruton's tyrosine kinase (BTK). [5] It is taken by mouth. [1]

Contents

The most common adverse reactions include fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. [4] [6] The most common adverse reactions when used to treat chronic lymphocytic leukemia or small lymphocytic leukemia include fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. [7]

Pirtobrutinib was approved for medical use in the United States in January 2023, [4] [8] [9] [10] and in the European Union in November 2023. [2]

Medical uses

In the US, pirtobrutinib is indicated to treat relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a Bruton's tyrosine kinase (BTK) inhibitor. [1] [11] In December 2023, the US Food and Drug Administration (FDA) expanded the indication for pirtobrutinib to include the treatment of adults with chronic lymphocytic leukemia or small lymphocytic leukemia. [7] [12]

In the EU, pirtobrutinib is indicated for the treatment of mantle cell lymphoma. [2]

Mechanism of action

B cells are white cells of the lymphocyte subtype that produce antibodies, but when some of them grow uncontrollably they can be a cause of cancer. A key enzyme in B cell stimulation and survival is BTK, and pirtobrutinib inhibits BTK in a way that is different from the prototypical BTK inhibitor ibrutinib by binding in a different way that avoids a genetic change (mutation at active site cysteine residue C481 in BTK) that can make some tumors less responsive to ibrutinib. [5]

History

Pirtobrutinib is manufactured by Eli Lilly and Company and was approved by the US Food and Drug Administration in January 2023, for the treatment of mantle cell lymphoma that has become refractory to other BTK inhibitors. [13]

Efficacy was evaluated in BRUIN (NCT03740529), an open-label, multicenter, single-arm trial of pirtobrutinib monotherapy that included 120 participants with mantle cell lymphoma previously treated with a Bruton's tyrosine kinase (BTK) inhibitor. [4] Participants had a median of three prior lines of therapy, with 93% having two or more prior lines. [4] The most common prior Bruton's tyrosine kinase inhibitors received were ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%); 83% had discontinued their last Bruton's tyrosine kinase inhibitor due to refractory or progressive disease. [4] The trial was conducted at 49 sites in 10 countries in the United States, Europe, Australia, and Asia. [6] The same trial was used to assess safety and efficacy. [6]

Efficacy was evaluated in BRUIN (NCT03740529], an open-label, international, single-arm, multicohort trial that included 108 participants with chronic lymphocytic leukemia or small lymphocytic lymphoma previously treated with at least two prior lines of therapy, including a Bruton's tyrosine kinase (BTK) inhibitor and a B-cell lymphoma-2 (BCL-2) inhibitor. [7] Participants received a median of five prior lines of therapy (range: 2 to 11). [7] Seventy-seven percent of participants discontinued the last BTK inhibitor for refractory or progressive disease. [7] Pirtobrutinib was administered orally at 200 mg once daily and was continued until disease progression or unacceptable toxicity. [7]

Society and culture

In April 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jaypirca, intended for the treatment of relapsed or refractory mantle cell lymphoma (MCL). [14] The applicant for this medicinal product is Eli Lilly Nederland B.V. [14] Pirtobrutinib was approved for medical use in the European Union in November 2023. [2]

Related Research Articles

<span class="mw-page-title-main">Bruton's tyrosine kinase</span> Kinase that plays a role in B cell development

Bruton's tyrosine kinase, also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.

<span class="mw-page-title-main">CD135</span> Protein-coding gene in the species Homo sapiens

Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3, receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).

<span class="mw-page-title-main">Mantle cell lymphoma</span> Type of blood cancer

Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991.

Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer. It was originated by GlycArt Biotechnology AG and developed by Roche.

<span class="mw-page-title-main">Phosphoinositide 3-kinase inhibitor</span>

Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

<span class="mw-page-title-main">Idelalisib</span> Chemical compound

Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers. Idelalisib acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase. It was developed by Gilead Sciences. It is taken orally.

FCM, or FMC in the context of chemotherapy is an acronym for a chemotherapy regimen that is used in the treatment of indolent B cell non-Hodgkin's lymphomas. In combination with Rituximab, this regimen is called R-FCM or R-FMC, or FCM-R, FMC-R.

<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

<span class="mw-page-title-main">Acalabrutinib</span> Chemical compound

Acalabrutinib, sold under the brand name Calquence, is a medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic Lymphoma (CLL/SLL). It may be used both in relapsed as well as in treatment-naive settings.

<span class="mw-page-title-main">Duvelisib</span> PI3K inhibitor

Duvelisib, sold under the brand name Copiktra, is a medication used to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma after other treatments have failed. It is taken by mouth. It is a PI3 kinase inhibitor.

<span class="mw-page-title-main">Umbralisib</span> Chemical compound

Umbralisib, sold under the brand name Ukoniq, is an anti-cancer medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). It is taken by mouth.

Lisocabtagene maraleucel, sold under the brand name Breyanzi, is a cell-based gene therapy used to treat B-cell lymphoma and follicular lymphoma.

<span class="mw-page-title-main">Zanubrutinib</span> Chemical compound

Zanubrutinib, sold under the brand name Brukinsa, is an anticancer medication used for the treatment of mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL). Zanubrutinib is classified as a Bruton's tyrosine kinase (BTK) inhibitor. It is given by mouth.

Brexucabtagene autoleucel, sold under the brand name Tecartus, is a cell-based gene therapy medication for the treatment of mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL).

BeiGene, Ltd. is a China-based drug developer. It specializes in the development of drugs for cancer treatment. Founded in 2010 by chief executive officer John V. Oyler and Xiaodong Wang, the multinational company headquartered in Cambridge, Massachusetts has offices in North America, Europe, South America, Asia and Australia. BeiGene has a large presence in Chinese market. BeiGene has developed several pharmaceuticals, including tislelizumab, a checkpoint inhibitor, and zanubrutinib, a Bruton's tyrosine kinase inhibitor.

Mosunetuzumab, sold under the brand name Lunsumio, is a monoclonal antibody used for the treatment of follicular lymphoma. It bispecifically binds CD20 and CD3 to engage T-cells. It was developed by Genentech.

<span class="mw-page-title-main">Nemtabrutinib</span> Chemical compound

Nemtabrutinib is a small molecule drug that works as a reversible Bruton's tyrosine kinase (BTK) inhibitor; unlike other BTK inhibitors it also works against some mutated forms of BTK. Merck paid $2.7 billion to acquire the company ArQule and the drug, which is being investigated as a cancer treatment.

<span class="mw-page-title-main">Orelabrutinib</span> Drug for treatment of cancer

Orelabrutinib is a drug for the treatment of cancer.

References

  1. 1 2 3 4 "Jaypirca- pirtobrutinib tablet, coated". DailyMed. 27 January 2023. Archived from the original on 11 February 2023. Retrieved 11 February 2023.
  2. 1 2 3 4 5 "Jaypirca EPAR". European Medicines Agency (EMA). 20 November 2023. Archived from the original on 22 November 2023. Retrieved 22 November 2023.
  3. ↑ "Jaypirca Product information". Union Register of medicinal products. 31 October 2023. Archived from the original on 22 November 2023. Retrieved 22 November 2023.
  4. 1 2 3 4 5 6 "FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma". FDA. 27 January 2023. Archived from the original on 28 January 2023. Retrieved 28 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. 1 2 Aslan B, Kismali G, Iles LR, Manyam GC, Ayres ML, Chen LS, et al. (May 2022). "Pirtobrutinib inhibits wild-type and mutant Bruton's tyrosine kinase-mediated signaling in chronic lymphocytic leukemia". Blood Cancer Journal. 12 (5): 80. doi:10.1038/s41408-022-00675-9. PMC   9123190 . PMID   35595730.
  6. 1 2 3 "Drug Trials Snapshots: Jaypirca". U.S. Food and Drug Administration (FDA). 27 January 2023. Retrieved 13 May 2024.
  7. 1 2 3 4 5 6 "FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma". U.S. Food and Drug Administration (FDA). 1 December 2023. Archived from the original on 3 December 2023. Retrieved 3 December 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  8. ↑ "U.S. FDA Approves Jaypirca (pirtobrutinib), the First and Only Non-Covalent (Reversible) BTK Inhibitor, for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma After at Least Two Lines of Systemic Therapy, Including a BTK Inhibitor" (Press release). Eli Lilly. 27 January 2023. Archived from the original on 30 January 2023. Retrieved 31 January 2023– via PR Newswire.
  9. ↑ Keam SJ (April 2023). "Pirtobrutinib: First Approval". Drugs. 83 (6): 547–553. doi:10.1007/s40265-023-01860-1. PMID   37004673. S2CID   257912433. Archived from the original on 19 November 2023. Retrieved 19 November 2023.
  10. ↑ Telaraja D, Kasamon YL, Collazo JS, Leong R, Wang K, Li P, et al. (August 2023). "FDA Approval Summary: Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma". Clinical Cancer Research. 30 (1): OF1–OF6. doi:10.1158/1078-0432.CCR-23-1272. PMC   10841293 . PMID   37624619. S2CID   265965744.
  11. ↑ De SK (October 2023). "Pirtobrutinib: First Non-covalent Tyrosine Kinase Inhibitor for Treating Relapsed or Refractory Mantle Cell Lymphoma in Adults". Current Medicinal Chemistry. 31. doi:10.2174/0109298673251030231004052822. PMID   37818564. S2CID   263828536.
  12. ↑ "Jaypirca (pirtobrutinib) Now Approved by U.S. FDA for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Who Have Received at Least Two Lines of Therapy, Including a BTK Inhibitor and a BCL-2 Inhibitor" (Press release). Eli Lilly. 1 December 2023. Archived from the original on 3 December 2023. Retrieved 3 December 2023– via PR Newswire.
  13. ↑ "FDA approves Eli Lilly's drug for rare blood cancer". Reuters . 27 January 2023. Archived from the original on 28 January 2023.
  14. 1 2 "Jaypirca: Pending EC decision". European Medicines Agency. 26 April 2023. Archived from the original on 26 April 2023. Retrieved 27 April 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

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