Pirtobrutinib

Pirtobrutinib

• CAS 2101700-15-4
• JAYPIRCA
• RXC-005
• LY3527727
• LOXO-305
• WHO 11681
• WeightAverage: 479.436
• Monoisotopic: 479.158052208
• Chemical FormulaC₂₂H₂₁F₄N₅O₃

5-amino-3-[4-[[(5-fluoro-2-methoxybenzoyl)amino]methyl]phenyl]-1-[(2S)-1,1,1-trifluoropropan-2-yl]pyrazole-4-carboxamide

FDA 2023, 1/27/2023, Jaypirca

To treat relapsed or refractory mantle cell lymphoma in adults who have had at least two lines of systemic therapy, including a BTK inhibitor
Drug Trials Snapshot

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]

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]

PATENTS

Guisot, N. (2017). Compounds useful as kinase inhibitors (WO 2017/103611 A1). World Intellectual Property Organization. https://patentimages.storage.googleapis.com/d7/16/21/9300e49071a21a/WO2017103611A1.pdf

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017103611&_cid=P10-MAG7OA-80884-1

[00381] Example 120: 5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1- (2,2,2-trifluoro-1 -methyl-ethyl)pyrazole-4-carboxamide

N-[(2,2,2-Trifluoro-1-methyl-ethylidene)aminolbenzamide

General procedure S, benzhydrazide (49.9 mmol) and 1,1,1- trifluoroacetone (74.9 mmol) gave, after washing, the titled compound as a white solid. UPLC-MS (ES ⁺ , Short acidic): 1.45 min, m/z 230.9 [M+H] ⁺

-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazole-4-carboxamide

General procedure M, N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide (0.83 mmol) gave, after purification, the titled compound (0.42 mmol) as a white solid. UPLC-MS (ES ⁺ , Short acidic): 1.55 min, m/z 480.1 [M+H] ⁺ . UPLC-MS (ES ⁺ , Long acidic): 3.57 min, m/z 480.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , δ): 8.84 (t, J = 6.1 Hz, 1H), 7.52 (dd, J = 9.2, 3.3 Hz, 1H), 7.48-7.41 (m, 4H), 7.37-7.32 (m, 1H), 7.19 (dd, J = 9.1, 4.3 Hz, 1H), 6.67 (s, 2H), 5.35-5.24 (m, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 1.62 (d, J = 6.9 Hz, 3H).

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Medical uses

In the United States, 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 European Union, 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

Legal status

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]

References

1. ^ Jump up to:^a b c d “Jaypirca- pirtobrutinib tablet, coated”. DailyMed. 27 January 2023. Archived from the original on 11 February 2023. Retrieved 11 February 2023.
2. ^ Jump up to:^{a b c d e} “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. ^ Jump up to:^{a b c d e f} “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.  This article incorporates text from this source, which is in the public domain.
5. ^ Jump up to:^a b 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. ^ Jump up to:^a b c “Drug Trials Snapshots: Jaypirca”. U.S. Food and Drug Administration (FDA). 27 January 2023. Retrieved 13 May 2024.
7. ^ Jump up to:^{a b c d e f} “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.  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. ^ Jump up to:^a b “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.

Further reading

• Mato AR, Woyach JA, Brown JR, Ghia P, Patel K, Eyre TA, et al. (July 2023). “Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia”. The New England Journal of Medicine. 389 (1): 33–44. doi:10.1056/NEJMoa2300696. hdl:11585/960014. PMID 37407001. S2CID 259358462.

External links

• “Pirtobrutinib”. National Cancer Institute. 16 February 2023.
• “Pirtobrutinib”. NCI Drug Dictionary.

1. Jensen JL, Mato AR, Pena C, Roeker LE, Coombs CC: The potential of pirtobrutinib in multiple B-cell malignancies. Ther Adv Hematol. 2022 Jun 16;13:20406207221101697. doi: 10.1177/20406207221101697. eCollection 2022. [Article]
2. Aslan B, Kismali G, Iles LR, Manyam GC, Ayres ML, Chen LS, Gagea M, Bertilaccio MTS, Wierda WG, Gandhi V: Pirtobrutinib inhibits wild-type and mutant Bruton’s tyrosine kinase-mediated signaling in chronic lymphocytic leukemia. Blood Cancer J. 2022 May 20;12(5):80. doi: 10.1038/s41408-022-00675-9. [Article]
3. Alu A, Lei H, Han X, Wei Y, Wei X: BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies. J Hematol Oncol. 2022 Oct 1;15(1):138. doi: 10.1186/s13045-022-01353-w. [Article]
4. Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M: Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi: 10.1016/S0140-6736(21)00224-5. [Article]
5. Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, Durham BH, Penson A, Witkowski MT, Lu SX, Bourcier J, Hogg SJ, Erickson C, Cui D, Cho H, Singer M, Totiger TM, Chaudhry S, Geyer M, Alencar A, Linley AJ, Palomba ML, Coombs CC, Park JH, Zelenetz A, Roeker L, Rosendahl M, Tsai DE, Ebata K, Brandhuber B, Hyman DM, Aifantis I, Mato A, Taylor J, Abdel-Wahab O: Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors. N Engl J Med. 2022 Feb 24;386(8):735-743. doi: 10.1056/NEJMoa2114110. [Article]
6. FDA Approved Drug Products: JAYPIRCA (pirtobrutinib) tablets for oral use [Link]
7. BioSpace: 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 [Link]

//////////////Jaypirca, FDA 2023, APPROVALS 2023, Pirtobrutinib, RXC-005, LY3527727, LOXO-305, LOXO 305, WHO 11681