Lurbinectedin Explained

Pronounce:
Tradename:Zepzelca
Dailymedid:Lurbinectedin
Pregnancy Au:D
Pregnancy Au Comment:[1] [2] [3]
Routes Of Administration:Intravenous
Class:Antineoplastic agent
Atc Prefix:L01
Atc Suffix:XX69
Legal Au:S4
Legal Ca:Rx-only
Legal Ca Comment:[4]
Legal Us:Rx-only
Cas Number:497871-47-3
Pubchem:57327016
Drugbank:12674
Chemspiderid:32701856
Unii:2CN60TN6ZS
Kegg:D11644
Chembl:4297516
Synonyms:PM-01183
Iupac Name:[(1''R'',2''R'',3''R'',11''S'',12''S'',14''R'',26''R'')-5,12-dihydroxy-6,6'-dimethoxy-7,21,30-trimethyl-27-oxospiro[17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1<sup>3,11</sup>.0<sup>2,13</sup>.0<sup>4,9</sup>.0<sup>15,23</sup>.0<sup>16,20</sup>]triaconta-4(9),5,7,15,20,22-hexaene-26,1'-2,3,4,9-tetrahydropyrido[3,4-''b'']indole]-22-yl] acetate
C:41
H:44
N:4
O:10
S:1
Smiles:CC1=CC2=C([C@@H]3[C@@H]4[C@H]5C6=C(C(=C7C(=C6[C@@H](N4[C@H]([C@H](C2)N3C)O)COC(=O)[C@@]8(CS5)C9=C(CCN8)C2=C(N9)C=CC(=C2)OC)OCO7)C)OC(=O)C)C(=C1OC)O
Stdinchi:1S/C41H44N4O10S/c1-17-11-20-12-25-39(48)45-26-14-52-40(49)41(38-22(9-10-42-41)23-13-21(50-5)7-8-24(23)43-38)15-56-37(31(45)30(44(25)4)27(20)32(47)33(17)51-6)29-28(26)36-35(53-16-54-36)18(2)34(29)55-19(3)46/h7-8,11,13,25-26,30-31,37,39,42-43,47-48H,9-10,12,14-16H2,1-6H3/t25-,26-,30+,31+,37+,39-,41+/m0/s1
Stdinchikey:YDDMIZRDDREKEP-HWTBNCOESA-N

Lurbinectedin, sold under the brand name Zepzelca, is a medication used for the treatment of small cell lung cancer.[5] [6] [7]

The most common side effects include leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.

Lurbinectedin is a synthetic tetrahydropyrrolo [4,3,2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity.[8] Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death.

Lurbinectedin was approved for medical use in the United States in June 2020.[9] [10]

Medical uses

Lurbinectedin is indicated for the treatment of adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Structure

Lurbinectedin is structurally similar to trabectedin, although the tetrahydroisoquinoline present in trabectedin is replaced with a tetrahydro β-carboline which enables lurbinectedin to exhibit increased antitumor activity compared with trabectedin.[11]

Synthesis

Synthesis of lurbinectedin starts from small, common starting materials that require twenty-six individual steps to produce the drug with overall yield of 1.6%.[12]

Mechanism of action

According to PharmaMar,[13] lurbinectedin inhibits the active transcription of the encoding genes. This has two consequences. It promotes tumor cell death and normalizes the tumor microenvironment. Active transcription is the process by which there are specific signal where information contained in the DNA sequence is transferred to an RNA molecule. This activity depends on the activity of an enzyme called RNA polymerase II. Lurbinectedin inhibits transcription through a very precise mechanism. Firstly, lurbinectedin binds to specific DNA sequences. It is at these precise spots that slides down the DNA to produce RNA polymerase II that is blocked and degraded by lurbinectedin. Lurbinectedin also has important role in tumor microenvironment. The tumor cells act upon macrophages to avoid them from behaving like an activator of the immune system. Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells.[14] [15] Attracted to oxygen-starved (hypoxic) and necrotic tumor cells they promote chronic inflammation. So, not only that macrophages inhibit immune system avoiding the destruction of tumor cells, but they also create tumor tissue that allows tumor growth. However, macrophages associated with tumors are cells that are addicted to the transcription process. Lurbinectedin acts specifically on the macrophages associated with tumors in two ways: firstly, by inhibiting the transcription of macrophages that leads to cell death and secondly, inhibiting the production of tumor growth factors. In this way, lurbinectedin normalizes the tumor microenvironment.

History

Lurbinectedin was approved for medical use in the United States in June 2020.

Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 participants with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. Participants received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity. The trial was conducted at 26 sites in the United States, Great Britain, Belgium, France, Italy, Spain and Czech Republic.

The U.S. Food and Drug Administration (FDA) granted the application for lurbinectedin priority review and orphan drug designations and granted the approval of Zepzelca to Pharma Mar S.A.[16]

Research

Clinical Trials

Lurbinectedin can be used as monotherapy in the treatment of SCLC. Lurbinectedin monotherapy demonstrated the following clinical results in relapsed extensive stage SCLC:

Lurbinectedin is also being investigated in combination with doxorubicin as second-line therapy in a randomized Phase III trial. While overall survival in this trial is not yet known, response rates at second line were

Lurbinectedin is available in the U.S. under Expanded Access Program (EAP).[18] [20]

External links

Notes and References

  1. Web site: Zepzelca . Therapeutic Goods Administration (TGA) . 22 September 2021 . 30 September 2021 . 30 September 2021 . https://web.archive.org/web/20210930230724/https://www.tga.gov.au/apm-summary/zepzelca . live .
  2. Web site: AusPAR: lurbinectedin . Therapeutic Goods Administration (TGA) . 4 May 2022 . 4 May 2022 . 4 May 2022 . https://web.archive.org/web/20220504040348/https://www.tga.gov.au/auspar/auspar-lurbinectedin . live .
  3. Web site: Updates to the Prescribing Medicines in Pregnancy database . Therapeutic Goods Administration (TGA) . 12 May 2022 . 13 May 2022 . 3 April 2022 . https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database . live .
  4. Web site: Summary Basis of Decision (SBD) for Zepzelca . Health Canada . 23 October 2014 . 29 May 2022 . 29 May 2022 . https://web.archive.org/web/20220529195106/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00566&lang=en . live .
  5. Web site: Zepzelca- lurbinectedin injection, powder, lyophilized, for solution . DailyMed . 15 June 2020 . 24 September 2020 . 24 January 2021 . https://web.archive.org/web/20210124010008/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=632bb50c-3bcb-4c85-9056-fc33410550ae . live .
  6. Jazz Pharmaceuticals . Jazz Pharmaceuticals Announces U.S. FDA Accelerated Approval of Zepzelca (lurbinectedin) for the Treatment of Metastatic Small Cell Lung Cancer . PR Newswire . 15 June 2020 . 15 June 2020 . 15 June 2020 . https://web.archive.org/web/20200615194936/https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-us-fda-accelerated-approval-of-zepzelca-lurbinectedin-for-the-treatment-of-metastatic-small-cell-lung-cancer-301077082.html . live .
  7. Web site: FDA grants accelerated approval to lurbinectedin for metastatic small . U.S. Food and Drug Administration (FDA) . 15 June 2020 . 16 June 2020 . 18 June 2020 . https://web.archive.org/web/20200618040051/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-lurbinectedin-metastatic-small-cell-lung-cancer . live .
  8. Web site: Lurbinectedin . National Cancer Institute . 15 June 2020 . 16 May 2020 . https://web.archive.org/web/20200516183047/https://www.cancer.gov/publications/dictionaries/cancer-drug/def/lurbinectedin . live .
  9. Web site: Zepzelca: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 15 June 2020 . 19 October 2020 . https://web.archive.org/web/20201019161748/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=213702 . live .
  10. Web site: Drug Trials Snapshots: Zepzelca . U.S. Food and Drug Administration (FDA) . 15 June 2020 . 28 June 2020 . 22 December 2020 . https://web.archive.org/web/20201222061727/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-zepzelca . live .
  11. Takahashi R, Mabuchi S, Kawano M, Sasano T, Matsumoto Y, Kuroda H, Kozasa K, Hashimoto K, Sawada K, Kimura T . 6 . Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary . PLOS ONE . 11 . 3 . e0151050 . March 2016 . 26986199 . 4795692 . 10.1371/journal.pone.0151050 . free . 2016PLoSO..1151050T .
  12. He W, Zhang Z, Ma D . A Scalable Total Synthesis of the Antitumor Agents Et-743 and Lurbinectedin . Angewandte Chemie . 58 . 12 . 3972–3975 . March 2019 . 30689274 . 10.1002/anie.201900035 . 59306678 .
  13. PharmaMar presentation of Lurbinectedin's Mechanism of Action Lurbinectedin of Action | https://www.youtube.com/watch?v=8daELhxAXcQ
  14. Qian BZ, Pollard JW . Macrophage diversity enhances tumor progression and metastasis . Cell . 141 . 1 . 39–51 . April 2010 . 20371344 . 4994190 . 10.1016/j.cell.2010.03.014 .
  15. Engblom C, Pfirschke C, Pittet MJ . The role of myeloid cells in cancer therapies . Nature Reviews. Cancer . 16 . 7 . 447–462 . July 2016 . 27339708 . 10.1038/nrc.2016.54 . 21924175 .
  16. Web site: Lurbinectedin Orphan Drug Designation and Approval . U.S. Food and Drug Administration (FDA) . 1 August 2018 . 16 June 2020 . 17 June 2020 . https://web.archive.org/web/20200617052957/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=646018 . live .
  17. Paz-Ares LG, Trigo Perez JM, Besse B, Moreno V, Lopez R, Sala MA, Ponce Aix S, Fernandez CM, Siguero M, Kahatt CM, Zeaiter AH, Zaman K, Boni V, Arrondeau J, Martinez Aguillo M, Delord J, Awada A, Kristeleit RS, Olmedo Garcia ME, Subbiah V . 6 . Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial . Journal of Clinical Oncology . May 2019 . 37 . 15_suppl . 8506 . 10.1200/JCO.2019.37.15_suppl.8506 . 190884224 .
  18. Calvo E, Moreno V, Flynn M, Holgado E, Olmedo ME, Lopez Criado MP, Kahatt C, Lopez-Vilariño JA, Siguero M, Fernandez-Teruel C, Cullell-Young M, Soto Matos-Pita A, Forster M . 6 . Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study . Annals of Oncology . 28 . 10 . 2559–2566 . October 2017 . 28961837 . 5834091 . 10.1093/annonc/mdx357 . vanc .
  19. PharmaMar and Bionical Emas Launch Expanded Access Program for Lurbinectedin in Relapsed Small Cell Lung Cancer in the U.S. . Bionical Emas . PR Newswire . 27 January 2020 . 4 May 2022 . 18 August 2022 . https://web.archive.org/web/20220818204932/https://www.prnewswire.com/news-releases/pharmamar-and-bionical-emas-launch-expanded-access-program-for-lurbinectedin-in-relapsed-small-cell-lung-cancer-in-the-us-300993470.html . live .
  20. Farago AF, Drapkin BJ, Lopez-Vilarino de Ramos JA, Galmarini CM, Núñez R, Kahatt C, Paz-Ares L . ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line . Future Oncology . 15 . 3 . 231–239 . January 2019 . 30362375 . 6331752 . 10.2217/fon-2018-0597 . vanc .

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