Brentuximab vedotin

Brentuximab vedotin
Monoclonal antibody
TypeWhole antibody
SourceChimeric (mouse/human)
TargetCD30
Names
Trade namesAdcetris
Other namesSGN-35, previously cAC10-vcMMAE
Clinical data
Drug classAntibody-drug conjugate
Main usesHodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL)[1]
Side effectsPeripheral nerve damage, tiredness, nausea, diarrhea, low white blood cells, fever, hair loss, mouth inflammation[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Routes of
    use    		Intravenous
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa611052
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only [1]
    Chemical and physical data
    FormulaC6476H9930N1690O2030S40 (C68H105N11O15)3–5
    Molar mass149.2–151.8 kg/mol

    Brentuximab vedotin, sold under the brand name Adcetris, is a medication used to treat Hodgkin lymphoma (HL) and certain non-Hodgkin lymphoma (NHL).[1] Specifically it is used for cases that are CD30 positive.[1] It is given by injection into a vein.[3]

    Common side effects include peripheral nerve damage, tiredness, nausea, diarrhea, low white blood cells, fever, hair loss, and mouth inflammation.[2] Other side effects may include anaphylaxis, infections, tumor lysis syndrome, liver problems, lung problems, Stevens-Johnson syndrome, and high blood sugar.[2] Use in pregnancy may harm the baby.[2] It is a monoclonal antibody that binds to CD30 linked to the cytotoxin monomethyl auristatin E.[1]

    Brentuximab vedotin was approved for medical use in the United States in 2011 and Europe 2012.[2][1] In the United Kingdom a 50 mg vial costs about £2,500 as of 2021.[3] In the United States this amount costs about 10,100 USD.[4]

    Medical uses

    It is used to treat relapsed HL and ALCL.[5]

    In November 2017, the FDA approved brentuximab vedotin as a treatment for patients with cutaneous T-cell lymphoma (CTCL) who have received prior systemic therapy.[6] This approval is for patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) and CD30-expressing mycosis fungoides (MF).[6]

    In March 2018, the FDA approved brentuximab vedotin to treat adults with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy.[7][8]

    In November 2018, the FDA expanded the approved use of brentuximab vedotin in combination with chemotherapy for adults with certain types of peripheral T-cell lymphoma (PTCL).[9] This is the first FDA approval for treatment of newly diagnosed PTCL.[9]

    Approval in Australia

    The Australian Pharmaceutical Benefits Advisory Committee (PBAC) considered a March 2014 application by the manufacturer for inclusion of brentuximab vedotin under a Pharmaceutical Benefits Scheme Section 100 (Efficient Funding of Chemotherapy) arrangement. While this application was accepted, the committee noted that on the basis of inadequate cost-benefit, the medicine would not be made available more generally for the first-line treatment of relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).[10]

    Side effects

    The most common adverse reactions (≥20%), regardless of causality, were chemotherapy-induced peripheral neuropathy (a progressive, enduring and often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs), neutropenia (an immune system impairment), fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough and vomiting.[2]

    Box warning

    On January 13, 2012, the FDA announced that because brentuximab vedotin had been linked with two cases of progressive multifocal leukoencephalopathy, they were requiring the addition of a black box warning to the drug label regarding this potential risk.[11][2]

    Interactions

    Patients who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be closely monitored for serious adverse events.[2]

    Chemistry

    Brentuximab vedotin[12] consists of the chimeric monoclonal antibody brentuximab (cAC10, which targets the cell-membrane protein CD30) linked with maleimide attachment groups, cathepsin-cleavable linkers (valine-citrulline), and para-aminobenzylcarbamate spacers to three to five units of the antimitotic agent monomethyl auristatin E (MMAE, reflected by the 'vedotin' in the drug's name).[13] The peptide-based linker bonds the antibody to the cytotoxic compound in a stable manner so the drug is not easily released from the antibody under physiologic conditions to help prevent toxicity to healthy cells and ensure dosage efficiency. The peptide antibody-drug bond facilitates rapid and efficient drug cleavage inside target tumor cell. The antibody cAC10 part of the drug binds to CD30 which often occurs on diseased cells but rarely on normal tissues. The antibody portion of the drug attaches to CD30 on the surface of malignant cells, delivering MMAE which is responsible for the anti-tumour activity.[14][15] Once bound, brentuximab vedotin is internalised by endocytosis and thus selectively taken up by targeted cells. The vesicle containing the drug is fused with lysosomes and lysosomal cysteine proteases, particularly cathepsin B, start to break down valine-citrulline linker and MMAE is no longer bound to the antibody and is released directly into the tumor environment. [16]

    Skeletal formula of brentuximab vedotin. Three to five units of MMAE are attached to the monoclonal antibody (MAB) brentuximab via the spacer para-aminobenzylcarbamate (marked green), a cathepsin-cleavable linker (Cit=citrulline, Val=valine, marked blue), and an attachment group consisting of caproic acid and maleimide (marked brown).[15][17]

    Society and culture

    Brentuximab vedotin is marketed as "Adcetris".[18]

    Research

    In a 2010, clinical trial,[19] 34% of patients with refractory Hodgkin Lymphoma achieved complete remission and another 40% had partial remission.[20] Tumor reductions were achieved in 94% of patients. In ALCL, 87% of patients had tumors shrink at least 50% and 97% of patients had some tumor shrinkage.[21]

    Reports in 2013, showed interim results[22] from a Phase II, open-label, single-arm study designed to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms. These results demonstrated that single-agent brentuximab vedotin induced a 42% objective response rate and manageable safety profile among advanced diffuse large B-cell lymphoma patients.[23][24]

    A phase III trial funded by Millennium Pharmaceuticals compared ABVD (a combination of the chemotherapy drugs doxorubicin, bleomycin, vinblastine, and dacarbazine) versus A+AVD (a combination of brentuximab vedotin plus AVD, or doxorubicin, vinblastine, and dacarbazine) for treatment of classical Hodgkin lymphoma and found substituting brentuximab vedotin for bleomycin has both improved efficacy and lowered toxicity.[25] A previously completed phase I study demonstrated that a greater number of patients experienced pulmonary toxicity with brentuximab vedotin-ABVD than with ABVD alone. Pulmonary fibrosis is a classical adverse effect of bleomycin; however, the incidence of pulmonary fibrosis in the brentuximab vedotin-ABVD arm was higher than the expected historical rate with ABVD alone.[11] Overall, 24 out of 25 patients treated with brentuximab vedotin and AVD achieved complete remission.[26]

    Brentuximab vedotin is also being investigated as a substitute for vincristine (another mitotic inhibitor which prevents tubulin polymerization) in patients with being treated with CHOP (a combination of cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone or prednisolone) for a non-Hodgkin lymphoma.

    A phase III clinical trial is currently comparing the two combination therapies (CHOP and CHP-brentuximab vedotin) with estimated completion in December 2017.[27]

    The ECHELON-1 phase 3 trial compared brentuximab vedotin with bleomycin both in combination with adriamycin, vinblastine, dacarbazine (AVD) chemotherapy as a firstline treatment for advanced classical Hodgkin lymphoma.[28]

    References

    1. 1 2 3 4 5 6 "Adcetris EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 31 October 2020. Retrieved 19 August 2020.
    2. 1 2 3 4 5 6 7 8 "Adcetris- brentuximab vedotin injection, powder, lyophilized, for solution". DailyMed. 26 November 2018. Archived from the original on 6 August 2020. Retrieved 19 August 2020.
    3. 1 2 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 911. ISBN 978-0857114105.
    4. ↑ "Adcetris Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 15 April 2021. Retrieved 11 January 2022.
    5. ↑ "Seattle Genetics' Antibody-Drug Conjugate Receives FDA Okay to Treat Lymphomas". Genetic Engineering & Biotechnology News. 22 August 2011. Archived from the original on 11 November 2017. Retrieved 23 September 2021.
    6. 1 2 "FDA Approves Brentuximab Vedotin for CTCL". OncLive. 2017. Archived from the original on 2017-11-09. Retrieved 2017-11-10.
    7. ↑ "FDA expands approval of Adcetris for first-line treatment of Stage III or IV classical Hodgkin lymphoma in combination with chemotherapy" (Press release). U.S. Food and Drug Administration (FDA). 20 March 2018. Archived from the original on 15 December 2019. Retrieved 20 March 2018. Public Domain This article incorporates text from this source, which is in the public domain.
    8. ↑ "brentuximab vedotin". U.S. Food and Drug Administration (FDA). 20 March 2018. Archived from the original on 19 August 2020. Retrieved 19 August 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    9. 1 2 "FDA approves first-line treatment for peripheral T-cell lymphoma under new review pilot". U.S. Food and Drug Administration (FDA) (Press release). 16 November 2018. Archived from the original on 19 August 2020. Retrieved 19 August 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    10. ↑ PBAC Meetings March 2014 - Brentuximab Vedotin, 50 mg injection, 1 x 50 mg vial Adcetris® - March 2014 Archived 2020-03-27 at the Wayback Machine, March, 2014
    11. 1 2 "FDA Drug Safety Communication: New Boxed Warning and Contraindication for Adcetris (brentuximab vedotin)". U.S. Food and Drug Administration (FDA). 13 January 2012. Archived from the original on 19 August 2020. Retrieved 19 August 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    12. ↑ ADC Review / Journal of Antibody-drug Conjugates: Brentuximab Vedotin Archived 2015-02-20 at the Wayback Machine, February 18, 2014
    13. ↑ ADC Review / Journal of Antibody-drug Conjugates: Monomethyl auristatin E (MMAE) Archived 2013-10-29 at the Wayback Machine, May 23, 2013
    14. ↑ "Clinical Trials with brentuximab vedotin (SGN-35)". Seattle Genetics. Archived from the original on 2011-07-16.
    15. 1 2 Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, et al. (August 2003). "cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity". Blood. 102 (4): 1458–65. doi:10.1182/blood-2003-01-0039. PMID 12714494.
    16. ↑ Vaklavas C, Forero-Torres A (August 2012). "Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma". Therapeutic Advances in Hematology. 3 (4): 209–25. doi:10.1177/2040620712443076. PMC 3627331. PMID 23606932.
    17. ↑ A. Klement (13 May 2013). "Sprunginnovation beim Hodgkin-Lymphom: Adcetris". Österreichische Apothekerzeitung (in Deutsch) (10/2013): 68.
    18. ↑ Onco'Zine - The International Cancer Network: European Medicines Agency Accepts Brentuximab Marketing Authorization Application Archived 2013-10-29 at the Wayback Machine, June 27, 2011
    19. ↑ Clinical trial number NCT00848926 for "A Pivotal Open-Label Trial of Brentuximab Vedotin for Hodgkin Lymphoma" at ClinicalTrials.gov
    20. ↑ Seattle Genetics and Millennium Report Positive Data from Pivotal Trial of Brentuximab Vedotin (SGN-35) in Relapsed or Refractory Hodgkin Lymphoma at 2010 Annual Meeting of the American Society of Hematology (ASH) (Corporate Press Release)
    21. ↑ "Is Seattle Genetics the Next Big Thing?". Minyanville Business News. December 2, 2010. Archived from the original on November 14, 2017. Retrieved September 23, 2021.
    22. ↑ Maeda T, Wakasawa T, Shima Y, Tsuboi I, Aizawa S, Tamai I (February 2006). "Role of polyamines derived from arginine in differentiation and proliferation of human blood cells". Biological & Pharmaceutical Bulletin. 29 (2): 234–9. doi:10.1182/blood.V122.21.848.848. PMID 16462024.
    23. ↑ Clinical trial number NCT01421667 for "A Study of Brentuximab Vedotin in Relapsed or Refractory Non-Hodgkin Lymphoma" at ClinicalTrials.gov
    24. ↑ "Brentuximab Vedotin Shows 42% Objective Response Rate in Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma, Study Shows". ADC Review / Journal of Antibody-drug Conjugates. 10 December 2013. Archived from the original on 17 December 2013.
    25. ↑ Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, et al. (January 2018). "Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma". The New England Journal of Medicine. 378 (4): 331–344. doi:10.1056/NEJMoa1708984. PMC 5819601. PMID 29224502.
    26. ↑ Younes A, Connors JM, Park SI, Fanale M, O'Meara MM, Hunder NN, Huebner D, Ansell SM (December 2013). "Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study". The Lancet. Oncology. 14 (13): 1348–56. doi:10.1016/S1470-2045(13)70501-1. PMID 24239220.
    27. ↑ Clinical trial number NCT01777152 for "A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients With CD30-positive Mature T-cell Lymphomas" at ClinicalTrials.gov
    28. ↑ Pagliarulo N (June 2017). "Seattle Genetics' Adcetris succeeds in study but shares slide". Industry Dive. Archived from the original on 2018-02-07. Retrieved 2021-09-23.
    Identifiers:
    • "Brentuximab vedotin". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-11-04. Retrieved 2021-09-23.
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