Obinutuzumab

Obinutuzumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD20
Names
Trade namesGazyva, Gazyvaro
Other namesAfutuzumab, GA101
Clinical data
Drug classMonoclonal antibody[1]
Main usesChronic lymphocytic leukemia (CLL), follicular lymphoma (FL)[2][1]
Side effectsUpper respiratory tract infection, pneumonia, urinary tract infection, shingles, diarrhea, pain, trouble sleeping, hair loss, fever, low platelets, low white blood cells[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: C
  • US: N (Not classified yet)
    Routes of
    use    		Intravenous infusion
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    Pharmacokinetics
    Elimination half-life28.4 days
    Chemical and physical data
    FormulaC6512H10060N1712O2020S44
    Molar mass146064.72 g·mol−1

    Obinutuzumab, previously known as afutuzumab, is a medication used for chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).[2][1] It is used in CLL when fludarabine cannot be used.[3] It is given by gradual injection into a vein.[1]

    Common side effects include upper respiratory tract infection, pneumonia, urinary tract infection, shingles, diarrhea, pain, trouble sleeping, hair loss, fever, low platelets, and low white blood cells.[1] Other side effects may include progressive multifocal leukoencephalopathy and hepatitis B reactivation.[2] It is a monoclonal antibody that attaches to CD20 and directs the immune system there.[1]

    Obinutuzumab was approved for medical use in the United States in 2013 and Europe in 2014.[2][1] In the United Kingdom it costs the NHS about £3,300 per 1 gram vial as of 2021.[3] This amount in the United States costs about 7,200 USD.[4]

    Medical uses

    Obinutuzumab is used in combination with chlorambucil as a first-line treatment for chronic lymphocytic leukemia.[5][6] Its progression-free survival is significantly better than rituximab in the same combination (26.7 months vs. 15.2 months, p < 0.001) but its overall survival is not significantly better (death rate 8% vs. 12%, p = .08).[6]

    It is also used in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of people with follicular lymphoma as a second line treatment to a regimen containing rituximab.[7][5]

    It was not tested in pregnant women.[5]

    Side effects

    Enteroviral infection after an individual received obinutuzumab.[8]

    Obinutuzumab has two black box warnings: hepatitis B reactivation and progressive multifocal leukoencephalopathy.[6][5]

    In the pivotal clinical trial of obinutuzumab in combination with chlorambucil, clinical trial subjects experienced infusion reactions (69%; 21% grade 3/4), neutropenia (40%; 34% grade 3/4), thrombocytopenia (15%; 11% grade 3/4), anemia (12%), and pyrexia and cough (10% each). More than 20% of subjects had abnormal lab tests including low calcium and sodium, high potassium, increases in serum creatinine and liver function tests, and low albumin levels.[6]

    There is a risk of thrombocytopenia and hemorrhage with obinutuzumab; consideration should be given to withholding medications that may increase the risk of bleeding.[6]

    Mechanism of action

    Obinutuzumab binds to CD20 on B cells and causes these cells to be destroyed by engaging the adaptive immune system, directly activating intracellular apoptosis pathways, and activating the complement system.[5] The CD20 is involved in BCR signalling of malignant B cells, and its levels are determined by several microenvironmental factors such as chemokine SDF1 or IL4 levels.[9]

    Chemistry

    Obinutuzumab is a fully humanized monoclonal antibody that binds to an epitope on CD20 that partially overlaps with the epitope recognized by rituximab.[6]

    GlycArt's technology platform allowed control of protein glycosylation; the cells in which obinutuzumab is produced were engineered to overexpress two glycosylation enzymes, MGAT3 and Golgi mannosidase 2, which reduce the amount of fucose attached to the antibody, which in turn increases the antibody's ability to activate natural killer cells.[10][11]

    Details of the antibody's structure are disclosed in the 2008 WHO INN naming proposal.[12]

    History

    Obinutuzumab was created by scientists at GlycArt Biotechnology, which had been founded in 2000 as a spin-out company of the Swiss Federal Institute of Technology in Zurich to develop afucosylated monoclonal antibodies; GA101 was one of its lead products when it was acquired by Roche in 2005.[13][14][15]

    Roche developed the drug in the US through its US subsidiary, Genentech, and in Japan through its Japanese subsidiary, Chugai. Genentech partnered with Biogen Idec to explore the use of the drug for primary biliary cirrhosis but as of 2014 it appeared the development in that indication had halted.[15]

    On November 13, 2013, the US Food and Drug Administration (FDA) approved obinutuzumab in combination with chlorambucil as a first-line treatment for chronic lymphocytic leukemia, and was the first drug with breakthrough therapy designation to gain approval.[16][17]

    In October 2014, NICE announced that NHS England would not fund use of the drug, due to data uncertainties in Roche's application.[18] In June 2015, NICE announced that it would fund restricted use of the drug.[19]

    In their final recommendation of obinutuzumab, in the January 2015 Pan-Canadian Oncology Drug Review (pERC) for treatment of chronic lymphocytic leukemia, published by the Canadian Agency for Drugs and Technologies in Health, the list price of obinutuzumab provided by the manufacturer Hoffmann-La Roche was $CDN 5,275.54 per 1,000 mg vial. At the recommended dose obinutuzumab costs $15,826.50" for the first 28-day cycle and "$5275.50 per 28 day cycle for subsequent cycles."[20]

    In February 2016, obinutuzumab was approved by the FDA under the Priority Review program for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma as a secondline treatment to a regimen containing rituximab.[7]

    It was previously known as "afutuzumab".[21]

    In January 2019, the US Food and Drug Administration (FDA) approved ibrutinib in combination with obinutuzumab for people with chronic lymphocytic leukemia/small lymphocytic lymphoma who have not received prior treatment.[22]

    Research

    As of 2014 clinical trials had been conducted exploring the use of obinutuzumab as a second line monotherapy in relapsed/refractory chronic lymphocytic leukemia, as a monotherapy for relapsed/refractory non-Hodgkin lymphoma in people who had high expression of CD20; and in combination with CHOP chemotherapy as a first line treatment for people with advanced CD20-positive diffuse large B-cell lymphoma.[15] It was called GA101 during research.

    References

    1. 1 2 3 4 5 6 7 8 "Gazyvaro". Archived from the original on 2 March 2021. Retrieved 6 November 2021.
    2. 1 2 3 4 "Obinutuzumab Monograph for Professionals". Drugs.com. Archived from the original on 7 October 2021. Retrieved 6 November 2021.
    3. 1 2 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 922. ISBN 978-0857114105.
    4. ↑ "Gazyva Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 24 January 2021. Retrieved 6 November 2021.
    5. 1 2 3 4 5 "Gazyva- obinutuzumab injection, solution, concentrate". DailyMed. 7 April 2020. Archived from the original on 24 January 2021. Retrieved 16 September 2020.
    6. 1 2 3 4 5 6 Evans SS, Clemmons AB (2015). "Obinutuzumab: A Novel Anti-CD20 Monoclonal Antibody for Chronic Lymphocytic Leukemia". Journal of the Advanced Practitioner in Oncology. 6 (4): 370–4. doi:10.6004/jadpro.2015.6.4.7. PMC 4677809. PMID 26705497.
    7. 1 2 FDA, Feb 26, 2016 Press Release: Obinutuzumab Archived 2019-04-23 at the Wayback Machine
    8. ↑ Barton-Burke, Margaret (29 November 2016). 2017 Oncology Nursing Drug Handbook. Jones & Bartlett Learning. p. 890. ISBN 978-1-284-11718-9. Archived from the original on 5 February 2022. Retrieved 5 February 2022.
    9. ↑ Pavlasova G, Mraz M (June 2020). "The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy". Haematologica. 105 (6): 1494–1506. doi:10.3324/haematol.2019.243543. PMID 32482755.
    10. ↑ Ratner M (January 2014). "Genentech's glyco-engineered antibody to succeed Rituxan". Nature Biotechnology. 32 (1): 6–7. doi:10.1038/nbt0114-6b. PMID 24406911.
    11. ↑ Umaña P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE (February 1999). "Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity". Nature Biotechnology. 17 (2): 176–80. doi:10.1038/6179. PMID 10052355. S2CID 20078393.
    12. ↑ WHO Drug Information, Vol. 22, No. 2, 2008 Proposed INN: List 99 Archived 2021-10-25 at the Wayback Machine, page 123
    13. ↑ "Roche - Roche acquires Swiss based GlycArt Biotechnology to strengthen expertise in therapeutic antibody research". roche.com. Archived from the original on 2015-02-05. Retrieved 2015-04-29.
    14. ↑ Presentation: GlycArt Biotechnology AG From Inception to trade sale – and what happened after... by Dr. Joël Jean-Mairet. Brussels, March 31, 2011
    15. 1 2 3 Cameron F, McCormack PL (January 2014). "Obinutuzumab: first global approval". Drugs. 74 (1): 147–54. doi:10.1007/s40265-013-0167-3. PMID 24338113. S2CID 40983655.
    16. ↑ "FDA approves Gazyva for chronic lymphocytic leukemia: Drug is first with breakthrough therapy designation to receive FDA approval" (Press release). FDA. November 13, 2013. Archived from the original on August 21, 2015. Retrieved July 20, 2015.
    17. ↑ "F.D.A. Clears New Cancer-Fighting Drug From Roche". The New York Times. Associated Press. 2 November 2013. Archived from the original on 6 October 2021. Retrieved 16 September 2020.
    18. ↑ "NICE denies Roche cancer drug due to 'data uncertainties'". PM Live. Archived from the original on 6 October 2014. Retrieved 3 October 2014.
    19. ↑ "NICE technology appraisal guidance (TA343)". Archived from the original on 15 March 2016. Retrieved 14 March 2016.
    20. ↑ "Final Recommendation for Obinutuzumab (Gazyva) for CLL Pan-Canadian Oncology Drug Review (pERC) Meeting: December 18, 2014; Early Conversion: pCODR" (PDF). Pan-Canadian Oncology Drug Review via Canadian Agency for Drugs and Technologies in Health. 27 January 2015. Archived (PDF) from the original on 18 October 2015. Retrieved 22 November 2015.
    21. ↑ WHO Drug Information, Vol. 23, No. 2, 2009 Proposed INN: List 101 Archived 2016-03-03 at the Wayback Machine, p 176
    22. ↑ "FDA Approves Ibrutinib/Obinutuzumab for Treatment-Naive Patients with Chronic Lymphocytic Leukemia". Archived from the original on 4 August 2020. Retrieved 4 June 2019.
    External sites:
    Identifiers:
    • "Obinutuzumab". NCI Dictionary of Cancer Terms. National Cancer Institute. Archived from the original on 2021-10-07. Retrieved 2021-10-24.
    • "Obinutuzumab". National Cancer Institute. Archived from the original on 2021-10-06. Retrieved 2021-10-24.
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