|Source||Humanized (from mouse)|
|Trade names||Gazyva (US), Gazyvaro (EU)|
|Elimination half-life||28.4 days|
|Chemical and physical data|
|Molar mass||146.1 kg/mol g·mol−1|
|(what is this?)|
Obinutuzumab (called afutuzumab until 2009, originally GA101) is a humanized anti-CD20 monoclonal antibody, originated by GlycArt Biotechnology AG and developed by Roche as a cancer treatment. It was approved under the trade name Gazyva by the US FDA in 2013, and as Gazyvaro by the EMA in Europe, for the treatment of chronic lymphocytic leukemia in combination with chemotherapy in treatment-naive patients, and as a second line treatment for follicular lymphoma.
Obinutuzumab is used in combination with chlorambucil as a first-line treatment for chronic lymphocytic leukemia. 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).
It is also used in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma as a second line treatment to a regimen containing rituximab.
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.
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.
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.
Details of the antibody's structure are disclosed in the 2008 WHO INN naming proposal.
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.
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.
On November 13, 2013 the US 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.
In October 2014, NICE announced that NHS England would not fund use of the drug, due to data uncertainties in Roche's application. In June 2015, NICE announced that it would fund restricted use of the drug.
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."
In February 2016, obinutuzmab 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.
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.
- WHO Drug Information, Vol. 23, No. 2, 2009 Proposed INN: List 101, p 176
- Evans SS, Clemmons AB Obinutuzumab: A Novel Anti-CD20 Monoclonal Antibody for Chronic Lymphocytic Leukemia. J Adv Pract Oncol. 2015 Jul-Aug;6(4):370-4. PMID 26705497 PMC 4677809
- FDA, Feb 26, 2016 Press Release: Obinutuzumab
- Obinutuzumab label Last revised Nov 2013
- Ratner M. Genentech's glyco-engineered antibody to succeed Rituxan. Nat Biotechnol. 2014 Jan;32(1):6-7. PMID 24406911
- Umaña P et al. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol. 1999 Feb;17(2):176-80. PMID 10052355
- WHO Drug Information, Vol. 22, No. 2, 2008 Proposed INN: List 99, page 123
- "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.
- Presentation: GlycArt Biotechnology AG From Inception to trade sale – and what happened after... by Dr. Joël Jean-Mairet. Brussels, March 31, 2011
- Cameron F, McCormack PL. Obinutuzumab: first global approval. Drugs. 2014 Jan;74(1):147-54. PMID 24338113
- FDA approves Gazyva for chronic lymphocytic leukemia: Drug is first with breakthrough therapy designation to receive FDA approval, FDA News Release, FDA, November 13, 2013, retrieved July 20, 2015
- Associated Press, published in the New York Times. November 1, 2013 F.D.A. Clears New Cancer-Fighting Drug From Roche
- "NICE denies Roche cancer drug due to 'data uncertainties'". PM Live. Retrieved 3 October 2014.
- "NICE technology appraisal guidance (TA343)". Retrieved 14 March 2016.
- "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. Retrieved 22 November 2015.