Monoclonal antibody | |
---|---|
Type | Whole antibody |
Source | Humanized (from mouse) |
Target | CD33 |
Clinical data | |
Trade names | Mylotarg |
AHFS/Drugs.com | Monograph |
MedlinePlus | a618005 |
License data | |
Pregnancy category |
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Routes of administration | Intravenous |
ATC code | |
Legal status | |
Legal status | |
Identifiers | |
CAS Number | |
DrugBank | |
ChemSpider |
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UNII | |
KEGG | |
ChEMBL | |
Chemical and physical data | |
Molar mass | 151500 g·mol−1 |
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Gemtuzumab ozogamicin, sold under the brand name Mylotarg, is an antibody-drug conjugate (a drug-linked monoclonal antibody) that is used to treat acute myeloid leukemia.[6][8][9]
The most common side effects include infection, febrile neutropenia, decreased appetite, hyperglycemia, mucositis, hypoxia, hemorrhage, increased transaminase, diarrhea, nausea, and hypotension.[10] However, the addition of gemtuzumab ozogamicin to standard chemotherapy regimens does not increase infection rates. [11]
In the United States, gemtuzumab ozogamicin is indicated for newly diagnosed CD33-positive acute myeloid leukemia (AML) for adults and children one month and older and for the treatment of relapsed or refractory CD33-positive AML in adults and children two years and older.[6][10]
Gemtuzumab is a monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins (ozogamicin).[6] CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells.[6]
Gemtuzumab ozogamicin was created in a collaboration between Celltech and Wyeth that began in 1991.[12][13] The same collaboration later produced inotuzumab ozogamicin.[14] Celltech was acquired by UCB in 2004[15] and Wyeth was acquired by Pfizer in 2009.[16]
In the United States, it was approved under an accelerated-approval process by the FDA in 2000, for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy.[17] The accelerated approval was based on the surrogate endpoint of response rate.[18] It was the first antibody-drug conjugate to be approved.[19]
Within the first year after approval, the FDA required a black box warning be added to gemtuzumab packaging. The drug was noted to increase the risk of veno-occlusive disease in the absence of bone marrow transplantation.[20] Later the onset of VOD was shown to occur at increased frequency in gemtuzumab patients even following bone marrow transplantation.[21] The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents.[22]
A randomized Phase III comparative controlled trial (SWOG S0106) was initiated in 2004, by Wyeth in accordance with the FDA accelerated-approval process. The study was stopped on August 20, 2009, prior to completion due to worrisome outcomes.[23] Among the patients evaluated for early toxicity, fatal toxicity rate was significantly higher in the gemtuzumab combination therapy group vs the standard therapy group. Mortality was 5.7% with gemtuzumab and 1.4% without the agent (16/283 = 5.7% vs 4/281 = 1.4%; P = .01).[18]
In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA.[24][25] However, some other regulatory authorities did not agree with the FDA decision, with Japan's Pharmaceuticals and Medical Devices Agency stating in 2011 that the "risk-benefit balance of gemtuzumab ozogamicin has not changed from its state at the time of approval".[26]
In 2017, Pfizer reapplied for US and EU approval, based on a meta-analysis of prior trials and results of the ALFA-0701 clinical trial, an open-label Phase III trial in 280 older people with AML.[19] In September 2017, gemtuzumab ozogamicin was approved again for use in the United States[8][27] and in the European Union.[7]