mepolizumab - Bosatria; SB-240563; interleukin-5 monoclonal antibody, humanized, recombinant
Status: BLA had been expected in 2009; MAA filed in EU, but withdrawn
Organizations involved:
GlaxoSmithKline Inc. – Manuf.; R&D; Tech.; U.S. mark.;
GlaxoSmithKline S.A. – Intl. mark.; Parent
Schering-Plough Corp. – R&D; Tech.
Merck & Co., Inc. – Parent
Description: Bosatria is formulation of mepolizumab, a recombinant humanized interleukin-5 (IL-5) monoclonal antibody expressed by transformed Chinese hamster ovary(CHO) cells. Mepolizumab has a molecular weight of 146 kDa
Biological.: Interleukin-5 (IL-5) stimulates the production, activation and maturation of eosinophils. Eosinophils are immune system cells that accumulate in response to allergic inflammatory reactions. They ingest antibody-antigen complexes and thereby become degranulated. Since the granules contain substances capable of blocking the action of histamine, serotonin and bradykinin, all of which are involved in inflammation, it has been proposed that eosinophils protect the tissues of the host not only by phagocytizing and degrading cytotoxic antibody-antigen complexes but also by damping the effects of chemical mediators of the inflammatory response.
Since mepolizumab binds IL-5 and has a long terminal half-life, treatment with mepolizumab causes a sustained reduction in the numbers of circulating eosinophils. Thus, mepolizumab may be a useful therapeutic agent for the treatment of conditions characterized by increased levels of eosinophils.
Companies.: Bosatria was commercially developed by SmithKline Beecham, now GlaxoSmithKline. It apparently was originally developed by Schering-Plough (now merged into Merck) and licensed to SKB, now GSK.
Bosatria has been in development by GlaxoSmithKline for well over a decade. It was originally developed and tested for broad indications:, including asthma and atopic dermatitis, diseases in which eosinophils play a major role. However, it was ineffective for these indications:, and GSK's recent strategy has focused on gaining orphan drug status and approval for hypereosinophilic syndrome.
Nomenclature: IL-5 Mab, rDNA/GSK [BIO]; Bosatria [TR]; mepolizumab [INN USAN]; Immunoglobulin G1, anti-(human interleukin 5) (human-mouse monoclonal SB-240563 gamma1-chain), disulfide with human-mouse monoclonal SB-240563 kappa-chain, dimer [CAS]; 196078-29-2 [CAS RN]; SB-240563 [SY]; SB 240563 [SY]; interleukin-5 monoclonal antibody, humanized, recombinant [SY]
Status: Bosatria has orphan drug status for hypereosinophilic syndrome. Filings for hypereosinophilic syndrome with orphan designation were expected in the U.S. and Europe in 2009.
On July 29, 2009, GSK withdrew its MAA filing for European Union (EU) approval for treatment of FIP1 negative (without the FIP1L1-PDGFRA fusion gene ) HES. The Committee for Medicinal Products for Human Use (CHMP) had informed the company that additional data would be required to further demonstrate clinical benefit and support the application for approval. GSK planned to conduct further clinical studies.
Tech. transfer: U.S. 5,976,821, "Monoclonal antibodies specific for human interleukin-5," assigned to the Baylor College of Medicine claims monoclonal antibodies which specifically bind to human interleukin-5 (IL-5) are described. It is not known whether GSK has licensed this patent.
U.S. 6,056,957, "Humanized monoclonal antibodies against human interleukin-5," assigned to Schering-Plough Corp. claims certain humanized IL-5 monoclonal antibodies and describes their humanization. Schering-Plough has also received 6,451,982, " Design, cloning and expression of humanized monoclonal antibodies against human interleukin-5;" 5,096,704,l " Method of treating eosinophilia," using IL-5 Mabs; 6,056,957, " Humanized monoclonal antibodies against human interleukin-5;" and other related patents.
Trials: Developing new treatments for such a rare orphan disease as HES and establishing a favorable benefit to risk profile is a significant challenge: small numbers of patients make recruitment for clinical trials difficult and there are no recognised clinical endpoints for HES as this disease affects patients in many different ways and in many different body organs.
Phase II trials in asthma were underway by April 1998 and in March 2002, Phase II trials were initiated in atopic dermatitis. However, mepolizumab had little efficacy in preclinical or clinical studies for atopic dermatitis, and it failed to sufficiently deplete eosinophils in clinical trials for asthma. In prior clinical studies, including trials in the EU and US, mepolizumab has shown a lack of effect on allergen-induced airway responses and inflammation, despite a significant reduction in blood and sputum eosinophil levels.
Bosatria has been in trials for severe asthma, nasal polyposis and eosinophilic oesophagitis.
A randomized, double-blind, placebo-controlled, multicentre, Phase III study (MHE100185) of mepolizumab over 9 months in 85 patients with hypereosinophilic syndrome was completed in 2006. All patients continued in a Phase III, open-label, long-term extension study. Results were reported in the New England Journal of Medicine, March 14, 2008. Significantly more Bosatria patients maintained control of their disease with a reduced dose of a corticosteroid, compared to those who received placebo (84% vs. 43%, p<0.001). More Bosatria patients were able to maintain disease control with a dose of prednisone of less than or equal to 10 mg/day. In the study, mepolizumab was generally well tolerated, with similar rates of adverse events reported in the mepolizumab and placebo groups. This was the largest study of any kind conducted in HES patients. An extension trial involving 78 patients, Study MHE100901, will provide further information on efficacy and safety. As of March 2008, duration in Study 901 ranged from one to three years.
A Phase III, compassionate use trial of mepalizumab (NCT00244686) in a projected 50 patients with hypereosinophilic syndrome was started in 2005 in the U.S. and is projected to end in 2009. Patients who have significant clinical disease but are unresponsive to traditional treatment and those who have demonstrated clinical benefit from previous anti-IL-5 treatment are eligible to take part in the trial.
Disease: Hypereosinophilic syndrome is a type of leukemia (chronic eosinophilic leukemia) for which it has been impossible to find the origin of the cancer cells. It is a disease in which cancer cells are found in the blood, the bone marrow and in tissues. Normally, the bone marrow makes cells called “blasts” that mature into several different types of blood cells, e.g., red cells, white cells and
platelets. In the hypereosinophilic syndrome, blasts that are developing into white blood cells called “eosinophils” become too numerous and are then found in the bone marrow, blood and in other tissues such as the heart, lungs, nerves and skin. The excess of eosinophils in tissues can cause disturbances in the function and thereby damage the affected organs. Hypereosinophilic syndrome is lifethreatening. It is diagnosed based on a persistent blood eosinophil count of >1500 cells, various end-organ damages (including skin, heart, lung, nervous system and digestive system), and with exclusion of known secondary causes of hypereosinophilia. The clinical effects of HES can vary greatly from patient to patient. The disease is often managed long term with a combination of drugs frequently including corticosteroids, such as prednisone.
Precise worldwide estimates of the prevalence of hypereosinophilic syndrome (HES) have not yet been established, but it is estimated that it affects between 2,000-5,000 patients in the U.S. In its European Union application for orphan designation for Bosatria, GSK estimated there were about 7,000 HES patients in the EU.
Index Terms:
Companies involvement:
Full monograph
222.4 IL-5 Mab, rDNA/GSK
Nomenclature:
IL-5 Mab, rDNA/GSK [BIO]
Bosatria [TR]
Immunoglobulin G1, anti-(human interleukin 5) (human-mouse
monoclonal SB-240563 gamma1-chain), disulfide with human-
mouse monoclonal SB-240563 kappa-chain, dimer [CAS]
Immunoglobulin G1, anti-(human interleukin 5) (human-mouse monoclonal SB-240563 gamma1-chain), disulfide with human-mouse monoclonal SB-240563 kappa-chain, dimer [CAS]
196078-29-2 [CAS RN]
interleukin-5 monoclonal antibody, humanized, recombinant [SY]
SB 240563 [SY]
SB-240563 [SY]
mepolizumab [USAN INN]
FDA Class: Biologic BLA
biopharmaceutical products
exempt from CBER lot release requirements
hamster source materials
hamster source materials
monoclonal antibodies, recombinant, chimeric
recombinant DNA
Chinese hamster ovary (CHO) cells
hP67.6, monoclonal antibody
interleukin-11/thioredoxin fusion protein
interleukin-2 receptors (IL-2r)
mammalian cell culture
P3x63Ag8.653 myeloma cells
transgenic goats
U.S. Standard Rabies Vaccine
orphan status
EU003 EU application withdrawn
UM999 Not Available/Not Marketed in US
US000 never filed/no plans
EM999 Not Available/Not Marketed in EU
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