Phase III study of Bosatria (mepolizumab) showed disease control with reduced corticosteroid use in hypereosinophilic syndrome
Data published in New England Journal of Medicine
Issued – Friday 14 March 2008, London, UK & Philadelphia, US
Results from a Phase III study demonstrate that significantly more patients who received GlaxoSmithKline’s investigational monoclonal antibody, Bosatria® (mepolizumab), for the treatment of hypereosinophilic syndrome (HES), were able to maintain control of their disease with a reduced dose of a corticosteroid, compared to those who received placebo (84% vs. 43%, p<0.001).[1]
In the study, published in the New England Journal of Medicine, more mepolizumab-treated patients were able to maintain disease control with a dose of prednisone, a corticosteroid, of less than or equal to 10 mg/day.[1] These results, involving 85 participants from the US, Europe, Canada and Australia, were also presented at the 2008 annual meeting of the American Academy of Asthma, Allergy and Immunology. It is the largest study of any kind conducted in HES patients.[1]
HES is a group of rare disorders characterised by persistent elevated levels of eosinophils (a type of white blood cell) in the blood and tissues leading to respiratory, cardiac, skin and gastrointestinal problems and can be fatal in some people with advanced disease.[2] While there is no cure2 for HES, corticosteroids are frequently used in both the initial and long term management of HES, however, they are not approved in this indication and their prolonged use is often associated with serious side effects.[3] In a post-hoc analysis, nearly half (47%) of patients treated with mepolizumab tapered off corticosteroids completely and remained steroid-free through the completion of the study, compared to 5% of patients treated with placebo (p<.001).[1]
Mepolizumab binds specifically to and inactivates a messenger protein called interleukin-5, which is the main controller of eosinophils in the blood.[4],[5] Of people who received mepolizumab in this trial, 95% were able to maintain eosinophil levels within the normal range (0-600/µL) for eight weeks or more, compared to 45% of the people who received placebo (p<0.001).[1]
In the study, mepolizumab was generally well tolerated, with similar rates of adverse events reported in the mepolizumab and placebo groups.[1] At the end of the 36-week trial, commonly reported side-effects included: fatigue (30% mepolizumab, 26% placebo), pruritus (28% mepolizumab, 21% placebo), headache (23% mepolizumab, 21% placebo), and arthralgia (21% mepolizumab, 17% placebo).[1] Of the five patients who withdrew from the study due to an adverse event (one mepolizumab, four placebo) and the 12 patients who experienced a non-fatal serious adverse event, none of the events were considered treatment-related by the investigator.[1] One death due to cardiac arrest was reported during the study and was considered not treatment-related by the investigator.[1]
“This study demonstrates that mepolizumab, if approved by regulators, may provide physicians with a new therapeutic option to provide disease control while reducing corticosteroid use in HES patients,” said Dr. Yvonne Greenstreet, Senior Vice President, Musculoskeletal, Inflammation, Gastrointestinal and Urology Medicine Development Centre, GlaxoSmithKline. “By developing this drug for an underserved, orphan indication, GSK has demonstrated its commitment to using the best science to develop the best medicines for people who need them.”
About mepolizumab
Mepolizumab is an investigational, humanized monoclonal antibody that binds specifically to and inactivates a protein cell messenger called interleukin-5, which is the main controller of eosinophils in the blood. The antibody treatment reduces the accumulation of eosinophils in the blood.[4],[5]
Precise worldwide estimates of the prevalence of HES have not yet been established, but it is estimated that it affects between 2,000-5,000 patients in the United States.[2]
Mepolizumab has been granted orphan drug status by regulatory authorities in the United States and the European Union. In the United States, the Orphan Drug designation applies to a disease or condition that affects less than 200,000 persons.[6] 2008 marks the 25th anniversary of the passage of the Orphan Drug Act.
In the EU, the EMEA defines orphan medicinal products as those used for diagnosing, preventing or treating life-threatening or very serious conditions that are rare and affect not more than five in 10,000 persons in the European Union.[7]
About study MHE100185
The trial, conducted between March 2004 and March 2006, involved 26 worldwide centres. Patients with HES (defined as blood eosinophil levels >1,500 per microliter for >6 months with end-organ involvement and no secondary cause of eosinophilia)[2] testing negative for the FIP1L1/PDGFRA fusion gene entered the trial in a run-in period of up to 6 weeks, during which their existing HES medications were discontinued and corticosteroid monotherapy (20 to 60 mg per day for at least 1 week) was administered until they reached stable clinical status. Stabilized patients were randomised to mepolizumab 750 mg or placebo (saline) intravenous infusion, administered every 4 weeks during a 36-week period.
The primary endpoint of Study 185 was the proportion of patients achieving a prednisone dose of ≤10 mg per day for ≥8 consecutive weeks. Secondary endpoints included the proportion of patients maintaining a blood eosinophil count <600 per microliter of blood for ≥8 weeks, time to treatment failure, proportion achieving a prednisone dose of ≤7.5 mg per day, proportion prednisone-free for ≥1 day, mean daily prednisone dose at Week 36, and proportion achieving a durable prednisone dose of ≤10 mg per day by Week 20 for ≥8 consecutive weeks. Post-hoc analyses included calculation of the proportion of patients achieving and maintaining prednisone independence during the study period as well as proportion of patients achieving the primary endpoint over a longer duration (≥ 24 weeks).
An ongoing extension trial involving 78 patients from Study 185, called Study MHE100901, will provide further information on efficacy and safety. Current treatment duration in Study 901 ranges from one to three years.
About HES
The precise cause or trigger for HES in patients who don’t have the FIP1L1/PDGFRA gene mutation is often unknown. Some patients, however, have been shown to have an increased number of abnormal T-lymphocytes, a type of immune blood cell, which produce high levels of interleukin-5.[2]
While there is no cure[2] and 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.[8]
About GlaxoSmithKline
GlaxoSmithKline is one of the world’s leading research-based pharmaceutical and healthcare companies. GlaxoSmithKline is committed to improving the quality of human life by enabling people to do more, feel better, and live longer. For company information visit www.gsk.com.
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References:
[1] Rothenberg ME et al. Treatment of Hypereosinophilic Syndrome with Mepolizumab. N Engl J Med 2008; 358:12 page numbers TBD
[2] Wilkins HJ, Crane MM, Copeland K, Williams WV. Hypereosinophilic syndrome: an update. Am J Hematol 2005; 80:148-157.
[3] Truhan AP, Ahmed AR. Corticosteroids: a review with emphasis on complications of prolonged systemic therapy. Ann Allergy 1989; 62:375-91.
[4] Ames RS, Tornetta MA, McMillan et al. Neutralizing murine monoclonal antibodies to human IL-5 isolated from hybridomas and a filamentous phage Fab display library. J Immunol 1995; 6355-6564.
[5] Hart TK, Cook RM, Zia-Amirhosseini P, et al. Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immunol 2001; 108:250-7.
[6] FDA website - http://www.fda.gov/cder/handbook/orphan.htm. Accessed on February 5, 2008.
[7] EMEA website - http://www.emea.europa.eu/htms/human/orphans/intro.htm. Accessed on February 5, 2008.
[8] Klion AD et al. Approaches to the treatment of hypereosinophilic syndromes: A workshop summary report. J Allergy Clin Immunol 2006; 117:1292–302.
