MEA115661: A multi-centre, open-label, long-term safety study of mepolizumab in asthmatic subjects who participated in the MEA115588 or MEA115575 trials

Mepolizumab is currently under clinical development for severe asthma.
Mepolizumab is a humanized antiinterleukin 5 (anti-IL5) antibody (IgG Kappa)
that binds to and inactivates IL-5. IL-5 is the principle eosinophilic
regulatory cytokine. It is critical for the development and release of
eosinophils from the bone marrow, enhances adhesion to endothelial cells, and
promotes the persistence and activation of eosinophils. Eosinophils are thought
to play a major role in maintaining airway inflammation. Mepolizumab binds with
high affinity to human interleukin-5 and blocks its binding to and the
activation of the IL-5 receptor (CD125). It is hypothesized that blocking IL-5
with mepolizumab will have a positive effect in reducing eosinophilic
inflammation in patients with severe refractory asthma who are dependent on
maintenance steroid to treat their asthma. This concept has been previously
investigated in a small study (N= 20) of asthmatics with persistent sputum
eosinophils. The results of this study demonstrated that mepolizumab was well
tolerated and effective in reducing the dose of prednisone while preventing
exacerbations, decreasing blood and sputum eosinophil numbers, and improving
lung function and quality of life.
Recently a study of IV mepolizumab of over 600 subjects with severe refractory
uncontrolled asthma has been completed. All 3 doses investigated (75mg, 250 mg
and 750mg) resulted in a clinically significant reduction in the frequency of
severe exacerbations when compared to placebo and produced a marked and
sustained suppression of blood eosinophils. The safety profile was similar
across all treatment arms and was similar to placebo.
A PK/PD model has been developed for mepolizumab with data obtained from prior
studies. Two of these 5 studies administered mepolizumab via the subcutaneous
(SC) route. The model well describes the relationship between plasma
mepolizumab concentration and eosinophil counts (irrespective of the route of
administration. Based on prior PK studies, the bioavailability of mepolizumab
administered SC is approximately 75% and therefore a dose of 100mg SC is
anticipated to provide similar exposure to the 75mg IV effective dose. A SC
route of administration has been chosen for the current study as it is
generally preferred by patients and is easy to administer.
The current study is an extension of the study MEA115575. Patients who have
completed this previous study may use mepolizumab in this extension study. The
purpose is to collect long term safety data. Also patients from the study
MEA115588, that is not being performed in Holland, may enter this extension
study.

Primary: To collect long term safety data.
Secondary: To collect data on long term asthma control.

Open-label non-comparative phase III study. Treatment with Mepolizumab 100 mg
s.c. every 4 weeks
Continuation of standard treatment for asthma.
Salbutamol rescue medication.
Study duration approx. 1 year and 3 months.
Follow-up phase 12 weeks.
Approx. 660 patients.

Treatment with mepolizumab.

Risk: adverse events of study treatment.
Burden: 15 visits in approx. 1 year and 3 months. Duration 1-2h.
S.c. injections (1 ml) with mepolizumab every 4 weeks during 1 year.
Blood draws 11x (approx. 10 ml/occasion), thereoff 2x fasting.
Pregnancy test every visit.
Physical examination 2x.
Pulmonary function test 4x.
ECG 3x.
Asthma Control Questionnaire 7x.