Clinical Trials

Date: 2017-05-17

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New English Journal of Medicine

Company: GSK (UK)

Product: mepolizumab

Action mechanism:

• monoclonal antibody. Mepolizumab is an investigational fully humanised IgG monoclonal antibody specific for interleukin 5 (IL-5) which is in development for severe refractory asthma in patients who exacerbate despite high-dose inhaled or oral corticosteroids and long-acting beta-2 agonist use. IL-5 is a cytokine which regulates the growth, activation and survival of eosinophils (white blood cells) and provides an essential signal for the movement of eosinophils from the bone marrow into the lung. Mepolizumab binds to human IL-5, stopping it from binding to its receptor on the surface of eosinophils. Inhibiting IL-5 binding in this manner reduces blood, tissue and sputum eosinophil levels, which in turn reduces the frequency of exacerbations.

Disease: eosinophilic granulomatosis with polyangiitis (EGPA) previously known as Churg-Strauss syndrome

Therapeutic area: Rare diseases

Country: Belgium, Germany, UK, USA

Trial details:

• The pivotal Phase III study, MEA115921, is a randomised, double-blind study with the purpose to investigate the efficacy and safety of a 300mg dose of mepolizumab (administered subcutaneously every 4 weeks) compared with placebo over a 52-week study treatment period in patients with relapsing or refractory EGPA receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy.
• The pivotal phase III study was a randomised, double-blind placebo controlled study designed to investigate the efficacy and safety of mepolizumab 300mg (administered subcutaneously every 4 weeks) compared to placebo, in patients already receiving standard of care, over a 52-week study treatment period. The study was conducted in 31 academic centres and hospitals across nine countries and enrolled 136 patients (mepolizumab n = 68; placebo = 68) with relapsing or refractory EGPA receiving standard of care therapy (i.e. treatment for more than four weeks on stable dose prednisolone/prednisone ?7.5mg - ?50mg day) with or without immunosuppressive therapy. The study population was representative of patients with EGPA treated with glucocorticoids with or without additional immunosuppressant therapy.

The co-primary endpoints were the total accrued weeks of remission over the full trial period, and the proportion of patients in remission at both Weeks 36 and 48. Remission was defined by a Birmingham Vasculitis Activity Score (BVAS), a scoring system to assess disease activity, of zero, and a prednisolone/prednisone dose ?4mg/day.

• (NCT02020889)

Latest news:

• • On May 17, 2017, GSK announced publication in the New England Journal of Medicine, of a randomised, double-blind, placebo controlled study investigating the efficacy and safety of mepolizumab, an IL-5 antagonist, vs placebo as an add-on therapy in patients with relapsing and/or refractory Eosinophilic Granulomatosis with Polyangiitis (EGPA). Efficacy results: In the 52-week pivotal phase III study, mepolizumab treatment demonstrated efficacy based on both co-primary efficacy endpoints and all secondary endpoints. Treatment with mepolizumab was in addition to standard of care (glucocorticoids with or without immunosuppressants).
• Patients treated with mepolizumab had a significantly greater accrued time in remission (defined as a prednisolone/prednisone dose of ?4mg/day and a Birmingham Vascular Activity Score = 0) over the 52-week treatment period compared to placebo, with 28% of patients on mepolizumab achieving remission for at least 24 weeks versus 3% on placebo (p<0.001). In addition, a higher proportion of patients in the mepolizumab group were in remission at both Weeks 36 and 48 compared to the placebo group (32% versus 3%; p<0.001).
• More patients treated with mepolizumab achieved remission within the first 24 weeks of the study and remained in remission until Week 52 compared to those receiving placebo (19% versus 1%; p=0.007). Over 52 weeks, time to first relapse was significantly longer for patients on mepolizumab (p<0.001); time to first major relapse was also longer for patients treated with mepolizumab compared to placebo (p=0.042). Patients treated with mepolizumab were also able to achieve significantly lower average doses of prednisolone/prednisone during Weeks 48 to 52 compared to placebo, with 44% able to taper their dose to ?4mg/day versus 7% on placebo (p<0.001).
• A total of 47% of mepolizumab-treated patients versus 81% of placebo-treated patients did not achieve protocol-defined remission. Approximately half the participants in the mepolizumab group had a relapse, nonetheless a 50% lower rate of relapse with mepolizumab treatment was seen than was observed with placebo in this trial (1.14 per year for the mepolizumab group versus 2.27 per year for the placebo group), which highlights the high morbidity and challenge of managing patients with this progressive disease.
• Safety results: There was no difference between the two treatment groups in the proportion of patients experiencing on-treatment adverse events (97% versus 94%) and overall the adverse event profile for mepolizumab was similar to that seen in previous studies with no new safety signals observed. Fewer patients in the mepolizumab group reported serious adverse events versus those in the placebo group (18% versus 26%), with the most frequently reported being asthma worsening/exacerbation (3% versus 6%). Systemic reactions were infrequent and reported with higher incidence in the mepolizumab group compared to placebo. One death was reported in a patient receiving mepolizumab which was not considered by the investigator to be related to study treatment.
• Results of this study in patients with relapsing and refractory EGPA will support GSK’s plans to submit regulatory applications, expected later in 2017.
• • On November 23, 2016, GSK announced that both co-primary endpoints and all secondary endpoints were met in the MEA115921 study investigating the efficacy and safety of mepolizumab in patients with relapsing and refractory Eosinophilic Granulomatosis with Polyangiitis (EGPA). A key goal of treatment for EGPA is to induce and maintain remission while reducing the use of corticosteroids and other immunosuppressive therapies. The co-primary endpoints for this 52-week study assessed the total duration of remission and the proportion of patients that achieved sustained remission following treatment with mepolizumab compared to treatment with placebo, both on top of standard of care.
•  The difference between the two treatment groups was statistically significant for both co-primary endpoints as defined, respectively, by: The duration of remission as defined by the proportion of patients achieving at least 24 weeks duration of remission, one of five pre-defined categories of duration, was 19/68 (28%) for mepolizumab and 2/68 (3%) for placebo. The proportion of patients achieving remission at both weeks 36 and 48 of the study treatment period. This was 22/68 (32%) for mepolizumab and 2/68 (3%) for placebo. The study included six secondary endpoints investigating relapse, remission and corticosteroid use, all considered clinically relevant for patients with EGPA. Patients demonstrated statistically significant differences, in favour of mepolizumab, for all secondary endpoints compared to placebo.
• Most frequent on-treatment serious adverse events reported for mepolizumab and placebo, respectively were asthma (4%, 4%), influenza (0, 3%) and pneumonia (0, 3%). One death was reported in a patient receiving mepolizumab which was not considered by the investigator to be related to study treatment.
• • On February 14, 2014, GSK has announced the start of a Phase III study to evaluate the efficacy and safety of mepolizumab, an investigational IL-5 antagonist, in patients with Eosinophilic Granulomatosis with Polyangiitis (EGPA). The study is being conducted as part of an agreement between GSK and the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health. Through this collaboration the mechanisms that underlie EGPA will also be investigated, with potential future benefits for patients.
• EGPA is one of the rarest systemic vasculitic (inflammation of blood vessel walls) diseases with an approximate prevalence of 4,300 patients in the United States and five European countries, respectively. The mean age of diagnosis is 48 years. While symptoms vary from one patient to another, almost all have asthma and/or nasal sinus polyps and blood eosinophilia. The current approach to disease management is primarily based on reduction of active inflammation and suppression of the immune response through the use of corticosteroid therapy with concomitant immunosuppressive therapy (e.g., methotrexate, azathioprine, mycophenolate mofetil) and/or cytotoxic agents (e.g., cyclophosphamide).

Is general: Yes