The MIRRA trial: Mepolizumab (Nucala) or placebo for the treatment of EGPA/Churg-Strauss Syndrome

Wechsler et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N. Engl. J. Med. 2017 376(20):1921-1932.

MIRRA-trial-mepolizumab-nucala-for-egpa

Disclosure:  I was a patient in this clinical trial from March 2015 to May 2016 and I am still taking mepolizumab to treat my EGPA. For more details and a full list of my disclosures, please see the Disclaimer page.

Game changer:  Why is this study important? This clinical trial was the first randomized controlled trial ever conducted for EGPA. It is also one of the largest clinical trials conducted for EGPA, requiring the participation of 31 trial sites to enroll enough patients with this rare disease.  Mepolizumab is the first medication to be approved by the FDA for the treatment of EGPA.  The results from this clinical trial supported the application for FDA approval which was granted in December 2017.

Trial sponsorship.  The trial was sponsored by a collaboration between GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. NIAID funded an investigator initiated clinical trial application, which provided support for five of eight clinical trial sites in the United States.  Disclosures related to the MIRRA trial and the published manuscript can be found in the supplemental data on the manuscript publisher’s website at the links provided at the bottom of this post.

The big picture.  This Phase III double blinded clinical trial tested mepolizumab (Nucala), a monoclonal antibody which targets IL-5, an important regulator of eosinophils, for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA).  The study focused on patients with EGPA who had relapsing disease (flares) or difficult to control symptoms (refractory disease).

Purpose of the study and study endpoints.  Patients with EGPA have high levels of eosinophils. Mepolizumab is a monoclonal antibody which targets IL-5, an important regulator of eosinophils, and reduces eosinophil levels in the blood, so it may be useful to help control symptoms related to EGPA.  The purpose of the study was to measure whether mepolizumab could lead to better remission in patients with EGPA compared to controls. The end points of the study were the number of weeks patients were in remission (no evidence of disease activity) and the number of patients in remission at weeks 36 and 48 of the trial.

Patient population.  Patients diagnosed with EGPA who had relapsed (had a flare) or were unable to go into remission (refractory disease) and were at least 18 years of age were eligible to be enrolled in the study.  136 patients were enrolled at 31 sites across nine countries between February 2014 and September 2016.

Outline of the study.  This was a Phase III clinical trial studying patients diagnosed with EGPA who were receiving typical treatment for their EGPA and who had relapsed (had a flare) or were unable to go into remission (refractory disease).  136 adult EGPA patients were randomized into two groups of 68 patients per group.  One group received their regular treatments with prednisone and other drugs like methotrexate or azathioprine (standard of care), plus monthly injections of mepolizumab (300 mg subcutaneously). The second group received their regular treatments plus a monthly subcutaneous injection of saline (placebo control).  Treatments were given monthly for one year (52 weeks).  The study was double-blinded, meaning that neither the patients nor their doctors knew whether they were receiving injections of the placebo or the drug.  Patients were monitored monthly and their EGPA symptoms were measured and scored.  Patients began a controlled taper of their daily prednisone dose one month after their first injection and continued tapering their prednisone doses according to a defined schedule.  The level of the symptoms and the number of weeks in remission (i.e. no major relapses or worsening symptoms) were compared between the mepolizumab and placebo control groups.

Mepolizumab led to more patients in remission than placebo.  Patients who received mepolizumab had more weeks with no EGPA symptoms (remission) than the patients who received the placebo, which allowed the patients to reduce the amount of prednisone they were taking.  However, only about half of the patients who received mepolizumab had their symptoms reduced enough to go into remission.  This means that mepolizumab could control symptoms and lead to remission in about half of the patients, but mepolizumab did not completely control symptoms in the other half of the patients.  Here is a quote from the abstract’s “conclusions” which summarized these results:

mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission

Mepolizumab helped patients remain in remission compared to patients in the placebo group. Patients taking mepolizumab had more weeks in remission than patients on placebo (28% vs. 3%).  The patients taking mepolizumab were also more likely to be in remission at the end of the trial than patients in the placebo group (32% in remission for the mepolizumab group vs. 3% for the placebo group at week 48 of the trial). As stated in the abstract’s “results” section:

mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001)

Mepolizumab also helped patients reduce the total dose of prednisone they were taking.  About half of the patients receiving mepolizumab were able to reduce their daily dose of prednisone to 4 mg or less per day by the end of the study, while only 7% of patients in the control group reached 4 mg or less of prednisone per day. This was stated in the abstract’s “results” section:

a total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52

Safety (adverse events).  Mepolizumab has been studied in other patient populations with eosinophilic diseases as well as healthy controls. The authors did not observe any increase in side effects in EGPA patients related to the mepolizumab treatment compared to side effects seen in the other studies of mepolizumab.

The take-home message.  Mepolizumab helped some patients get into remission and it reduced their symptoms of EGPA.  Mepolizumab didn’t work for all patients.  Only about half of the patients taking mepolizumab were able to achieve remission, and some of the patients who achieved remission did go on to relapse or have flares.  Mepolizumab also helped the patients who went into remission reduce the amount of daily prednisone they were taking.

What’s next?  In addition to mepolizumab (Nucala), other anti-IL-5 inhibitors, including reslizumab  (Cinqair) and benralizumab (Fasenra) are available. Cinqair and Fasenra have not been studied specifically for EGPA, but could possibly be effective treatments for EGPA.  For more information on how these drugs work, see here.

My thoughts.  Below is an breakdown of the patients in the study and whether they went into remission or had relapses during the course of the trial.

remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group

MIRRA-trial-schematic

Download a pdf of the image above here.

Mepolizumab is useful for maintaining remission in EGPA patients with a history of relapses or refractory disease.  By the end of the trial, which lasted a year, 47% of patients in the mepolizumab group did not achieve remission, which means that 53% of patients on mepolizumab DID reach remission.  In comparison, 81% of patients in the control group did not reach remission, which means that 19% of patients in the control group DID reach remission.  Of the patients who achieved remission, 32% in the mepolizumab group were in remission at the end of the trial vs. 3% of patients in the control group.  However, more patients were in remission on mepolizumab at week 48 at the end of the trial (32% out of 53%) versus on the patients on placebo who achieved remission (3% out of 19%).

EGPA patients with a history of relapse (flares) are likely to have more flares.  Since this was the first randomized controlled clinical trial for EGPA, meaning the patients were a carefully selected and well studied group of patients with similar clinical characteristics, the control group in this trial can tell us alot about the natural course of EGPA.  19% of patients in the control group reached remission without mepolizumab, which suggests that 19% of the patients treated with mepolizumab who went into remission (out of a total of 53%) might have gone into remission anyway, even without the mepolizumab. Tthis suggests that some EGPA patients with a history of relapses or flares or with refractory disease could go into remission after a year of standard treatment, but it’s not clear which patients are likely to go into remission and which patients will not. However, only 3% of the control patients out of 19% ended the trial in remission, meaning that EGPA patients with a history of relapse (flares) who are on standard care are very likely to have more relapses or flares.  This means that patients with a history of flares should be on the lookout for signs of EGPA symptoms. Please keep in mind that the patients in this trial had a history of relapses or disease that was refractory to standard treatment and the results may not apply to patients with less severe symptoms of EGPA.

Mepolizumab as an add-on treatment to reduce prednisone dose.  In my opinion, the real strength of this study was its effect in reducing patients’ daily prednisone dose. Many EGPA patients, myself included, struggle to maintain remission and will have flares (relapses) when they try to reduce their prednisone or their other immunosuppressive drugs.  This trial focused on patients with difficult to control symptoms who either had a relapse or had difficulty reaching remission (refractory disease).  Mepolizumab could be a good add-on treatment to the other drugs these patients are taking.  Mepolizumab could help these patients go into remission and help them to reduce their total daily prednisone dose.

Mepolizumab for airway symptoms.  Eosinophils are known to play an important role in many respiratory and airway disorders including some types of asthma so Mepolizumab is also being used to treat other eosinophilic diseases of the lungs.  Mepolizumab may be particularly useful for EGPA patients who have difficulty controlling lung and sinus symptoms.  It’s not clear whether mepolizumab can help control EGPA symptoms in other organs.

Mepolizumab for treating less severe symptoms of EGPA?  This study enrolled patients with relapses (flares) or refractory disease.  Although patients with less severe disease symptoms or no prior history of relapses were not evaluated in this trial, mepolizumab could help these patients, especially those with less severe but persistent asthma and other airway symptoms, to achieve and maintain remission while allowing them to reduce or possibly eliminate their need for prednisone.  Taking mepolizumab, like any drug, is not without risks and the benefits to the patient must outweigh the possible risks and side effects of the drug.

Reference:  Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, Merkel PA, Moosig F, Specks U, Cid MC, Luqmani R, Brown J, Mallett S, Philipson R, Yancey SW, Steinfeld J, Weller PF, Gleich GJ; EGPA Mepolizumab Study Team. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. 2017 376(20):1921-1932.

Links.  Below are some links to access the original article.  Supplemental data and author disclosure forms can be found on the journal’s website at the links provided below.

PubMed PMID: 28514601 (link-free full text)

PubMed Central PMCID: PMC5548295 (link-free full text)

Journal website, supplemental data, disclosures:  Go to the New England Journal of Medicine’s website to view the article, the supplemental data, and author disclosure forms for this article (link-free full text)

Clinical trial number:  NCT02020889. For more information about the clinical trial, visit the webpage for this clinical trial at www.clinicaltrials.gov (link-free full text)

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