Mepolizumab: A Key Agent in the Fight against Eosinophilic Granulomatosis with Polyangiitis
In December 2017, the Food and Drug Administration approved mepolizumab, the first treatment for Eosinophilic Granulomatosis with Polyangiitis (EGPA), formerly known as the Churg-Strauss Syndrome.1 For the 5,000 people in the United States suffering from EGPA, mepolizumab provides an alternative treatment from the current standard of care - a chronic immunosuppressive treatment and the heavy burden of side effects.2 EGPA is a disorder caused by the body’s immune reaction, causing blood vessel inflammation in the cerebral, cardiac, renal, and respiratory systems. Inflamed blood vessels resist blood flow and cause permanent organ damage that can be fatal if left untreated. Corticosteroids can be used to manage symptoms through global immune system suppression, but can drastically reduce a patient’s quality of life, with side effects including muscle loss, heart arrhythmia, and social isolation to avoid infection. In contrast, mepolizumab is a targeted therapy that aims to reduce eosinophil concentration, the immune cell responsible for mediating inflammation in EGPA.3 This targeted immunotherapy is effective in not only reducing adverse events but increasing the proportion of patients who can achieve remission after therapy and time in remission. The impact of EGPA and the therapeutic potential of mepolizumab will be discussed in detail in the context of how it works, who can benefit, current limitations, and future directions.
EGPA is a rare disorder with a global prevalence of 14-45 per million individuals.2 The typical age of onset is between the ages 30-50 in people who have a history of difficult-to-control asthma and/or nasal problems.2 Although the exact cause is unknown, many believe that EGPA is the result of an overactive immune response that is triggered by a combination of genetic predisposition and environmental factors, including certain medication.4 However, no specific medication has been linked as a causal factor. The disease has highly variable symptoms, but can be best categorized into three stages. The first stage is the allergic stage, where individuals with EPGA often experience asthma, hay fever, and sinusitis.5 Microscopically, this corresponds to when the individual inhales an antigen, a foreign body that produces an immune response, initiating allergic inflammation pathways in genetically susceptible individuals.4 Levels of eosinophils, a disease-fighting white blood cell often seen in allergic reactions, and T-cells, another white blood cell, are elevated as part of this response. This characterizes the second stage, called the eosinophilic stage, where abnormally high levels of eosinophils cause serious damage through the production of tissue inflammation.5 The third stage is the vasculitic stage, where blood vessel inflammation reduces blood flow to vital organs and tissues and is often fatal.5
Although EGPA manifests with diverse symptoms that can range from mild to severe, there are five organ systems that are commonly involved in disease progression. Involvement of the central nervous systems can cause symptoms like convulsions, coma, and stroke because of limited blood flow to the brain.4 Inflammation of EGPA also has consequences on the gastrointestinal symptoms, including abdominal pain, intestinal perforation and pancreatitis.4 Similarly, cardiac involvement can manifest as valvular heart disease, congestive heart failure, and pericarditis (inflammation of the lining around the heart). Cardiac problems are the leading cause of mortality in EGPA patients, both as a result of disease progression as well as the cardiac damage due to long-term corticosteroid use. 4,6 Vascular inflammation also has impacts on the skin and nerves, producing the sensation of “pins and needles” through peripheral nerve damage and skin lesions due to vasculitis of the skin.4 The diversity of symptoms associated with EGPA and its low prevalence makes the condition extremely hard to diagnose and treat.
Gloria Pieterse from Ireland is an EGPA patient who has been living with the condition for more than 18 years.7 At the time when she became ill, very little was known about the cause of the disease, symptom presentation, and thus, treatment was very difficult. She recalls being on a string of medications to treat her diagnoses of asthma, ulcerative colitis, and septicaemia.7 She was quickly put on long-term steroid therapy, causing her to develop steroid cataracts that necessitated corneal grafts. Gloria’s immunosuppressive corticosteroid therapy also made her fearful of contracting an infection, forcing her to avoid social situations and distanced her from family and friends.7 The story of a painfully elusive diagnosis and years of living with the consequences of corticosteroid therapy is too familiar of a story for most EGPA patients.
GlaxoSmithKline (GSK) is a pharmaceutical research and development organization who is looking to rewrite the EGPA experience with mepolizumab, a humanized monoclonal antibody. Mepolizumab interferes with the normal function of interleukin-5, which is responsible for the maturation of eosinophils.3 As a result, mepolizumab has shown very promising effects in reducing eosinophil activity and is already approved for use in eosinophilic asthma.8 The selective inhibition of eosinophil-induced inflammation has led mepolizumab to perform significantly better than corticosteroids in the context of eosinophilic asthma.8 Subsequently, GSK began investigating whether this drug can be prescribed for other eosinophil-induced conditions, such as EGPA, through the MIRRA study, which investigated the efficacy of mepolizumab compared with corticosteroids in patients with refractory EGPA.3 Refractory EGPA is a subgroup of EGPA patients who have previously undergone treatment and entered a state of remission before relapsing and presenting again with symptoms. This population is considered particularly difficult to treat because of the lack of a complete response in the first course of their treatment. The randomized study looked at 136 patients and found that patients who received the mepolizumab treatment had a significantly greater proportion of patients who can achieve remission and patients had a longer disease-free state.3 There were also fewer serious adverse events in patients who received mepolizumab. This groundwork study would provide critical evidence for the FDA approval of the drug in December 2017.1
The most common side effects of mepolizumab include headaches, injection site reactions (redness, itchiness, swelling), back pain, and fatigue.1 Mepolizumab has fewer side effects than traditional therapy with corticosteroids, which can decrease the structural stability of connective tissue (cartilage, bone, and nervous system tissue), cause cardiomyopathy through weakening of heart muscle, and decreasing potassium levels that are critical to maintaining a regular heart rhythm.6 Patients who do not respond favourably to corticosteroid therapy also receive an immunosuppressant called cyclophosphamide, which can cause ovarian failure, bladder fibrosis, and bone marrow suppression.4 The hope is that mepolizumab will be able to circumvent many of the detrimental side effects of the current standard of care.
The benefits of mepolizumab come at a high cost. Compared to oral prednisone therapy, a common corticosteroid to treat EGPA, a month of therapy would cost $3,090 (US pricing) for patients receiving mepolizumab vs $38 (UK pricing) if patients had no prescription drug coverage.9,10 For many, this is too high of a price to pay. Consider the mounting evidence that both therapies need to be administered long term to keep patients in remission, the accessibility of EGPA may be limited due to its high cost. Thus, despite a recent FDA approval that offers hope for EGPA patients to access this beneficial therapy with reduced side effects, whether patients can afford this new therapy is still a big question. However, uncertainty remains with whether insurance companies, Medicare or Medicaid, would be providing coverage. As with all orphan drugs, it will be interesting to evaluate the impact of mepolizumab on EPGA patients given the financial and practical considerations.
1. FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome. US Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm588594.htm. Published 2017.
2. GSK achieves approval for Nucala (mepolizumab) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) for adults in the US. GSK. https://www.gsk.com/en-gb/media/press-releases/gsk-achieves-approval-for-nucala-mepolizumab-for-the-treatment-of-eosinophilic-granulomatosis-with-polyangiitis-egpa-for-adults-in-the-us/. Published 2017.
3. Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. 2017;376(20):1921-1932. doi:10.1056/NEJMoa1702079.
4. Noth I, Strek ME, Leff AR. Churg-Strauss syndrome. In: Lancet. Vol 361. ; 2003:587-594. doi:10.1016/S0140-6736(03)12518-4.
5. Churg-Strauss Syndrome. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/churg-strauss-syndrome/symptoms-causes/syc-20353760. Published 2016.
6. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol. 2001;33(4):289-294. doi:10.1097/00004836-200110000-00006.
7. Pieterse G. My story as a long term survivor of CSS. CSS Association. http://www.cssassociation.org/patient-stories-reader/items/my-story-as-a-long-term-survivor-of-css.html. Published 2006.
8. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma. N Engl J Med. 2014;371(13):1198-1207. doi:10.1056/NEJMoa1403290.
9. Choy MS, Dixit D, Bridgeman MB. Mepolizumab (Nucala for Severe Eosinophilic Asthma. Pharamacy Ther. 2016;41(10):619-622. http://pubmedcentralcanada.ca/pmcc/articles/PMC5046999/.
10. Kerkhof M, Tran TN, Soriano JB, et al. Healthcare resource use and costs of severe, uncontrolled eosinophilic asthma in the UK general population. Thorax. 2017:thoraxjnl-2017-210531. doi:10.1136/thoraxjnl-2017-210531.
Cite This Article:
Zhang B., Chan G., Palczewski K., Lewis K., Ho J. Mepolizumab: A Key Agent in the Fight against Eosinophilic Granulomatosis with Polyangiitis. Illustrated by D. Jung. Rare Disease Review. January 2019. DOI:10.13140/RG.2.2.35348.96648.