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FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome
The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA. Continue reading.
December 12, 2017
The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA.
According to the National Institutes of Health, EGPA (formerly known as Churg-Strauss syndrome) is a condition characterized by asthma, high levels of eosinophils (a type of white blood cell that helps fight infection), and inflammation of small- to medium-sized blood vessels. The inflamed vessels can affect various organ systems including the lungs, gastrointestinal tract, skin, heart and nervous system. It is estimated that approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year, with an overall prevalence of 10.7 to 14 per 1,000,000 adults.
“Prior to today’s action, patients with this challenging, rare disease did not have an FDA-approved treatment option,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded indication of Nucala meets a critical, unmet need for EGPA patients. It’s notable that patients taking Nucala in clinical trials reported a significant improvement in their symptoms.”
Nucala was previously approved in 2015 to treat patients age 12 years and older with a specific subgroup of asthma (severe asthma with an eosinophilic phenotype) despite receiving their current asthma medicines. Nucala is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells.
Nucala is administered once every four weeks by subcutaneous injection by a health care professional into the upper arm, thigh, or abdomen.
The safety and efficacy of Nucala was based on data from a 52-week treatment clinical trial that compared Nucala to placebo. Patients received 300 milligrams (mg) of Nucala or placebo administered subcutaneously once every four weeks while continuing their stable daily oral corticosteroids (OCS) therapy. Starting at week four, OCS was tapered during the treatment period. The primary efficacy assessment in the trial measured Nucala’s treatment impact on disease remission (i.e., becoming symptom free) while on an OCS dose less than or equal to 4 mg of prednisone. Patients receiving 300 mg of Nucala achieved a significantly greater accrued time in remission compared with placebo. A significantly higher proportion of patients receiving 300 mg of Nucala achieved remission at both week 36 and week 48 compared with placebo. In addition, significantly more patients who received 300 mg of Nucala achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared with patients who received the placebo.
The most common adverse reactions associated with Nucala in clinical trials included headache, injection site reaction, back pain, and fatigue.
Nucala should not be administered to patients with a history of hypersensitivity to mepolizumab or one of its ingredients. It should not be used to treat acute bronchospasm or status asthmaticus. Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash, have occurred. Patients should discontinue treatment in the event of a hypersensitivity reaction. Patients should not discontinue systemic or inhaled corticosteroids abruptly upon beginning treatment with Nucala. Instead, patients should decrease corticosteroids gradually, if appropriate.
Health care providers should treat patients with pre-existing helminth infections before treating with Nucala because it is unknown if Nucala would affect patients’ responses against parasitic infections. In addition, herpes zoster infections have occurred in patients receiving Nucala. Health care providers should consider vaccination if medically appropriate.
The FDA granted approval of Nucala to GlaxoSmithKline.
The first non-inhaled treatment for a difficult-to-treat form of severe asthma is getting closer to market after GlaxoSmithKline said it would initiate global filings for the drug at the end of this year, on the back of strong late-stage clinical data.
Mepolizumab – a monoclonal antibody that inhibits interleukin 5 – is being investigated as a treatment for severe eosinophilic asthma in patients who experience exacerbations despite high-dose oral or inhaled corticosteroids (ICS) and an additional controller such as long-acting beta-2 agonist.
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Recent studies have concluded that mepolizumab may improve exacerbations in patients with severe eosinophilic asthma, an adult-onset asthma which represents less than 5% of all asthma.
IL-5 is a chemical messenger in the immune system that stimulates the growth of eosinophils. In eosinophilic asthma, eosinophils are present in the lungs. When mepolizumab was given to people with eosinophilic asthma, it eliminated eosinophils from the bloodstream,and reduced eosinophils in the lungs and bone marrow. Mepolizumab also reduced the number of asthma exacerbations, and reduced the need for corticosteroids.Mepolizumab improved the quality of life, but the improvement was “not clinically meaningful,” according to a reviewer. 
In a recent multi-centre, double-blinded, randomised, controlled trial study of Mepolizumab in severe eosinophilic asthma, Mepolizumab reduced the number of clinically significant exacerbations compared to a placebo. Additionally Mepolizumab reduced sputum and blood eosinophil counts and was shown to be safe for up to 12 months.
Mepolizumab is also in development for the management of hypereosinophilic syndrome by GlaxoSmithKline (GSK) and has received orphan drug designation by the FDA. Mepolizumab has been shown to reduce the need for corticosteroids and improve symptoms in FIP1L1/PDGFRA negative hypereosinophilic syndrome.
UK pharma giant GlaxoSmithKline (LSE: GSK) says that a pivotal Phase III study of mepolizumab, an investigational IL-5 antagonist monoclonal antibody, met its primary endpoint of reduction in the frequency of exacerbations, in patients with severe eosinophilic asthma.
Mepolizumab could add £400 million ($668 million) to GSK’s revenue by 2021, according to estimates from Barclays reported by The Wall Street Journal. Analysts from Deutsche Bank forecast £300 million in mepolizumab sales by 2018 for the company, already a leader in the asthma treatment sector.
The study (MEA115588) evaluated the efficacy of two-dose regimens of mepolizumab in the treatment of patients with severe eosinophilic asthma. Patients remained on their current asthma maintenance therapy throughout the study and were randomized to receive either mepolizumab 75mg intravenous (IV), 100mg subcutaneous (SC), or placebo every four weeks.
For the primary end point, both mepolizumab treatment arms showed statistically significant reductions in the frequency of clinically significant exacerbations of asthma compared to placebo (75mg IV, 47%, p<0.001; 100mg SC, 53%, p<0.001).
Adverse events reported in the study were similar across all treatment groups. The most common reported adverse events across all treatment groups were nasopharyngitis, headache, upper respiratory tract infection and asthma. The frequency of adverse events was 83% in the placebo group, 84% in the mepolizumab 75mg IV and 78% in the mepolizumab 100mg SC group. The frequency of serious adverse events was 14% in the placebo group, 7% in the mepolizumab 75mg IV and 8% in the mepolizumab 100mg SC group.
Backs up earlier studies; regulatory filing mooted at year end
Dave Allen, head of GSK Respiratory Therapy Area Unit, R&D, said: “We are really pleased to have generated further positive data on mepolizumab, consistent with the findings from our earlier exacerbation study. We now have two studies showing a reduction in exacerbations in a specific group of patients with a severe form of asthma who continue to exacerbate despite treatment with high doses of their current maintenance therapies. This is very positive news for patients. For GSK it is exciting that this is the first non-inhaled treatment for severe asthma and we will be progressing towards global filings at the end of the year.”
In addition, a second Phase III study (MEA115575) designed to evaluate the use of mepolizumab 100mg SC, every four weeks in comparison to placebo in reducing daily oral corticosteroid use while maintaining asthma control also met its primary endpoint. The study showed that patients on mepolizumab 100mg SC were able to achieve greater reductions in their maintenance oral corticosteroid dose during weeks 20-24 compared to patients on placebo (p =0.008), while maintaining asthma control.
In this study adverse events were similar across treatment groups. The most common reported adverse events in the two treatment groups were headache, nasopharyngitis, bronchitis, sinusitis, fatigue and asthma. The frequency of adverse events was 92% in the placebo and 84% in the mepolizumab treatment group. Frequency of serious adverse events was 18% in the placebo group and 1% in the mepolizumab group.
Mepolizumab Useful in Refractory Eosinophilic Asthma, a Rare Subtype of Asthma
Eosinophil.Eeosinophilic form of asthma represents less than 5% of cases of adult-onset asthma and is difficult to treat.
Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment.
Mepolizumab therapy reduced exacerbations by 43% and improved Asthma Quality of Life Questionnaire (AQLQ) scores in patients with refractory eosinophilic asthma.
Eosinophils may have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in patients with eosinophilic asthma.
- Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009 Mar 5;360(10):973-84.
- Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009 Mar 5;360(10):985-93.
- Eosinophils in asthma – closing the loop or opening the door? Sally E. Wenzel, N Engl J Med. 2009 Mar 5;360(10):1026-7.
- Pavord, Ian D; Korn, Stephanie; Howarth, Peter; Bleecker, Eugene R; Buhl, Roland; Keene, Oliver N; Ortega, Hector; Chanez, Pascal (August 2012). “Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial”. The Lancet 380 (9842): 651–659. doi:10.1016/S0140-6736(12)60988-X.
- Phase III study of Bosatria (mepolizumab) showed disease control with reduced corticosteroid use in hypereosinophilic syndrome
- http://content.nejm.org/cgi/content/abstract/358/12/1215 Rothenberg et al 2008