WILMINGTON, Del. — Positive results from the MANDARA Phase III trial for FASENRA® (benralizumab) in patients with EGPA were published in the New England Journal of Medicine today, as the first head-to-head trial of biologics in patients with EGPA, and the first to demonstrate that more than half of patients achieved remission with eosinophil-targeting biologic therapies. These findings were also presented today as a late-breaking poster at the American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting in Washington, DC, February 23-26.
MANDARA compared benralizumab to mepolizumab in patients with EGPA receiving oral corticosteroids (OCS) with or without stable immunosuppressive therapy. Patients were randomized to receive either a single 30 mg subcutaneous injection of benralizumab, or three separate 100 mg subcutaneous injections of mepolizumab, once every four weeks. Full results showed that benralizumab met the primary endpoint of the trial and demonstrated non-inferior rates of remission compared to mepolizumab. The primary endpoint of adjusted rate of remission was 59% for benralizumab-treated patients at weeks 36 and 48, compared with 56% for mepolizumab (difference in rates: 3%; 95% CI:, –13,18). Remission in EGPA is defined as Birmingham Vasculitis Activity Score (BVAS)=0 and OCS dose less than or equal to 4 mg/day.
A higher proportion of FASENRA-treated patients were able to fully taper off OCS during weeks 48 through 52 (41% in the benralizumab arm vs. 26% in the comparator arm (difference: 16%; 95% CI: 1,31). Additionally, 86% of benralizumab patients vs. 74% in the comparator arm (difference: 12%; 95% CI: −1, 25) had at least a 50% reduction in OCS dose during weeks 48 through 52.
Dr. Michael Wechsler, Professor of Medicine and Director of The Asthma Institute at National Jewish Health, and International Coordinating Investigator of the MANDARA trial said: “Patients with EGPA typically rely on long-term, high-dose OCS, which can cause serious and lasting side effects, and often suffer recurrent relapses when attempting to taper off their treatment. These findings are an exciting step forward as they affirm that eosinophil-targeting biologic treatments helped more patients achieve remission and taper off of steroid therapy.”
Sharon Barr, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca said, “The results from this trial are an important step forward for the EGPA community, as this is the first trial to demonstrate that remission from EGPA with an eosinophil-targeting biologic is achievable for the majority of patients. This is a significant advancement and shows that benralizumab helped patients achieve remission and reduce chronic OCS usage, in a convenient, single, monthly subcutaneous injection, and could alleviate some of the impact of this debilitating disease.”
Elevated levels of eosinophils play a central role in EGPA disease pathophysiology. All patients with EGPA have very high levels of eosinophils at some point in their disease, both in peripheral blood and in affected tissues or organs. Approximately half of patients with EGPA have concomitant, adult-onset severe eosinophilic asthma, and often have sinus and nasal symptoms.
FASENRA has a unique mode of action that leads to near complete depletion of eosinophils. Treatment with benralizumab was associated with a greater reduction of blood eosinophil counts from week 1 compared to mepolizumab and maintained at all timepoints. At week 1 mean blood eosinophil count ratio to baseline was 0.15 vs. 0.39 respectively (adjusted geometric mean ratio: 0.38; 95% CI: 0.29, 0.49) and 0.10 vs. 0.26 at week 52 (adjusted geometric mean ratio: 0.36; 95% CI: 0.27, 0.49). Benralizumab was well tolerated with no new safety signals, which is consistent with the known profile of the medicine.
FASENRA is currently approved as an add-on maintenance treatment for SEA in 80 countries including the US, Japan and in the EU, and is approved for self-administration in the US, EU and other countries.
AstraZeneca has been working with regulatory authorities around the world in order to bring benralizumab to EGPA patients as quickly as possible.
Eosinophilic granulomatosis with polyangiitis
EGPA, formerly known as Churg-Strauss Syndrome, is a rare, immune-mediated inflammatory disease that is caused by inflammation of small to medium-sized blood vessels. It is estimated that 118,000 people throughout the world live with EGPA.
EGPA can result in damage to multiple organs, including lungs, upper airway, skin, heart, gastrointestinal tract and nerves. The most common symptoms and signs include extreme fatigue, weight loss, muscle and joint pain, rashes, nerve pain, sinus and nasal symptoms, and shortness of breath. Without treatment, the disease may be fatal. Almost half (47%) of patients do not achieve remission with current treatments.
There are limited treatment options for EGPA. Patients are often treated with chronic high-dose OCS and experience recurrent relapses when attempting to taper off OCS. Mepolizumab is currently the only approved treatment for EGPA.
MANDARA
MANDARA was a randomised, double blind, double-dummy, active-controlled, parallel group, multicentre 52-week Phase III trial which compared the efficacy and safety of Fasenra to mepolizumab in adult patients with relapsing or refractory EGPA. In the blinded trial, 140 patients were randomised 1:1 (70 per treatment group) to receive either a single 30mg subcutaneous injection of Fasenra or three separate 100mg subcutaneous injections of mepolizumab once every four weeks.
The primary endpoint was the proportion of patients who were in remission at both weeks 36 and 48. Remission is defined as Birmingham Vasculitis Activity Score (BVAS)=0 and OCS dose less than or equal to 4 mg/day. Fasenra remission was compared to the historical placebo rate from mepolizumab’s Phase III trial, MIRRA. The primary statistical analysis was to demonstrate non-inferiority of Fasenra versus mepolizumab based on the primary endpoint.
All patients who complete the 52-week double-blind treatment period were eligible to continue into an ongoing open label extension (OLE) period, intended to allow each patient at least one year of treatment with open-label Fasenra.
Mepolizumab is a humanized IL-5 antagonist monoclonal antibody.
Fasenra
Fasenra is a monoclonal antibody that binds directly to IL-5 receptor alpha on eosinophils and attracts natural killer cells to induce rapid and near-complete depletion of blood and tissue eosinophils in most patients via apoptosis (programmed cell death).
Fasenra (benralizumab) is currently approved in more than 80 countries, including the US, EU, Japan, and is approved for self-administration in the US, EU and other countries.Fasenra has been prescribed to over 120,000 patients globally.
Fasenra is in development for other diseases including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps and hypereosinophilic syndrome.
Fasenra was developed by AstraZeneca and is in-licensed from BioWa, Inc., a wholly-owned subsidiary of Kyowa Kirin Co., Ltd., Japan.
Respiratory & Immunology
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