Shots 

• While sharing the details on Fasenra, Andrew highlights the unmet medical need in the healthcare sector as there’s only one approved treatment for EGPA 

• With mepolizumab as the comparator drug for the trial, Andrew shares the positive results in achieving remission rates. Andrew sheds light on the unique mechanism of benralizumab that directly targets eosinophils, to treat EGPA 

• Andrew further shares the prospects of Fasenra as AstraZeneca looks forward to exploring its potential in treating other diseases like chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, and hypereosinophilic syndrome. 

Saurabh: Could you provide an in-depth overview of the Phase III (MANDARA) trial of Fasenra for EGPA and its significance in the context of treating this condition? 

Andrew: The Phase III MANDARA trial, which represents the first head-to-head trial of biologics in EGPA, was designed to compare the efficacy of benralizumab to the only approved treatment, mepolizumab, in adults with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA). 

Fasenra met the primary endpoint in the blinded trial – which was the proportion of patients who were in remission at both weeks 36 and 48 on benralizumab (single 30mg injection once every four weeks) compared to the approved dose of mepolizumab (three separate 100mg injections every four weeks). 

EGPA is a rare, immune-mediated vasculitis caused by inflammation of small to medium-sized blood vessels. The condition can result in damage to multiple organs, and without treatment, can be fatal. There is currently only one approved treatment for EGPA – which was the comparator in this trial – and there continues to be a high unmet medical need, leading to a high burden for patients with EGPA. 

Additionally, not all patients respond to currently available treatments, and while patients are often treated with chronic high-dose oral corticosteroids (OCS), they can experience recurrent relapses when attempting to taper off these medications, as well as adverse events associated with long-term use. 

MANDARA is the first trial to demonstrate that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to mepolizumab. This adds to the importance of benralizumab, with its unique mechanism of action that directly targets eosinophils, as a potential treatment option for EGPA. 

We look forward to sharing more details about the trial with the scientific community in the near future. 

Saurabh: Tell our readers about the primary endpoint that the trial met, and why it is significant in the context of treating EGPA. 

Andrew: The primary endpoint in the trial was the proportion of patients who were in remission at both weeks 36 and 48 on benralizumab compared to the approved dose of mepolizumab. The primary statistical analysis was to demonstrate the non-inferiority of benralizumab versus mepolizumab based on the primary endpoint.   

Demonstrating non-inferiority against mepolizumab means that there could be another potential treatment option to help patients achieve remission from the debilitating impacts of this inflammatory disease. 

Saurabh: We are curious to know how Fasenra works to treat EGPA, and what sets it apart from other treatment options for this condition. 

Andrew: Elevated levels of eosinophils play a central role in EGPA disease pathophysiology. 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. 

Benralizumab has a unique mechanism of action that directly targets eosinophils. Compared with other treatment options, it is administered as a single 30mg subcutaneous injection every four weeks versus the approved dose of mepolizumab, which is three 100mg injections every four weeks. 

Saurabh: Shed some light on the patient population involved in this Phase III trial. Were there any specific inclusion criteria or demographics that are worth highlighting? 

Andrew: 140 adult patients with relapsing or refractory EGPA participated in the trial. Only those who were receiving OCS with or without stable immunosuppressive therapy were eligible for inclusion in the trial. 

Saurabh: Would you like to tell us about the ongoing research or future directions related to Fasenra or EGPA treatment that viewers should be aware of? 

Andrew: We are pleased with the high-level results from the MANDARA Phase III trial, which add to the potential importance of benralizumab as a treatment option for EGPA. With Fasenra’s well-established long-term safety and efficacy profile, which includes real-world data, we believe we are well-positioned to maintain our leadership position in severe asthma and strive to achieve the same in EGPA. 

As well as continuing to advance the science when it comes to Fasenra’s role as the leading biologic in the treatment of severe eosinophilic asthma, AstraZeneca is exploring Fasenra’s potential as a treatment across several other diseases where eosinophils are expected to play a role, including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps and hyper eosinophilic syndrome. 

Saurabh: What are your next steps after successfully completing this Phase III trial? Are there plans for regulatory submissions or further studies? 

Andrew: We will be sharing full results from the trial with the scientific community at an upcoming medical meeting as well as with regulatory authorities around the world. We remain on track for regulatory submission in H2 2023 and look forward to bringing benralizumab to EGPA patients as quickly as possible. 

Image Source: Canva 

About the Author 

Andrew Menzies-Gow 

Andrew Menzies-Gow is the Global Medical Head for Respiratory Biologics at AstraZeneca. Prior to joining the company in January 2023, Andrew was the clinical and research lead for the adult severe asthma service and Director of the Lung Division at the Royal Brompton & Harefield Hospitals, London, UK. Andrew was a Professor of Practice (Respiratory Medicine) at Imperial College, London, UK, where his research interests focused on novel therapies for severe asthma and was the National Clinical Director for Respiratory Disease at NHS England.