Spontaneous Resolution of Atopic Dermatitis Incidental to Participation in Benralizumab Clinical Trial for Severe, Uncontrolled Asthma

A Case Report

David N. Pham

Disclosures

J Med Case Reports. 2021;15(103) 

In This Article

Discussion and Conclusions

This case is notable in that the patient was enrolled in a clinical trial focused on a specific drug indication—severe, uncontrolled asthma with elevated blood eosinophil counts—but experienced dramatic resolution of symptoms for a different condition that may have a related mechanism of action. Evidence is increasing that the pathology of asthma, AD, and other diseases that are part of the so-called atopic march are a result of a self-reinforcing and progressive cascade of epithelial barrier dysfunction in the skin, gut mucosa, and respiratory mucosa, allowing increased penetration of allergens and microbes that elicit a systemic, T cell-mediated eosinophilic hyper-response.[2,3,8] Because this inappropriate eosinophilic response is characteristic of all of the atopic diseases, it is conceivable that treatments targeting the underlying T cell–eosinophil interaction could potentially show efficacy against more than one condition.[2–6] However this hypothesis must be investigated for each combination of drug and condition and the therapies currently on the market are, so far, limited to single indications.

Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody (mAb) directed against the ⍺ chain of IL-5R, a receptor that is abundant on the surface of eosinophils and basophils and is essential to their function and survival.[9,10] The engineered afucosylation enhances the receptor binding affinity of benralizumab as well as its antibody-dependent cell-mediated cytotoxicity function,[9] resulting in near-total depletion of eosinophils from the circulation, and from the airways and lungs, and approximately 80% depletion of eosinophilic progenitors from the bone marrow.[10,11]

CALIMA was a randomized, double-blind, parallel-group, placebo-controlled, phase 3 clinical trial conducted at 303 sites in 11 countries.[7] Patients enrolled in the study were aged 12–75 years with severe asthma uncontrolled by medium- to high-dose inhaled corticosteroids (ICS) with long-acting β2-agonists (LABA) and a history of two or more exacerbations in the previous year. Patients were randomized in a 1:1:1 ratio to receive 56 weeks of treatment with benralizumab 30 mg subcutaneous every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo. The study population was also stratified (2:1) by baseline blood eosinophil counts (at least 300 cells/μL versus less than 300 cells/μL). The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dose ICS plus LABA with baseline blood eosinophils at least 300 cells/μL (intent-to-treat analysis). Secondary endpoints were FEV1 and total asthma symptom score.

Of 2505 patients enrolled and 1306 randomized, 728 patients were included in the primary analysis population. The study found that 56 weeks of add-on therapy with benralizumab at either dose level reduced annual exacerbation rates in patients with severe asthma and elevated baseline blood eosinophil counts by up to 36% compared with placebo (Q4W rate ratio 0.64 [95% CI 0.49–0.85], p = 0.0018, n = 241; and Q8W rate ratio 0.72 [95% CI 0.54–0.95], p = 0.0188, n = 239). Benralizumab also significantly improved pre-bronchodilator FEV1 in the Q4W and Q8W groups, and total asthma symptom score in the Q8W group. Furthermore, patients in both active dose groups experienced near-complete depletion of blood eosinophils by the 4-week sampling time point. The drug was well tolerated with few drug-related adverse events.

On the basis of the results of CALIMA and another pivotal trial, SIROCCO,[7,12] benralizumab was approved in 2017 by the US Food and Drug Administration as Fasenra® for add-on maintenance treatment of patients with severe asthma, aged 12 years and older, with an eosinophilic phenotype.[13] The medication is not approved for treatment of other eosinophilic conditions and is not for relief of acute bronchospasm or status asthmaticus. Results from the first year of a long-term safety study (the BORA phase 3 extension trial) are consistent with efficacy and safety outcomes from the pivotal trials.[14] To date, benralizumab has not been evaluated clinically for its efficacy against AD, although a phase 2 study is being planned to further characterize its potential therapeutic role.

The asthma symptoms of the patient in this case responded to benralizumab in a manner consistent with the aggregate responses in patients in the Q8W arm of the CALIMA trial, with a reduced 56-week exacerbation rate, improved lung function, reduced asthma symptom score, and near-total depletion of blood eosinophils. The observed reduction in AD symptoms occurred concurrent with that response, as is evident in Figure 1, with a substantial decrease in inflammation at 2 months compared with baseline, and skin healing at 5 months. It is noteworthy that the improvements in the patient's AD symptoms occurred in the absence of any systemic steroid use for asthma exacerbation; the patient received systemic steroids only once during the study period, on day 363.

It is important to acknowledge that the findings reported here were incidental, observed during a case that was part of a large prospective clinical trial. A post hoc attempt to identify other patients in the study with similar findings would be practically infeasible and limited by unavoidable selection bias. However, the strength of the observed effect in this case suggests a potential area for investigation.

In conclusion, we observed spontaneous resolution of AD coincident with participation in a clinical trial for benralizumab to treat severe, uncontrolled, eosinophilic asthma. Given the plausible overlap in pathologic mechanisms between asthma and AD, further studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be efficacious in managing multiple allergic diseases.

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