Trial Outcomes & Findings for A Phase III Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES) (NCT NCT04191304)

A total of 134 participants were randomized at 40 study centres across 15 countries. Of the 134 participants randomized, 133 received treatment during the 24-week double-blind (DB) period. One participant did not receive treatment due to withdrawal.

The study consisted of 2 phases: a double-blind (DB) treatment period followed by an open-label extension (OLE) period. A total of 127 participants completed the DB period, of whom 126 subsequently entered the OLE period. One participant did not enroll in the OLE period due to withdrawal.

Full Analysis Set

The time to first HES worsening/flare is calculated as: start date of the first HES worsening - date of randomisation + 1. For participants who do not experience a HES worsening/flare, the time to first HES worsening/flare is right censored at the end of the DB period corresponding to the earliest date (date of the first of Benra open label dose, study day 183, date of last contact, and data cut-off date). The number of participants with events and censored observations is presented.

The proportion of participants who experience an HES worsening/flare or who withdraw from the study prior to completing the 24-week DB treatment period. The proportion is calculated as the number of participants with an HES worsening/flare or withdrawal divided by the total number of participants in the analysis population. The number and proportion (expressed as percentage) or participants who experienced HES worsening/flare is presented.

The annualised rate of HES worsening/flare events was analysed using a negative binomial regression model adjusted for region, with the logarithm of follow-up time included as an offset variable. Annualized flare rates are model estimated marginal rates. A separate HES worsening/flare is considered if the start date of an HES worsening/flare is at least 14 days apart from the stop date of a preceding HES worsening/flare.

Time to first haematologic relapse is calculated as start date of the first haematologic relapse - date of randomisation + 1. Haematologic relapse is defined as the first occurrence of an absolute eosinophil count (AEC) ≥ 1000 cells/μL post-baseline. For participants who do not experience haematologic relapse, the time to first haematologic relapse is right censored at the end of the DB period corresponding to the earliest date of (date of the first of Benra open label dose, study day 183, date of last contact, and data cut-off date). The number of participants with events and censored observations is presented.

Fatigue severity was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a questionnaire. Each item is scored on a 5-point Likert scale (1 to 5), and the total raw score is converted to a T-score. T-scores are standardized such that 50 represents the population mean with a standard deviation of 10. Standardized T-score range is from 29.4 to 83.2, with higher scores indicating more severe fatigue. A reduction in T-score indicates an improvement in fatigue severity. The least squares (LS) mean (95% CI) change from baseline in T-score at Week 24 is presented.

The proportion of patients who have a haematologic relapse or withdraw from the study over the DB treatment period is defined as the number of participants who have a first haematologic relapse or withdraw prior to completing in the DB period divided by the number of participants in the the analysis. Haematologic relapse is defined when AEC post baseline is ≥ 1,000 cells/Ul for the first time. The number and proportion (expressed as percentage) of participants who experienced haematologic relapse is presented.

The proportion of participants who maintained an AEC of \< 500 cells/µL throughout the 24-week DB treatment period. The proportion is defined as the number of participants who maintained AEC \< 500 cells/µL divided by the total number of participants in the analysis population. The number and proportion (expressed as percentage) of participants who maintained AEC \< 500 cells/µL is presented.

The proportion of patients who required an increase in systemic corticosteroids (SCS) from baseline during the 24-week DB treatment period. An increase in SCS includes an increase of at least 1 mg prednisone equivalent for participants receiving oral corticosteroids at baseline, or initiation of a new or additional course of systemic corticosteroids for treatment of HES or a closely related condition. Baseline is defined as the last valid value on or prior to randomisation. The number and proportion (expressed as percentage) of participants who require an increase in SCS from baseline.

HRQoL was assessed using the 36 Item Short Form Health Survey, version 2 (SF 36v2). Change from baseline in HRQoL was evaluated using the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores at Week 12 and Week 24 during the DB treatment period. PCS and MCS scores are norm-based and standardized to a general population with a mean of 50 and a standard deviation of 10, with higher scores indicating better HRQoL. Scores generally range from 0 to 100. PCS and MCS scores are derived from weighted combinations of domain scores using standard scoring algorithms. An increase in score indicates an improvement. LS mean (95% CI) changes from baseline for PCS and MCS scores are presented.

Patient Global Impression of Severity (PGI-S) is a single-item, participant-reported assessment of disease severity during the DB treatment period. PGI-S captures the participant's perception of overall symptom severity at the time of assessment using categorical response options ranging from "No symptoms" to "Very severe". The number and percentage of participants in each response category are presented at each timepoint.

Patient Global Impression of Change (PGI-C) is a single-item, participant-reported assessment that captures the participant's overall evaluation of response to treatment during the DB treatment period. PGI-C reflects the participant's perception of change in disease status compared with baseline using categorical response options ranging from "Much better" to "Much worse." The number and percentage of participants in each response category are presented at each time point.

Serum concentrations of benralizumab measured over time during the DB period to characterise the pharmacokinetics of benralizumab in participants with HES. Baseline is defined as the last valid value on or prior to the date of randomisation.

Immunogenicity of benralizumab, as assessed by the incidence and prevalence of anti-drug antibodies (ADA), including nAbs, measured from baseline through the 24-week DB treatment period in participants with HES.