Trials in Progress: A Two-Cohort, Open-Label, Single-Arm Study of Emapalumab, an Anti-Interferon Gamma (IFNγ) Monoclonal Antibody, in Patients with Macrophage Activation Syndrome (MAS) in Rheumatic Diseases

Introduction: MAS is a severe, life-threatening complication of rheumatic diseases such as Still's disease and systemic lupus erythematosus (SLE). MAS is a form of secondary hemophagocytic lymphohistiocytosis, characterized by a hyperinflammatory state caused by immune cell dysregulation which can lead to multiorgan damage. Sustained activation and expansion of T lymphocytes and macrophages stimulates the hypersecretion of proinflammatory cytokines such as IFNγ.

The mainstay of treatment for MAS is high doses of glucocorticoids (GCs); however, they do not always provide adequate control in all patients. Additional treatments are used without a standardized approach; however, morbidity and mortality remain high. Preliminary data from a pilot study including 9 patients with inadequate response to high-dose intravenous GCs (NCT03311854) showed that emapalumab, a fully human anti-IFNγ monoclonal antibody, led to rapid neutralization of IFNγ and was efficacious in controlling MAS with a favorable safety profile [De Benedetti et al. Annals Rheumatic Dis 2020;79(Suppl. 1):194]. A study to further evaluate the efficacy and safety of emapalumab in patients with MAS in Still's disease and SLE is enrolling patients.

Objective: To describe the design and objectives of a Phase 2/3 study aiming to confirm the efficacy and safety of emapalumab in the treatment of MAS in rheumatic disease.

Study Design and Methods: This open-label, single arm, multicenter, interventional study (Figure 1) is enrolling pediatric and adult subjects into two cohorts 1) MAS in Still's disease (systemic juvenile idiopathic arthritis and adult onset Still's disease; n=25) and 2) MAS in SLE (n=16). Eligible patients must present with an inadequate response to high doses of GCs. Each cohort is a single-arm study composed of two phases: an optional run-in phase and an interventional phase. Key eligibility criteria vary by cohort and phase (Table 1). During the run-in phase, patients are treated with GCs according to the investigators' clinical practice and followed until MAS remission or inadequate response, or for a maximum of 12 weeks. Patients with an inadequate response to GCs (and potentially to other therapies) enroll in the interventional phase to be treated with intravenous emapalumab (initial dose 6mg/kg, subsequent doses 3mg/kg) for 4 weeks or until a complete response (CR) is achieved, and are followed off-drug for 1 year.

Based on the assumptions of a successful treatment with GCs (null hypothesis) of up to 40% for cohort 1 (i.e. CR rate of 40%) and 30% for cohort 2 (i.e. CR rate of 30%), if the truth is 70% complete responders (for both cohorts), then a total of 25 and 16 patients, respectively, is required to demonstrate a statistically significant proportion of CR with a power of 80% using a one-sided exact binomial test at a significance level of 2.5%. The study design for cohort 1 is a group sequential design, including an interim analysis assessing efficacy with an adjusted type 1 error after 16 patients have reached Week 8 after the first dose of emapalumab.

The primary endpoint of the study is CR (response criteria defined in Table 2) at Week 8 after first emapalumab administration. Secondary efficacy endpoints include GC tapering, survival, time to first CR, overall response (CR and partial response), time to first overall response, MAS recurrence, PK/PD profile of emapalumab, and patient-reported outcomes. Safety endpoints include assessments of adverse events, abnormal laboratory parameters, and anti-drug antibodies.

Summary: This ongoing trial is designed to address the unmet need for new efficacious and safe therapies for the treatment of MAS.

Figure 1

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Figure 1

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