Trial in Progress: A Phase 1b Study of ELA026 in Patients with Secondary Hemophagocytic Lymphohistiocytosis

Background: ELA026 is a fully human, monoclonal immunoglobulin G1 (IgG1) signal regulatory protein (SIRP)-directed antibody. SIRP is a cell surface protein expressed on cells of the myeloid lineage and T cells, which are implicated in driving pathology in hemophagocytic lymphohistiocytosis (HLH).

HLH is a rare, aggressive, and life-threatening syndrome of excessive immune activation. Patients typically present with fever, hepatosplenomegaly, and pancytopenia. The disease is associated with a massive systemic inflammatory response requiring immediate treatment. Left untreated, patients progress to a clinical hyperinflammatory state that can lead to multi-organ failure, circulatory shock, and death. Secondary HLH (sHLH), the most common form of HLH, is typically triggered by malignancy, autoimmune disease, or infection. Currently, there are no approved therapies for sHLH. The HLH-94 treatment protocol (etoposide, dexamethasone, and cyclosporin) is used with variable degrees of effectiveness.

Preclinical studies with ELA026 have demonstrated its ability to induce both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of human monocytes and ADCC of human SIRP+ activated T lymphocytes. Administration of ELA026 to non-human primates causes a rapid, potent, and reversible reduction of circulating monocyte, granulocyte, and T cell counts. Following washout of ELA026, reconstitution of all affected cell types to predose levels is observed within hours/days, providing evidence that bone marrow hematopoiesis is unaffected. By reducing myeloid-derived antigen presenting cells (monocytes/macrophages) and interferon gamma-producing CD8+ T cells, ELA026 has the potential to halt the initiation and progression of the inflammatory process in sHLH.

Objectives: Primary objectives are to evaluate the safety of ELA026 and identify a dose for Phase 2/3 testing. Secondary objectives are to determine the efficacy (best response by 4 weeks), characterize the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects, and assess the immunogenicity of ELA026. Efficacy criteria were based on modified HLH-2004 criteria, similar to what were used in a prior pivotal trial for primary HLH (Locatelli F, et al. N Engl J Med. 2020;382(19):1811-22).

Study Design: This Phase 1b, open-label, single-arm, multicenter study is investigating the safety, efficacy, PK, and PD of ELA026 following multiple intravenous (IV) doses administered in up to 24 adolescent or adult patients who are treatment naïve or who have relapsed/refractory sHLH regardless of underlying trigger (NCT05416307). Patients must be at least 12 years of age at the time of sHLH diagnosis. Patients are ineligible if they have received hemopoietic stem cell transplantation within 100 days or chimeric antigen receptor (CAR) T-cell therapy within 3 months prior to the first dose of ELA026.

This study utilizes an adaptive 3+3 design, with an intra-patient dose-escalation phase and a fixed-dose phase (Figure 1). In Cohort 1, after a patient has received 3 daily IV doses at a pharmacologically active dose level, the dose will be escalated until that patient (1) demonstrates monocyte reduction and ferritin biomarker evidence of improvement, (2) develops dose-limiting toxicity; or (3) receives the maximum allowable dose. Biomarker evidence of improvement is defined as: (1) monocyte depletion ≥75% from baseline to the end of the dosing interval and (2) serum ferritin reduction ≥20% from baseline levels ≥3000 ng/mL (or if baseline ferritin levels are <3000 ng/mL, any decrease in these, along with improvement in (a) fasting triglyceride levels, (b) coagulation parameters, and/or (c) sIL2 receptor levels compared to baseline).

At the completion of Cohort 1, a Data Monitoring Committee will determine the optimal fixed dose for Cohort 2 to confirm its safety and efficacy. Optional Cohorts 3 and 4 will explore less frequent dosing schedules. Subcutaneous administration also may be evaluated. Total treatment duration is 12 weeks.

No formal statistical hypothesis is being tested.

At the completion of Phase 1b, an appropriate dose, route of administration, and dose interval will be determined for a Phase 2/3 trial.

The study is sponsored by Electra Therapeutics, Inc.

Leach:Electra Therapeutics: Consultancy. Lane:Electra Therapeutics: Current Employment. Kim:Electra Therapeutics: Current Employment; Star Therapeutics: Current Employment; Catalyst Biosciences: Ended employment in the past 24 months; BioMarin Pharmaceutical: Ended employment in the past 24 months. Moore:Star Therapeutics: Current Employment; Electra Therapeutics: Current Employment. Panicker:Star Therapeutics: Current Employment; Electra Therapeutics: Current Employment. Patou:Electra Therapeutics: Current Employment.