Intravenous Efgartigimod for the Treatment of Primary Immune Thrombocytopenia in Adults: A Planned, Phase 3, Randomized, Double-Blinded, Placebo-Controlled, Parallel-Arm Study with Open-Label Period (ADVANCE NEXT)

Background and Significance: Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder resulting in thrombocytopenia, bleeding, and constitutional symptoms. Most patients with ITP have anti-platelet immunoglobulin G (IgG) autoantibodies, which may interact with platelet and megakaryocyte glycoproteins and cause increased platelet destruction and reduced production. Although various ITP treatment options are available, many patients do not have a sustained clinical response and require additional therapy. This unmet need is especially critical in patients with chronic primary ITP.

Efgartigimod is a human IgG1 antibody Fc fragment that reduces total serum IgG levels, including pathogenic IgG autoantibodies, through neonatal Fc receptor blockade. The efficacy and safety of intravenous (IV) efgartigimod in adults with chronic and persistent primary ITP, including those who received multiple prior ITP therapies, was demonstrated in the phase 3 ADVANCE IV trial.

This study will assess the efficacy, safety/tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and immunogenicity of efgartigimod IV in adults with chronic primary ITP, who have demonstrated insufficient response to previous ITP treatment.

Study Design and Methods: This phase 3, randomized, double-blinded, placebo-controlled, parallel-arm, multicenter study, followed by an open-label treatment period (OLTP), will take place in ~20 countries globally (ADVANCE NEXT, EudraCT: 2024-515451-38). The study will enroll ~63 participants aged ≥18 years with a confirmed diagnosis of primary ITP (according to International Working Group on ITP criteria) of >12 months’ duration who have received prior ITP therapy with ≥1 of the following: corticosteroids, IV immunoglobulin, anti-D immunoglobulin in non-splenectomized, Rho(D)-positive patients, thrombopoietin receptor agonists, or rituximab. Key exclusion criteria include receipt of any medicinal product <12 weeks or <5 half-lives (whichever is longer) before screening, use of concurrent ITP treatments except those permitted by the protocol, current participation in an interventional trial, and known autoimmune disease, or any medical condition that would affect the assessment of ITP symptoms.

Participants will be randomized 2:1 to efgartigimod IV 10 mg/kg or placebo during a 24-week double-blinded treatment period (DBTP). Treatment will be initiated with ≥4 once-weekly infusions and may be adjusted to once every other week based on platelet count (PC) response. At the end of the DBTP, participants may enter a 52-week OLTP to receive efgartigimod IV 10 mg/kg, including those with insufficient response during the DBTP. Following completion of the first OLTP, participants may begin a second 52-week OLTP to continue receiving efgartigimod IV 10 mg/kg.

The primary endpoint is the extent of disease control, defined as the number of cumulative weeks during the DBTP with PC of ≥50 × 10⁹/L. Primary endpoint analysis will be performed on the full analysis set in the DBTP. Secondary endpoints during the DBTP include assessment of sustained and overall PC response, incidence/severity of bleeding, and use of rescue ITP therapy. Other secondary endpoints include long-term efficacy of efgartigimod IV, adverse events, PK/PD parameters, and development of antibodies against efgartigimod. Exploratory endpoints will assess the effect of efgartigimod IV on participant-reported outcomes and quality of life, and on ITP pathophysiology (blood measurements of immature platelet fractions and thrombopoietin levels).

Conclusion: This phase 3 study will assess the efficacy, safety/tolerability, PK/PD, and immunogenicity of efgartigimod IV in adults with chronic primary ITP who have an unmet need for treatment options that provide sustained clinical response.