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.

Al-Samkari:Vaderis: Research Funding; Sobi: Consultancy, Research Funding; Pharmacosmos: Consultancy; Novartis: Consultancy, Research Funding; Alpine: Consultancy; Alnylam: Consultancy; argenx: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy, Research Funding. McDonald:AbbVie: Honoraria; Sobi: Honoraria; Argenx: Honoraria; Grifols: Research Funding; Amgen: Honoraria; Novartis: Honoraria. Carpenedo:Sobi: Honoraria, Speakers Bureau; Sanofi: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zaja:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; argenx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hutchmed: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooper:Sanofi: Consultancy, Honoraria; argenx: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Rigel: Research Funding. Cataland:Genentech: Research Funding; Alexion: Research Funding; Novartis: Consultancy; argenx: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding. Drazer:Argenx: Consultancy. Miyakawa:Janssen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Kasei: Honoraria; Chugai: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Novo Nordisc: Research Funding; BioMarin: Research Funding; Alexion: Research Funding; Zenyaku: Consultancy; UCB: Consultancy, Research Funding; argenx: Consultancy, Honoraria. Michel:Grifols: Speakers Bureau; Argenx: Honoraria; Alexion: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Sobi: Honoraria, Speakers Bureau. Ayguasanosa:argenx: Current Employment, Current equity holder in publicly-traded company. Brahmbhatt:Argenx: Current Employment, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Lan:argenx: Current Employment, Current holder of stock options in a privately-held company. Matthijssens:argenx: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Broome:argenx: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Alexion: Honoraria, Research Funding; Electra: Research Funding; Alpine: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Ghanima:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Principia BioPharma: Consultancy; Sobi: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; UCB: Consultancy, Research Funding; argenx: Consultancy; Cellphire: Consultancy; Alpine: Consultancy; Kedrion: Consultancy; HiBio: Consultancy; Hutchmed: Consultancy; Takeda: Consultancy; BMS: Honoraria, Research Funding; Bayer: Honoraria, Research Funding.

As of 2024, efgartigimod is approved for use in patients with primary immune thrombocytopenia (ITP) in Japan but not currently approved by the FDA or EMA. Since efgartigimod, a human IgG1 fragment, is a natural ligand of FcRn, it prevents recycling of endogenous IgG antibodies, including anti-platelet autoantibodies in the case of primary ITP. The ADVANCE IV trial (NCT04188379) investigated intravenous efgartigimod across patients with ITP, demonstrating significantly increased sustained platelet count responses compared with placebo, including those who had received multiple previous ITP therapies. The trial outlined here (ADVANCE NEXT) aims to investigate efgartigimod IV further in patients with chronic ITP, who are most in need of additional treatment options. In ADVANCE NEXT, following a 24-week double-blinded treatment period where participants will be randomized 2:1 to efgartigimod or placebo, there will be two 52-week open-label treatment periods, where efgartigimod will be continue to be administered to assess long-term efficacy and safety.