Efficacy and Safety of Intravenous Efgartigimod in Adults with Primary Immune Thrombocytopenia: Results of a Phase 3, Multicenter, Double-Blinded, Placebo-Controlled, Randomized Clinical Trial (ADVANCE IV)

Author(s): Catherine M. Broome1, Vickie McDonald2, Yoshitaka Miyakawa3, Monica Carpenedo4, David J. Kuter5, Hanny Al-Samkari6, James B. Bussel7, Marie Godar8, Jaume Ayguasanosa8, Kristof De Beuf8, Francesco Rodeghiero9, Marc Michel10, Adrian C. Newland11
Source: https://doi.org/10.1182/blood-2022-167838
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Another new (potential) option for refractory ITP patients, efgartigimod is an IgG1-Fc-fragment engineered to reduce IgG autoantibody levels.  131 patients enrolled and 67% had >=3 prior lines of therapy, placebo-controlled study.  The study group had a 90% sustained platelet response, with >50% having plt counts of >30k >= 7 days apart.


In immune thrombocytopenia (ITP), immunoglobulin G (IgG) platelet autoantibodies accelerate platelet clearance and impair platelet production. IgG homeostasis is regulated by the neonatal Fc receptor (FcRn). Efgartigimod (EFG), a human IgG1 Fc-fragment, is a natural ligand of FcRn engineered to competitively bind to FcRn with high affinity and prevent recycling of endogenous IgG, but not albumin, thereby reducing IgG levels including IgG autoantibody levels.


The efficacy and safety of intravenous (IV) EFG were evaluated in ADVANCE, a phase 3, multicenter, randomized, double-blinded, placebo (PBO)-controlled trial (NCT04188379) in adults with persistent or chronic ITP. Participants with an average of 2 platelet counts (PLTs) of <30×109/L during screening were randomized 2:1 to receive 10 mg/kg EFG or PBO for 24 weeks. Concurrent oral corticosteroids, oral immunosuppressants, dapsone, danazol, fostamatinib, and oral thrombopoietin receptor agonists (not romiplostim) were permitted but required to remain at the entry dosage and frequency. Participants received weekly dosing (weeks 1-4) followed by response-dependent weekly or every 2 weeks (q2w) dosing (weeks 5-16) and then maintained their dosing regimen from weeks 17-24. The primary and key secondary endpoints were tested in hierarchical order. The primary endpoint was the proportion of chronic ITP participants with a sustained PLT response (PLT of ≥50×109/L in ≥4 of 6 visits between weeks 19 and 24 without intercurrent events, e.g., rescue therapy at week 12 or later). Key secondary endpoints included extent of disease control (cumulative weeks with PLTs of ≥50×109/L) in the chronic population, proportion of participants in the overall population (chronic and persistent) with sustained PLT response, incidence of bleeding events, and a durable sustained platelet response (PLT of ≥50×109/L in ≥6 of 8 visits between weeks 17 and 24) in the overall population. Safety and pharmacodynamic measures were also evaluated.


131 participants (118 chronic ITP, 13 persistent ITP; 86 EFG, 45 PBO) were randomized. Participants had long-standing, severe ITP (median time since diagnosis of 4.57 years; baseline median PLT of 17×109/L) and were heavily pretreated (67.2% had ≥3 prior ITP therapies). In chronic ITP participants, sustained PLT response was reached in more EFG-treated participants (21.8%; 17/78) than PBO (5.0%; 2/40; p=0.0316). EFG achieved all PLT-related secondary endpoints (Table1). Model-based mean changes from baseline in PLT levels over time showed a clear differentiation from PBO as of week 1, indicating an early onset of PLT response in the EFG group. A sustained PLT response was achieved in 90% (9/10) of participants who reached and maintained the q2w fixed dosing. EFG-treated participants responded better than PBO regardless of age, sex, severity of disease, time since diagnosis, prior ITP treatment, or background medication (Figure1). International working group (IWG) response (consecutive visits ≥7 days apart with PLTs of ≥30×109/L and 2-fold increase from baseline in the absence of bleeding events) was seen in 51.2% (44/86) of EFG treated participants compared to 20.0% (9/45) in the PBO group.

Mean IgG levels in EFG-treated participants decreased steadily over the first 4 weeks of treatment, after which the mean maximum reductions from baseline remained greater than 60% throughout the trial. Mean IgG levels were similar in the group on q2w treatment. Adverse events (AEs) were reported in 93.0% (80/86) of participants in the EFG group and 95.6% (43/45) in the PBO group. Most frequent AEs included bruising, headache, hematuria, and petechiae. Serious AEs were reported in 8.1% (7/86) of participants in the EFG group and in 15.6% (7/45) in the PBO group, and none were treatment related. These included bleeding or events related to bleeding (n=5), infections (n=4), and worsening primary ITP (n=3). No deaths or increased risk of infection were observed.


Compared to PBO, EFG showed an early PLT increase, higher sustained PLT response, and more weeks with PLT ≥50×109/L. EFG achieved the primary and all PLT-related secondary endpoints and also showed that 51.2% of participants on EFG achieved IWG response criteria versus 20% on PBO. EFG was well tolerated with no new safety signals. Long-term efficacy and safety data are being evaluated in the open-label extension trial (ADVANCE+; NCT04225156).

Author Affiliations

1Georgetown University, Washington, DC 2Barts Health NHS Trust, London, United Kingdom 3Saitama Medical University Hospital, Saitama, Japan 5Division of Hematology Oncology, Massachusetts General Hospital, Boston, MA 4ASST Ospedale San Gerardo di Monza, Hematology and Transplant Unit, Monza, Italy 6Massachusetts General Hospital, Boston, MA 7Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 8argenx, Ghent, Belgium 9Haematology Project Foundation, Affiliated to the Department of Haematology, S. Bortolo Hospital, Vicenza, Italy 10Department of Internal Medicine, National Reference Center for Immune Cytopenias, Henri Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France 11Centre for Haematology, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom

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