Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia

Abstract

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, characterized by a low platelet count (<100 × 10 9 /L) in the absence of other causes associated with thrombocytopenia. In most patients, IgG autoantibodies directed against platelet receptors can be detected. They accelerate platelet clearance and destruction, inhibit platelet production, and impair platelet function,

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations

“…28 An FIH study of efgartigimod reported that following administration of both single and multiple doses of efgartigimod, reductions in IgG 1-3 followed a similar pattern, with slightly smaller reductions observed for IgG 4 . 23 This pattern of lower reductions for IgG 4 in comparison with IgG 1-3 was also observed in the phase 2 studies of efgartigimod, 20,22 suggesting perhaps less efficient FcRn blockade by efgartigimod (a mutated Fc portion of IgG 1 ) for IgG 4 . In contrast, FIH studies of rozanolixizumab and orilanolimab both reported that administration of single doses resulted in dose-dependent reductions in IgG 1-4 , with the most pronounced changes seen for IgG 3 .…”

“…Efgartigimod was well tolerated over the full duration of the study, with no dose-related safety observations, no increased risk of infection versus placebo, and a safety profile consistent with previous FIH and MG studies. Changes in serum albumin were similar between placebo and efgartigimod groups, mostly within 610% to 15% of baseline, and changes were not considered clinically relevant, suggesting that efgartigimod does not interfere with albumin binding 22 (Table I).…”

“…Single TEAE reports considered possibly related to efgartigimod and temporally associated with its administration included decreases in total lymphocyte counts, T lymphocytes and B lymphocytes, and monocytes, and an increase in neutrophil counts (Table I). [18][19][20][21][22][23][24][25] Hematologic changes (ie, abnormal differential WBC counts) observed in 3 patients following treatment with efgartigimod were mild and asymptomatic, and most likely explained by concomitant use of immunosuppressants. However, the first-in-human (FIH) study of efgartigimod 23 also reported abnormal differential WBC counts (mild decrease in CD8, CD3, CD56, CD4, and CD19 lymphocyte counts) after receipt of the drug (3 of 4 healthy volunteers who received 25 mg/kg and 4 of 4 who received 50 mg/kg).…”

“…Current evidence shows that inhibition of FcRn selectively reduces serum IgG, with no relevant reductions in IgM, IgA, IgE, or albumin 18,[23][24][25] (Table I). Reduction in IgG is transient and reversible, with mean maximum reductions in serum IgG of 45% to 85% from baseline, returning to near-baseline levels 50 to 57 days (28 days for orilanolimab) after single doses, 18,24,25 and 50 to 80 days after multiple doses, 20,22,23,25 indicating that function of the memory B-and plasma-cell compartments remains unaffected by inhibition of FcRn (Table I). During clinical trials of FcRn inhibitors, no rebound effect on levels of total IgG has been observed; for specific antibodies and autoantibodies, rebound is unknown and considered unlikely.…”

“…[18][19][20][21] Should these therapies prove successful, they will provide an alternative to high-dose IVIg and PLEX, reducing treatment burden on health care systems and patients. FcRn inhibitors currently in clinical trials include efgartigimod, 20,22,23 rozanolixizumab, 19,21,24 nipocalimab (M281), 25 and orilanolimab (SYNT001) 18 ; additional FcRn inhibitors in development include IMVT-1401/RVT-1401, CSL730/M230, and ABY-039 (see Patel and Bussel 17 for further details).…”