Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia

Abstract

Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.

Emerging Therapies in Immune Thrombocytopenia

“…In a recent multicenter, open-labeled phase 2 trial (NCT00718692) including 66 adult ITP patients (median age of 54 years, median ITP duration of 5.8 years, median of 4 prior lines of treatment), rozanolixizumab showed a good tolerance, with only 15 of the 51 adverse events reported being related to treatment, mostly consistent with mild-to-moderate headaches [ 73 ]. The response (platelet count ≥50 G/L) was achieved in 66.7% and 54.5% of patients receiving a single subcutaneous infusion at 15 and 20 mg/kg, respectively.…”

“…The response (platelet count ≥50 G/L) was achieved in 66.7% and 54.5% of patients receiving a single subcutaneous infusion at 15 and 20 mg/kg, respectively. With a median platelet count of 15.5 G/L prior to treatment, 50% of the patients achieved a platelet count ≥50 G/L within the first week following infusion [ 73 ].…”

Primary Immune Thrombocytopenia: Novel Insights into Pathophysiology and Disease Management

“…Rozanolixizumab is anti-neonatal Fc receptor (FcRn) antibody that reduces plasma IgG levels. In a recent phase 2 study, >50% patients with persistent/chronic primary ITP achieved clinically relevant platelet responses (≥50 × 10 9 /L) by day 8 after a single injection of rozanolixizumab at a dose of 15 and 20 mg/kg [ 157 ]. Treatment related mild-to-moderate adverse events have been seen in 15 of 66 (21%) patients, and no serious infections have been reported.…”

In Translation: FcRn across the Therapeutic Spectrum

“…Of particular relevance is myasthenia gravis, a condition where autoantibodies generated against components of the post-synaptic neuromuscular junction cause muscle weakness and fatigue [ 185 ]. The therapeutics currently undergoing clinical testing in this setting include IgG1 mAbs (nipocalimab, RVT-1401), IgG4 mAbs (rozanolixizumab, SYNT001), and IgG1 Fc fragments (efgartigimod) [ 186 , 187 , 188 , 189 ]. Early clinical data suggest that all of these can reduce circulating IgG levels to a nadir of ~25–50% at their respective doses, with only mild or reversible effects on albumin.…”