Phan,Nicholas J. patients were randomized to batoclimab 680 mg (n= 6), batoclimab 340 mg (n= 5), or placebo (n= 6). Batoclimab was associated with significantly greater reductions in Lu AE58054 (Idalopirdine) total immunoglobulin G and antiacetylcholine receptor antibodies from baseline to 6 weeks postbaseline than placebo. Reductions in immunoglobulin G subclasses were generally consistent with total immunoglobulin G. While clinical measures showed directionally favorable improvements over time, the study was not powered Lu AE58054 (Idalopirdine) to draw conclusions about therapeutic efficacy. No safety issues were identified. == Interpretation == The safety profile, pharmacodynamics, and preliminary clinical benefits observed in this study support further investigation of subcutaneous batoclimab injections as a potential patientadministered therapy for seropositive generalized myasthenia gravis. == Introduction == Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease that causes fatigable muscle weakness. Extraocular and eyelid muscles are particularly susceptible to weakness, though other muscles for chewing, talking, and swallowing are also frequently involved.1The spectrum of symptoms ranges from a purely ocular form to generalized disease with severe weakness of the limb, bulbar, and respiratory muscles, and there is potential for significant morbidity and mortality.1,2Autoimmune MG results from the presence of autoantibodies recognizing proteins in the motor endplate at the neuromuscular junction, which leads to impaired neuromuscular transmission.1Most commonly, in 80% of MG patients, antiacetylcholine receptor (AChR) antibodies (immunoglobulin G; IgG) are Rabbit polyclonal to GR.The protein encoded by this gene is a receptor for glucocorticoids and can act as both a transcription factor and a regulator of other transcription factors.The encoded protein can bind DNA as a homodimer or as a heterodimer with another protein such as the retinoid X receptor.This protein can also be found in heteromeric cytoplasmic complexes along with heat shock factors and immunophilins.The protein is typically found in the cytoplasm until it binds a ligand, which induces transport into the nucleus.Mutations in this gene are a cause of glucocorticoid resistance, or cortisol resistance.Alternate splicing, the use of at least three different promoters, and alternate translation initiation sites result in several transcript variants encoding the same protein or different isoforms, but the full-length nature of some variants has not been determined. detected.2,3,4 The neonatal Fc receptor (FcRn) is critical to the regulation of IgG levels in the serum. FcRn regulates IgG degradation, thereby prolonging its circulating halflife. Targeting the FcRn pathway dramatically reduces circulating IgG, thus supporting its evaluation for the treatment of autoantibodymediated autoimmune diseases.5Batoclimab (RVT1401; Immunovant Inc., New York, NY, USA) is a fully human antiFcRn monoclonal antibody being developed as a lowvolume subcutaneous (SC) injection that functions by inhibiting the binding of IgG to FcRn. This results in the rapid catabolism of IgG via lysosomal degradation.6In patients with MG, antiFcRn therapy is expected to lead to a significant reduction in the levels of various pathogenic IgG, including the antiAChRIgG and the antimusclespecific tyrosine kinase (MuSK)IgG, both of which have been identified as drivers of disease pathology in various subtypes of MG.1,2In a firstinhuman study in healthy volunteers, onceweekly SC injection of batoclimab, administered at doses of 340 mg or 680 mg, reduced total IgG concentrations by an average of 63% and 78%, respectively, at 3 weeks postbaseline.6 The primary objectives of this study were to assess the safety and tolerability profile of lowvolume SC injections of batoclimab and to determine its effects on total IgG, IgG subclasses (14), and antiAChRIgG antibody levels in patients with MG. The secondary objectives were to assess the pharmacokinetics (PK) of SC batoclimab and to examine its effects on MGspecific outcome measures to gather insights into the design of a possible efficacy trial in the future. == Methods == == Study design == This proofofconcept, randomized, doubleblind, threearm, placebocontrolled, Phase 2a trial was performed to evaluate the safety, tolerability, PK, pharmacodynamics (PD), and preliminary efficacy of batoclimab in patients with antiAChR antibodypositive gMG (Clinicaltrials.gov:NCT03863080). In total, Lu AE58054 (Idalopirdine) 17 patients from 11 centers in two countries (Canada and United States) were randomized 1:1:1 to receive onceweekly SC injections of batoclimab 340 mg, batoclimab 680 mg, or matching placebo for 6 weeks. Subsequently, all patients had the option to enter a 6week openlabel extension (OLE), which was designed to assess the transition from a weekly regimen to an everyotherweek dosing regimen. Patients entering the OLE received 3 more doses of batoclimab 340 mg once every 2 weeks for 6 weeks, followed by 6 weeks of treatmentfree followup (Fig.1). Patients who did not participate in the OLE entered a 12week treatmentfree followup period. == Figure 1. == Schematic design and patient flow for the doubleblind Phase 2a trial with OLE. OLE, openlabel extension; q2w, once every Lu AE58054 (Idalopirdine) 2 weeks; qw, once weekly; R, randomization.aPatients not entering the OLE entered followup;bPatients not entering the OLE were planned to not receive study treatment;cPlanned followup for patients not entering the OLE was 12 weeks. == Standard protocol approvals, registrations, and patient consent == Independent ethics committees/institutional review boards provided written approval for the study protocol and all amendments. The study Lu AE58054 (Idalopirdine) was also performed in compliance with the protocol, Good Clinical Practice, Declaration of Helsinki, International Council for Harmonisation, and other applicable regulatory requirements. Written informed consent was obtained from all patients prior to entering the study. The study was registered on 5 March 2019, the first patient was enrolled on 10 July 2019, and.