Atrioventricular Block Elimination by Rozanolixizumab Treatment

About This Grant

Abstract Selectively targeting IgG recycling at the maternal-fetal interface to reduce pathogenic IgG by inhibition of the fetal neonatal Fc gamma receptor (FcRn) and acceleration of IgG destruction, carries the potential to eradicate autoantibody mediated diseases affirming the prediction “no antibody, no disease.” The nearly invariant finding of high titer autoantibodies reactive with SSA/Ro52kD and 60kD ribonucleoproteins in pregnancies complicated by cardiac neonatal lupus (cardiac-NL), strongly implicates these autoantibodies as required for the development of disease. Maternal IgG accessibility to the fetal circulation is mediated by binding to syncytiotrophoblast expressed FcRn. Importantly, we recently demonstrated anti-SSA/Ro52kD and 60kD in cord blood and serosal cavities from 3 midtrimester fetuses dying with cardiac-NL, proving very early transplacental passage. The signature cardiac disease, detected in the midtrimester, is irreversible 3° atrioventricular block with extensive endocardial fibroelastosis, valvular dysfunction, and cardiomyopathy in some cases. Cardiac-NL is fatal in nearly 20%, requires life-long pacing in survivors, and can result in cardiac dysfunction by early adulthood in 30%. The risk in fetuses exposed to high titer anti-SSA/Ro autoantibodies with no prior affected siblings approaches 4% as supported by the ongoing Surveillance and Treatment tO Prevent AV Block Likely to Occur Quickly (STOP BLOQ) trial. Our group has shown that hydroxychloroquine (HCQ) reduces cardiac-NL recurrence from an historic benchmark of 18% to 8%. Accordingly, the development of monoclonal antibodies that block FcRn, recently shown safe and effective in fetal hemolytic disease, presents an unprecedented preventative strategy. Driven by the rationale that cardiac-NL will be thwarted by a dual mechanism of action, lowering maternal anti- SSA/Ro autoantibodies and blocking placental transport, we propose AVERT (Atrioventricular block Elimination by Rozanolixizumab Treatment) led by STOP BLOQ mPIs, Jill Buyon (rheumatologist, immunologist) and Bettina Cuneo (fetal cardiologist) complemented by Justin Brandt (maternal fetal medicine). Rozanolixizumab (roza) is an FcRn blocker FDA approved for myasthenia gravis. In Aim 1, an open label prospective single arm study of pregnant subjects with high titer anti-SSA/Ro and a previous cardiac-NL offspring will address whether roza 10mg/kg weekly from 14-25 weeks plus HCQ will significantly reduce the recurrence rate. Limiting study drug to before and during the vulnerable period for cardiac-NL should decrease the need for maternal or neonatal IVIG rescue. A very low recurrence rate of 2% is expected and will be compared to 8% (HCQ alone) with 80% power, Type I error rate of 5%. The first stage of this Simon’s 2 stage design will enroll 35 patients with termination due to inefficacy if ≥ 2 cardiac-NL occur out of 35. Stage 2 will recruit 54 additional patients; the drug will be considered efficacious if < 4/89 develop cardiac-NL. In Aim 2, timing and durability of anti-SSA/Ro52kD and 60kD will be evaluated following treatment with roza. Aim 3 will determine fetal, neonatal and maternal safety of roza. Positive results may set precedent for universal anti-SSA/Ro testing in pregnancy.