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Background: Subcutaneous emicizumab, a factor VIII (FVIII)-mimicking bispecific monoclonal antibody, can effectively prevent bleeds in haemophilia A (HA) patients with/without inhibitors; however, its standard-dose regimens are financially burdensome. Low-dose emicizumab prophylaxis may alternatively be applied to noninhibitor HA patients in resource-limited settings., Methods: During 2023, Thai patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype (historical annualized bleeding rate [ABR] >5 bleeds/year before regular FVIII prophylaxis) who received low-/intermediate-dose FVIII secondary prophylaxis ≥8 months were enrolled. After the 4-day washout period, low-dose emicizumab prophylaxis (2.0-2.5 mg/kg every fortnight for two loading doses, then every 4 weeks) was implemented for 8 months. Pre-/post-emicizumab ABR, annualized joint bleeding rates (AJBR), haemophilia joint health scores (HJHS) and haemophilia-specific quality-of-life (QoL) scores were analysed. Emicizumab plasma levels on modified one-stage FVIII assays were also monitored., Results: In 15 subjects, ABR (median of differences, -2 bleeds/year; interquartile range, -3 to 0; p = 0.002), but not AJBR (p = 0.07), were reduced after switching to low-dose emicizumab prophylaxis, although the pre-dose emicizumab plasma levels at the steady state, achieved since week 12, were modest (median monthly level, 8.4 µg/mL; interquartile range, 4.3-10.4). Concurrently, HJHS (p = 0.008) and QoL score (p < 0.001) were decreased, and 46.7% had zero bleeds while receiving low-dose emicizumab., Conclusions: Low-dose emicizumab, compared to low-/intermediate-dose FVIII secondary prophylaxis, meaningfully improves bleeding prevention, joint health and QoL in patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype. This regimen potentially helps address previously unmet needs in HA care among low-to-middle-income countries., Trial Registration: ClinicalTrials.gov identifier NCT06155955., (© 2024 John Wiley & Sons Ltd.)

Recurrent episodes of decompensated heart failure (HF) represent an emerging cause of hospitalizations in developed countries with an urgent need for effective therapies. Recently, the pregnancy-related hormone relaxin (RLN) was found to mediate cardio-protective effects and act as a positive inotrope in the cardiovascular system. RLN binds to the RLN family peptide receptor 1 (RXFP1), which is predominantly expressed in atrial cardiomyocytes. We therefore hypothesized that ventricular RXFP1 expression might exert potential therapeutic effects in an in vivo model of cardiac dysfunction. Thus, mice were exposed to pressure overload by transverse aortic constriction and treated with AAV9 to ectopically express RXFP1. To activate RXFP1 signaling, RLN was supplemented subcutaneously. Ventricular RXFP1 expression was well tolerated. Additional RLN administration not only abrogated HF progression but restored left ventricular systolic function. In accordance, upregulation of fetal genes and pathological remodeling markers were significantly reduced. In vitro, RLN stimulation of RXFP1-expressing cardiomyocytes induced downstream signaling, resulting in protein kinase A (PKA)-specific phosphorylation of phospholamban (PLB), which was distinguishable from β-adrenergic activation. PLB phosphorylation corresponded to increased calcium amplitude and contractility. In conclusion, our results demonstrate that ligand-activated cardiac RXFP1 gene therapy represents a therapeutic approach to attenuate HF with the potential to adjust therapy by exogenous RLN supplementation., Competing Interests: Declaration of interests N.S., P.S., H.A.K., and P.W.J.R are listed as inventors of a filed patent related to relaxin receptor 1 for use in treatment and prevention of heart failure (PCT/EP2019/081962). The other authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)