C1-esterase inhibitor human 3,000unit powder and solvent for solution for injection vials

Background and objectivesSeveral treatments for long-term prophylaxis (LTP) of hereditary angioedema (HAE) are in clinical use, such as garadacimab, lanadelumab, subcutaneous C1 esterase inhibitor (C1INH), and berotralstat. In the absence of head-to-head comparative evidence, indirect comparison methods are needed to compare LTP treatments in patients with HAE. The objective of this analysis was to estimate the comparative efficacy, safety, and impact on quality of life of LTP treatments for patients with HAE through NMAs.MethodsA systematic literature review was conducted to identify randomized controlled trials (RCTs) investigating LTP treatments in patients (at least 12 years old) with HAE (PROSPERO protocol #CRD42022359207). A network meta-analysis (NMA) feasibility assessment evaluated trial suitability and Bayesian NMAs were conducted for evaluable efficacy, safety, and quality of life (QoL) outcomes.ResultsThe results of these NMAs show improved efficacy, QoL, and reduced rate of adverse events with garadacimab (200 mg once monthly), lanadelumab (300 mg every two or four weeks), subcutaneous C1INH (60 IU/kg twice weekly), and berotralstat (150 mg once daily) compared to placebo in the treatment of patients with HAE. For the primary outcome of time-normalized number of HAE attacks, garadacimab statistically significantly reduced the rate of attacks compared to lanadelumab Q4W and berotralstat. A similar statistically significant reduction was shown for HAE attacks treated with on-demand treatment. Garadacimab showed statistically significant reduction in the rate of moderate and/or severe HAE attacks compared to lanadelumab Q2W. Garadacimab also showed statistical improvements in change from baseline in AE-QoL total score as compared to berotralstat.ConclusionsOverall, garadacimab ranked as the most probable effective treatment among all comparators assessed, with lanadelumab Q2W or subcutaneous C1INH ranking second, across most outcomes.

Abstract licence: CC BY-NC

ObjectiveThe association of cerebrospinal fluid (CSF) protein levels with cognitive function in the general population remains largely unexplored. We performed Mendelian randomization (MR) analyses to query which CSF proteins may have potential causal effects on cognitive performance.Methods and analysisGenetic associations with CSF proteins were obtained from a genome-wide association study conducted in up to 835 European-ancestry individuals and for cognitive performance from a meta-analysis of GWAS including 257,841 European-ancestry individuals. We performed Mendelian randomization (MR) analyses to test the effect of randomly allocated variation in 154 genetically predicted CSF protein levels on cognitive performance. Findings were validated by performing colocalization analyses and considering cognition-related phenotypes.ResultsGenetically predicted C1-esterase inhibitor levels in the CSF were associated with a better cognitive performance (SD units of cognitive performance per 1 log-relative fluorescence unit (RFU): 0.23, 95% confidence interval: 0.12 to 0.35, p = 7.91 × 10-5), while tyrosine-protein kinase receptor Tie-1 (sTie-1) levels were associated with a worse cognitive performance (-0.43, -0.62 to -0.23, p = 2.08 × 10-5). These findings were supported by colocalization analyses and by concordant effects on distinct cognition-related and brain-volume measures.ConclusionsHuman genetics supports a role for the C1-esterase inhibitor and sTie-1 in cognitive performance.

Abstract licence: CC BY

INTRODUCTION Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH), and icatibant in the treatment of acute angioedema attacks in adults with HAE. MATERIALS AND METHODS A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH, and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE, and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate OR synonyms OR icatibant). Only randomized clinical studies were selected. RESULTS Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH, and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in shorter time to beginning of relief of symptoms, time to minimal symptoms, the probability of the treatment response after 4 hours is increased, and the safety profile is comparable to placebo. CONCLUSIONS Due to significant heterogeneity of identified trials, the scientific evidence available was insufficient to point out the most effective therapeutic option in the treatment of acute oedemas in HAE.

Abstract licence: CC BY 4.0