EFFICACY OF ALIROCUMAB IN 1,191 PATIENTS WITH A WIDE SPECTRUM OF MUTATIONS IN GENES CAUSATIVE FOR FAMILIAL HYPERCHOLESTEROLEMIA

Background Mutation(s) in genes involved in the low-density lipoprotein receptor (LDLR) pathway are typically the underlying cause of familial hypercholesterolemia. Objective The objective of the study was to examine the influence of genotype on treatment responses with alirocumab. Methods Patients from 6 trials (n = 1191, including 758 alirocumab-treated; Clinicaltrials.gov identifiers: NCT01266876; NCT01507831; NCT01623115; NCT01709500; NCT01617655; NCT01709513) were sequenced for mutations in LDLR , apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), LDLR adaptor protein 1, and signal-transducing adaptor protein 1 genes. New mutations were confirmed by Sanger sequencing. Results One or more specific gene mutations were found in 898 patients (75%): 387 and 437 patients had heterozygous LDLR defective and negative mutations, respectively; 46 had a heterozygous APOB -defective mutation; 8 patients had a heterozygous PCSK9 gain-of-function mutation; 293 (25%) had no identifiable mutation in the genes investigated. LDL cholesterol reductions at Week 24 were generally similar across genotypes: 48.3% (n = 131) and 54.3% (n = 89) in LDLR -defective heterozygotes with alirocumab 75 mg Q2W (with possible increase to 150 mg at Week 12) and 150 mg Q2W, respectively; 49.7% (n = 168) and 60.7% (n = 88) in LDLR -negative heterozygotes; 54.1% (n = 20) and 50.1% (n = 6) in APOB -defective heterozygotes; 60.5% (n = 5) and 94.0% (n = 1) in PCSK9 heterozygotes; and 44.9% (n = 85) and 55.4% (n = 69) in patients with no identified mutations. Overall rates of treatment-emergent adverse events were similar for alirocumab vs controls (placebo in 5 trials, ezetimibe control or atorvastatin calibrator arm in 1 trial), with only a higher rate of injection-site reactions with alirocumab. Conclusions In this large patient cohort, individuals with a wide spectrum of mutations in genes underlying familial hypercholesterolemia responded substantially and similarly to alirocumab treatment

Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Background Mutations in the genes for the low-density lipoprotein receptor ( LDLR ), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR , apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 ( LDLRAP1 ), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH

In-silico identification and prioritization of therapeutic targets of asthma

Abstract Asthma is a “common chronic disorder that affects the lungs causing variable and recurring symptoms like repeated episodes of wheezing, breathlessness, chest tightness and underlying inflammation. The interaction of these features of asthma determines the clinical manifestations and severity of asthma and the response to treatment" [cited from: National Heart, Lung, and Blood Institute. Expert Panel 3 Report. Guidelines for the Diagnosis and Management of Asthma 2007 (EPR-3). Available at: https://www.ncbi.nlm.nih.gov/books/NBK7232/ (accessed on January 3, 2023)]. As per the WHO, 262 million people were affected by asthma in 2019 that leads to 455,000 deaths ( https://www.who.int/news-room/fact-sheets/detail/asthma ). In this current study, our aim was to evaluate thousands of scientific documents and asthma associated omics datasets to identify the most crucial therapeutic target for experimental validation. We leveraged the proprietary tool Ontosight® Discover to annotate asthma associated genes and proteins. Additionally, we also collected and evaluated asthma related patient datasets through bioinformatics and machine learning based approaches to identify most suitable targets. Identified targets were further evaluated based on the various biological parameters to scrutinize their candidature for the ideal therapeutic target. We identified 7237 molecular targets from published scientific documents, 2932 targets from genomic structured databases and 7690 dysregulated genes from the transcriptomics and 560 targets from genomics mutational analysis. In total, 18,419 targets from all the desperate sources were analyzed and evaluated though our approach to identify most promising targets in asthma. Our study revealed IL-13 as one of the most important targets for asthma with approved drugs on the market currently. TNF, VEGFA and IL-18 were the other top targets identified to be explored for therapeutic benefit in asthma but need further clinical testing. HMOX1, ITGAM, DDX58, SFTPD and ADAM17 were the top novel targets identified for asthma which needs to be validated experimentally

Corrigendum to “Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia” J Clin Lipidol 11 (2017) 1338-1346 (Journal of Clinical Lipidology (2017) 11(6) (1338–1346.e7), (S1933287417304415), (10.1016/j.jacl.2017.08.016))

The authors regret that the row labels for the following data in Table 1 were transposed: ApoB and non-HDL-C; and TG and Lp(a). The authors would like to apologise for any inconvenience caused

Unstationary aspects of foehn in a large valley part I: operational setup, scientific objectives and analysis of the cases during the special observing period of the MAP subprogramme FORM

The Rhine valley, which stretches from the main Alpine crest to the Lake of Constance, was chosen as the target area to study unstationary aspects of foehn during the Special Observing Period (SOP) of the Mesoscale Alpine Programme (MAP). This large valley is up to 10?km wide and has some of the highest foehn frequencies in the European Alps. The MAP subprogram FORM (FOehn in the Rhine valley during MAP) was designed to investigate various aspects of the foehn including the interaction of foehn flow with the boundary layer and the processes that remove the cold air pool. The subprogram was also focused on improving the understanding and forecasting of foehn-related phenomena such as waves and turbulence. A large number of in-situ and remote sensing observing systems were deployed to take measurements during the field phase of MAP. Among them were about 50 surface stations, up to 9 radiosonde stations, 2 wind profilers, 4 Doppler sodars, 2 scintillometers, 1 scanning and 1 backscatter lidar and different research aircraft. This paper gives an overview of the objectives of FORM, describes the target area and its instrumentation, and provides a detailed synoptic description of the 12 foehn cases observed during the MAP SOP

Föhn in the Rhine Valley during MAP: A review of its multiscale dynamics in complex valley geometry

This paper summarizes the findings of seven years of research on föhn conducted within the project Föhn in the Rhine Valley during MAP (FORM) of the Mesoscale Alpine Programme (MAP). It starts with a brief historical review of föhn research in the Alps, reaching back to the middle of the 19th century. Afterwards, it provides an overview of the experimental and numerical challenges identified before the MAP field experiment and summarizes the key findings made during MAP in observation, simulation and theory. We specifically address the role of the upstream and cross-Alpine flow structure on föhn at a local scale and the processes driving föhn propagation in the Rhine Valley. The crucial importance of interactions between the föhn and cold-air pools frequently filling the lower Rhine Valley is highlighted. In addition, the dynamics of a low-level flow splitting occurring at a valley bifurcation between the Rhine Valley and the Seez Valley are examined. The advances in numerical modelling and forecasting of föhn events in the Rhine Valley are also underlined. Finally, we discuss the main differences between föhn dynamics in the Rhine Valley area and in the Wipp/Inn Valley region and point out some open research questions needing further investigation. Copyright © 2007 Royal Meteorological Societ