Explore the vast range of titles available.

This phase 3 trial evaluated the safety and efficacy of inclisiran, a small interfering RNA that inhibits hepatic PCSK9 synthesis, in 482 adults with heterozygous familial hypercholesterolemia, who received subcutaneous injections of inclisiran or placebo on days 1, 90, 270, and 450. Changes in cholesterol were assessed up to day 540.

Lipoprotein(a) is similar to LDL cholesterol but contains apolipoprotein(a). A trial tested the effects of an oligonucleotide drug targeting apo(a) mRNA on lipoprotein(a) concentrations in patients with CVD.

Background Heterozygous familial hypercholesterolemia (HeFH) is largely underdiagnosed and undertreated in China where few patients achieved recommended target levels of low density lipoprotein cholesterol (LDL-C). We conducted the first randomized, placebo-controlled clinical trial in Chinese patients with HeFH to assess the efficacy and safety of tafolecimab, a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody. Methods Patients diagnosed with HeFH by Simon Broome criteria and on a stable lipid-lowering therapy for at least 4 weeks were randomized 2:2:1:1 to receive subcutaneous tafolecimab 150 mg every 2 weeks (Q2W), tafolecimab 450 mg every 4 weeks (Q4W), placebo Q2W or placebo Q4W in the 12-week double-blind treatment period. After that, participants received open-label tafolecimab 150 mg Q2W or 450 mg Q4W for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Secondary endpoints included proportion of participants achieving ≥50% LDL-C reductions and proportion of participants with LDL-C <1.8 mmol/L at week 12 and 24, the change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and lipoprotein(a) levels, as well as the change from baseline to week 24 in lipid levels. Results In total, 149 participants were randomized and 148 received at least one dose of the study treatment. At week 12, tafolecimab treatment induced significant reductions in LDL-C levels (treatment difference versus placebo [on-treatment estimand]: −57.4% [97.5% CI, −69.2 to −45.5] for 150 mg Q2W; −61.9% [−73.4 to −50.4] for 450 mg Q4W; both P <0.0001). At both dose regimens, significantly more participants treated with tafolecimab achieved ≥50% LDL-C reductions or LDL-C <1.8 mmol/L at week 12 as compared with corresponding placebo groups (all P <0.0001). Meanwhile, non-HDL-C, apolipoprotein B and lipoprotein(a) levels were significantly reduced in the tafolecimab groups at week 12. The lipid-lowering effects of tafolecimab were maintained till week 24. During the double-blind treatment period, the most commonly-reported adverse events in the tafolecimab groups included upper respiratory tract infection, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase and hypertension. Conclusions Tafolecimab administered either 150 mg Q2W or 450 mg Q4W yielded significant and persistent reductions in LDL-C levels and showed a favorable safety profile in Chinese patients with HeFH. Trial registration ClinicalTrials.gov, NCT04179669.

: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (i) are a class of lipid-lowering drugs suggested to hold a plethora of beneficial effects independent of their LDL cholesterol-lowering properties. However, the mechanism underlying such observations is debated. : Human aortic endothelial cells (TeloHAEC) were pre-treated with 100 µg/mL of the PCSK9i evolocumab and then exposed to 20 ng/mL of IL-6, a major driver of cardiovascular diseases (CVD), in both naïve state and after siRNA-mediated suppression of the NAD-dependent deacetylase sirtuin-3 (SIRT3). Inflammation, autophagy, and oxidative stress were assessed through Western Blots, ELISAs, and/or immunofluorescence coupled by flow cytometry. To explore the human relevance of the findings, we also evaluated the expression of IL-6, SIRT3, IL-1β, the ratio LC3B II/I, and PCSK9 within the plaques of patients undergoing carotid endarterectomy (n=277), testing possible correlations between these proteins. : PCSK9i improved a range of phenotypes including the activation of inflammatory pathways, oxidative stress, and autophagy. Indeed, treatment with PCSK9i was able to counteract the IL-6 induced increase in inflammasome activation, the accrual of autophagic cells, and mitochondrial ROS accumulation. Of note, silencing of SIRT3 reverted the beneficial effects observed with PCSK9i treatment on all these phenomena. In atheroma specimens, the expression of PCSK9 was inversely related to that of SIRT3 while positively correlating with IL-6, IL-1β, and the ratio LC3B II/I. : Overall, these data suggest that PCSK9i bear intrinsic anti-inflammatory, anti-autophagic, and antioxidant properties in endothelial cells, and that these pleiotropic effects might be mediated, at least in part, by SIRT3. These results provide an additional mechanism supporting the emerging knowledge relative to the benefit of PCSK9i on CVD beyond LDL-lowering and uncover SIRT3 as a putative mediator of such pleiotropy.

PurposeProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an indispensable lipid-lowering treatment option, but their cost-effectiveness has been questioned. This study aimed to perform a health economic evaluation of evolocumab versus placebo in patients with myocardial infarction (MI) in China.MethodsA Markov cohort state-transition model was developed in decision analysis software to estimate the incremental cost-effectiveness ratio (ICER), defined as cost per quality-adjusted life-year (QALY) saved. The simulation subjects could undergo non-fatal MI and/or stroke, or vascular or non-vascular death event. We integrated the Chinese population-specific demographics and event rates with the risk reduction of evolocumab based on the FOURIER trial and/or lowering of low-density lipoprotein cholesterol (LDL-C). Age-related change, event costs and utilities were included from published sources.ResultsAt its current list price [33,748 Chinese yuan (CNY) annually per person], the ICER for evolocumab therapy was 927,713 CNY per QALY gained when integrating the FOURIER trial with absolute reduction of LDL-C. The probability of cost-effectiveness of evolocumab versus placebo was 1.96%, with a generally accepted threshold of 212,676 CNY per QALY gained. A reduction in acquisition price by approximately 70% (to less than 10,255 CNY annually) was needed to be cost-effective. Alternative scenario analyses of therapeutic benefit showed that the ICER for evolocumab in MI patients with uncontrolled familial hypercholesterolemia (FH) was 187,736 CNY per QALY gained.ConclusionEvolocumab in patients with MI was not cost-effective based on the price in 2019 in China; however, treatment with evolocumab was more favorable in MI patients with FH.

Background Recaticimab (SHR-1209, a humanized monoclonal antibody against PCSK9) showed robust LDL-C reduction in healthy volunteers. This study aimed to further assess the efficacy and safety of recaticimab in patients with hypercholesterolemia. Methods In this randomized, double-blind, placebo-controlled phase 1b/2 trial, patients receiving stable dose of atorvastatin with an LDL-C level of 2.6 mmol/L or higher were randomized in a ratio of 5:1 to subcutaneous injections of recaticimab or placebo at different doses and schedules. Patients were recruited in the order of 75 mg every 4 weeks (75Q4W), 150Q8W, 300Q12W, 150Q4W, 300Q8W, and 450Q12W. The primary endpoint was percentage change in LDL-C from the baseline to end of treatment (i.e., at week 16 for Q4W and Q8W schedule and at week 24 for Q12W schedule). Results A total of 91 patients were enrolled and received recaticimab and 19 received placebo. The dose of background atorvastatin in all 110 patients was 10 or 20 mg/day. The main baseline LDL-C ranged from 3.360 to 3.759 mmol/L. The least-squares mean percentage reductions in LDL-C from baseline to end of treatment relative to placebo for recaticimab groups at different doses and schedules ranged from −48.37 to −59.51%. No serious treatment-emergent adverse events (TEAEs) occurred. The most common TEAEs included upper respiratory tract infection, increased alanine aminotransferase, increased blood glucose, and increased gamma-glutamyltransferase. Conclusion Recaticimab as add-on to moderate-intensity statin therapy significantly and substantially reduced the LDL-C level with an infrequent administration schedule (even given once every 12 weeks), compared with placebo. Trial registration ClinicalTrials.gov , number NCT03944109

Background and Objectives Limited data exist on the efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inclisiran among patients with neuromuscular disorders and statin‐induced myotoxicity and/or hepatotoxicity. We assessed the safety and efficacy of PCSK9 inhibitors and inclisiran in this specific patient subgroup. Methods We conducted an observational cohort study evaluating patients with available clinical and laboratory data prior to and at prespecified time points following treatment initiation with PCSK9 inhibitors or inclisiran. Results Eleven patients with neuromuscular disorders and statin intolerance were included in this study. Median follow‐up time after PCSK9 inhibitor or inclisiran initiation was 14 (9–17) months. PCSK9 inhibitors or inclisiran use led to a significant decrease in mean low‐density lipoprotein cholesterol levels. Moreover, all patients tolerated these lipid‐lowering agents without exacerbation of their underlying myositis, myopathy, neuromuscular junction disorder, and without presenting any adverse event or relapse of myotoxicity and/or hepatotoxicity. Discussion The present real‐world study highlights the potential therapeutic value of PCSK9 inhibitors and inclisiran among patients with neuromuscular disorders and statin intolerance. The findings of this study are in accordance with previous reports, showing that PCSK9 inhibitors are safe as a lipid lowering treatment for long‐term use among patients with statin‐associated immune‐mediated necrotizing myopathy (IMNM).

Early neurological deterioration (END) is associated with a poor prognosis in acute ischemic stroke (AIS). Effectively lowering low-density lipoprotein cholesterol (LDL-C) can improve the stability of atherosclerotic plaque and reduce post-stroke inflammation, which may be an effective means to lower the incidence of END. The objective of this study was to determine the preventive effects of evolocumab on END in patients with non-cardiogenic AIS. This was a multicenter, prospective, open-label, blinded-endpoint clinical trial. Participants with AIS within 24 h were randomly assigned to either the group receiving combination therapy of evolocumab and atorvastatin, which is a 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, i.e., a \"statin\" (PI group), or the group receiving atorvastatin monotherapy (AT group). The primary outcome was END within 7 days, defined as a 2-point increase in the National Institutes of Health Stroke Scale (NIHSS) score or a 1-point increase in motor function within 24 h-7 days from the onset of AIS. Secondary outcomes included LDL-C target achievement rate on day 7 (≤ 1.8 mmol/L with a reduction exceeding 50% from baseline), inflammatory factors (interleukin [IL]-6, IL-8, and tumor necrosis factor [TNF]-α) before and after 7 days of treatment, and stroke-related death with 7 days. Safety endpoints included any adverse events. Patients with AIS (n = 272) were randomly assigned to the PI (n = 136) or AT (n = 136) groups. Within 7 days, 18 (13.2%) and 33 (24.3%) patients experienced END in the PI and AT groups, respectively (relative risk [RR] -0.90; 95% confidence interval [CI]: -1.59 to -0.22; p = 0.010). On the seventh day, LDL-C target achievement rate in the PI and AT groups was 74.3% and 14.7%, respectively (RR 3.27; 95% CI: 2.40-4.15; p = 0.001). Changes in IL-6 over 7 days were significantly lower in the PI group compared with the AT group, respectively (median 1.02 [range -1.91, 5.47] versus 2.54 [-0.83, 15.20]; p = 0.033). On the 90th day of follow-up, 83.1% and 65.4% of patients had a modified Rankin Scale score ≤ 2 in the PI and AT groups, respectively (RR 0.51; 95% CI: 0.66-2.66; p = 0.001). There was no significant difference in stroke recurrence between the two groups within 90 days (RR -1.72; 95% CI: -4.57 to 1.13; p = 0.237). Regarding adverse events, 15 and 22 patients in the PI and AT groups, respectively, experienced slight abnormalities in liver and kidney function laboratory values during the 7-day treatment period (odds ratio 0.62; 95% CI: 0.30-1.29; p = 0.203), but no serious adverse events were observed in either group. These results suggest that the combination therapy of evolocumab and atorvastatin within 24 h of AIS onset may effectively reduce the incidence of END compared with atorvastatin monotherapy. Additionally, in the early stages of AIS, this combination therapy can reduce blood LDL-C levels, and inhibit IL-6 elevation, potentially improving the prognosis of patients with AIS within 90 days. China Clinical Trials Registry (No: ChicTR2200059445, 29 April 2022, https://www.chictr.org.cn/ ).

Many cancers evade immunosurveillance by downregulating surface major histocompatibility class (MHC)-I. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes MHC-I degradation and is elevated in glioma. Evolocumab is a clinically approved PCSK9 inhibitor which restores MHC-I expression in pre-clinical cancer models. However, monoclonal antibodies have limited blood brain/tumor barrier penetrance (BBB/BTB). We conducted a window-of-opportunity trial, evaluating evolocumab’s BBB/BTB penetrance and biological effect (PesKE; NCT04937413). Patients with newly diagnosed or recurrent glioma undergoing a clinically indicated biopsy or resection were enrolled (n = 32, M: 16, F: 16; control average age: 51.85, evolocumab: 53). Intervention participants (n = 6) received a single subcutaneous evolocumab dose pre-procedure, of which 4 provided research tissue. No significant adverse events were observed. Evolocumab was detected in all analyzed intervention tissue, with an average tumor: blood ratio of 0.0222 (SD ± 0.0190), akin to other monoclonals. Evolocumab quantitation was 4.44× greater in contrast-enhancing (mean 0.0068 fmol/mcg (SD ± 0.001)) vs non-contrast enhancing cases (mean 0.0015 fmol/mcg (SD ± 0.0004)). Proteomic analysis found positive trends between evolocumab and MHC-I subtypes (HLA-A-C, E-G), with a significant positive correlation with HLA-H (R 2  = 0.9584, p  = 0.021*). Tumor tissue with higher evolocumab titers demonstrated increased surface MHC-I and CD8 + T cell infiltration. Increased CD8 + TNF , FASLG and GZMA transcription was observed in high titer tissue compared to low titer tissue and untreated controls. Pre-resection evolocumab is well tolerated but exhibits BBB/BTB penetrance akin to other monoclonal antibodies. Increased tumoral evolocumab/PCSK9i may enhance tumoral MHC-I/effector CD8 + infiltration. Future work will explore combining evolocumab with BBB/BTB opening therapies like low-intensity focused ultrasound.

Background Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have been demonstrated to produce significantly greater reduction in LDL cholesterol levels and cardiovascular events than standard statin therapy. However, evidence on the impact of PCSK9 inhibitors on coronary plaque composition and morphology is limited. Methods In this open-label randomized study, eligible patients with intermediate coronary lesions and elevated LDL cholesterol values were randomized to either alirocumab 75 mg Q2W plus statin (atorvastatin 20 mg/day or rosuvastatin 10 mg/day) therapy or standard care. Optical coherence tomography (OCT) assessments for target lesions were obtained at baseline and at 36 weeks of follow-up. Results LDL cholesterol levels were significantly decreased in both the alirocumab and standard care arms, whereas the absolute reduction in LDL cholesterol was significantly greater in patients treated with alirocumab (1.72 ± 0.51 vs. 0.96 ± 0.59, P  < 0.0001). Compared with standard care, the addition of alirocumab to statins was associated with significantly greater increases in minimum fibrous cap thickness (18.0 [10.8–29.2] μm vs 13.2 [7.4–18.6] μm; P  = 0.029), greater increases in minimum lumen area (0.20[0.10–0.33] mm 2 vs 0.13 [0.12–0.24] mm 2 ; P  = 0.006) and a greater diminution in maximum lipid arc (15.1̊ [7.8–24.5] vs. 8.4̊ [2.0–10.5]; P  = 0.008). Conclusions The addition of alirocumab to statins can not only provide additional LDL cholesterol lowering effects but also have a potential role in promoting a more stable plaque phenotype. Trial registration ClinicalTrials.gov Identifier: NCT04851769. Registered 2 Mar 2019.