Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a): A Randomized Clinical Trial.

Importance: Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities. Objectives: To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a). Design, Setting, and Participants: Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023. Interventions: Participants were randomized to receive (1) a single subcutaneous dose of placebo (n = 8), zerlasiran 300 mg (n = 6) or 600 mg (n = 6); or (2) 2 doses of placebo (n = 9), zerlasiran 200 mg (n = 9) at a 4-week interval or 300 mg (n = 9) or 450 mg (n = 9) at an 8-week interval. Main Outcomes Measures: The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations. Results: Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, -30% (IQR, -51% to -18%) for the 300 mg of zerlasiran group, and -29% (IQR, -39% to -7%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, -17 to 28) nmol/L for the placebo group, -258 (IQR, -289 to -188) nmol/L for the 200 mg of zerlasiran group, -310 (IQR, -368 to -274) nmol/L for the 300-mg dose group, and -242 (IQR, -343 to -182) nmol/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, -4% to 21%), -97% (IQR, -98% to -95%), -98% (IQR, -99% to -97%), and -99% (IQR, -99% to -98%), respectively, attenuating to 0.3% (IQR, -2% to 21%), -60% (IQR, -71% to -40%), -90% (IQR, -91% to -74%), and -89% (IQR, -91% to -76%) 201 days after administration. Conclusions: Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration. Trial Registration: ClinicalTrials.gov Identifier: NCT04606602.

Harnessing RNA Interference for Cholesterol Lowering: The Bench-to-Bedside Story of Inclisiran.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021, <20 years after the discovery of PCSK9, inclisiran became the first RNA interference therapeutic approved in the United States for LDL-C lowering in patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and has since been approved for use in patients with primary hyperlipidemia. This article reviews the journey of inclisiran from bench to bedside, including early development, the clinical trial program, key characteristics of inclisiran, and practical points for its use in the clinic.

In adults with ATTR cardiac amyloidosis, patisiran reduced decline in functional capacity at 12 mo.

SOURCE CITATION: Maurer MS, Kale P, Fontana M, et al; APOLLO-B Trial Investigators. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389:1553-1565. 37888916.

Downregulation of salusins alleviates hypertrophic cardiomyopathy via attenuating oxidative stress and autophagy.

INTRODUCTION: Salusins, which are translated from the alternatively spliced mRNA of torsin family 2 member A (TOR2A), play a vital role in regulation of various cardiovascular diseases. However, it remains unclear precisely regarding their roles in hypertrophic cardiomyopathy (HCM). Therefore, this study was conducted to explore therapeutic effect and the underlying mechanisms of salusins on HCM. MATERIAL AND METHODS: In vivo experiments, Sprague-Dawley rats were used to induce HCM model by angiotensin (Ang) II infusion for 4 weeks. The rats were randomly divided into four groups, namely, Saline + Control shRNA (n = 7), Ang II + Control shRNA (n = 8), Saline + TOR2A shRNA (n = 7), and Ang II + TOR2A shRNA groups (n = 8). After HCM induction, doppler echocardiography is recommended to evaluate heart function. In vitro experiments, primary neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (NRCFs) were obtained from newborn rats, and were treated with Ang II (10-6 M) for 24 h. RESULTS: After treatment with Ang II, levels of salusin-α and salusin-ß were elevated in serum and cardiac tissues of rats and in the neonatal rat cardiomyocytes and cardiac fibroblasts. Downregulation of salusins alleviated the Ang II-induced cardiac hypertrophy by suppressing the increased atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (ß-MHC) and cardiac fibrosis by blocking collagen I, collagen III and transforming growth factor-beta (TGF-ß), and it also attenuated oxidative stress by suppressing the increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels and reversing the decreased superoxide dismutase (SOD) activity and autophagy by inhibiting the increased microtubule-associated protein light chain 3B (LC3B), Beclin1, autophagy related gene (Atg) 3 and Atg5 in the cardiac tissues of Ang II-infused rats and in the Ang II-treated NRCMs. CONCLUSIONS: All these findings suggest that the levels of salusins were elevated in the HCM, and targeting of salusins contributes to alleviation of cardiac hypertrophy and fibrosis probably via attenuating oxidative stress and autophagy. Accordingly, targeting of salusins may be a strategy for HCM therapy.

First Report of Inclisiran Utilization for Hypercholesterolemia Treatment in Real-world Clinical Settings in a Middle East Population.

PURPOSE: Inclisiran is the first small interfering RNA-based treatment approved for reducing pro-atherogenic lipoproteins in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of low-density lipoprotein cholesterol (LDL-C). We report the first evaluation of the effects of inclisiran in a Middle East population. METHODS: We conducted a retrospective review of patients initiating inclisiran treatment at an outpatient diabetology, endocrinology, and cardiology center between May 2021 and December 2022. All patients followed up for 90 days or more, or with at least 1 lipid determination post initiation were included. Participants were categorized into primary prevention (n = 57) and secondary prevention (n = 89) groups according to previous atherosclerotic cardiovascular disease. FINDINGS: Inclisiran was initiated in 146 patients; mean (SD) age was 54.8 (12.12) years, 82 patients (56.2%) were male, 28 patients (19.2%) had received a diagnosis of familial hypercholesterolemia, 89 patients (61%) had received a diagnosis of diabetes mellitus, and 35 patients (23.9%) had a statin intolerance. Median (interquartile range) follow-up was 137 (90 to 193) days. At 90 days, median (interquartile range) reductions in serum LDL-C and triglycerides were -37.9% (-9.5% to -51.2%) and -12.0% (-9.8% to -40.5%), respectively, in primary prevention and -54.1% (-17.1% to -71.4%) and -15.3% (-14% to -38.8%), respectively, in secondary prevention (all, P < 0.001). LDL-C goals were attained in 110 patients (75.3%). Nonattainment of LDL-C goal was attributed to system effect in 26 patients (72.2%), biological effect in 5 patients (13.9%), and discontinuation of treatment in 5 patients (13.9%). Therapy was well tolerated. IMPLICATIONS: This study is the first from the Middle East and North Africa region that reported the real-world efficacy and safety profile of inclisiran in a mixed-risk population of patients with heterozygous familial hypercholesterolemia and other non-familial hypercholesterolemia indications. Clinically meaningful and sustained reductions in pro-atherogenic lipids with good tolerability were observed after inclisiran initiation. Fewer AEs were reported in this predominantly Arabic population, consistent with previous safety reports for inclisiran. It is important to note that no patient stopped inclisiran treatment due to AEs. Strengths of our study included an optimal cohort, patient heterogeneity, and high retention. In addition, we were able to report mean robust effects of inclisiran and good medication tolerability, quite like randomized studies and open-label extension periods. Despite this, our study had some limitations, including selection bias due to the retrospective design and the absence of a comparative group.

AGK2 pre-treatment protects against thioacetamide-induced acute liver failure via regulating the MFN2-PERK axis and ferroptosis signaling pathway.

BACKGROUND: Acute liver failure (ALF) is an unpredictable and life-threatening critical illness. The pathological characteristic of ALF is massive necrosis of hepatocytes and lots of inflammatory cells infiltration which may lead to multiple organ failure. METHODS: Animals were divided into 3 groups, normal, thioacetamide (TAA, ALF model) and TAA + AGK2. Cultured L02 cells were divided into 5 groups, normal, TAA, TAA + mitofusin 2 (MFN2)-siRNA, TAA + AGK2, and TAA + AGK2 + MFN2-siRNA groups. The liver histology was evaluated with hematoxylin and eosin staining, inositol-requiring enzyme 1 (IRE1), activating transcription factor 6ß (ATF6ß), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylated-PERK (p-PERK). C/EBP homologous protein (CHOP), reactive oxygen species (ROS), MFN2 and glutathione peroxidase 4 (GPX4) were measured with Western blotting, and cell viability and liver chemistry were also measured. Mitochondria-associated endoplasmic reticulum membranes (MAMs) were measured by immunofluorescence. RESULTS: The liver tissue in the ALF group had massive inflammatory cell infiltration and hepatocytes necrosis, which were reduced by AGK2 pre-treatment. In comparison to the normal group, apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ in the TAA-induced ALF model group were significantly increased, which were decreased by AGK2 pre-treatment. The levels of MFN2 and GPX4 were decreased in TAA-induced mice compared with the normal group, which were enhanced by AGK2 pre-treatment. Compared with the TAA-induced L02 cell, apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ were further increased and levels of MFN2 and GPX4 were decreased in the MFN2-siRNA group. AGK2 pre-treatment decreased the apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ and enhanced the protein expression of MFN2 and GPX4 in MFN2-siRNA treated L02 cell. Immunofluorescence observation showed that level of MAMs was promoted in the AGK2 pre-treatment group when compared with the TAA-induced group in both mice and L02 cells. CONCLUSIONS: The data suggested that AGK2 pre-treatment had hepatoprotective role in TAA-induced ALF via upregulating the expression of MFN2 and then inhibiting PERK and ferroptosis pathway in ALF.

Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial.

BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. METHODS: ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. RESULTS: The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was -1.68% (95% CI, -29.19% to 25.83%; P=0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was -60.6% with inclisiran treatment (P<0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. CONCLUSIONS: Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03851705.

Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial.

Importance: Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no approved pharmacological treatments. Objectives: To assess the safety, tolerability, pharmacokinetics, and effects of lepodisiran on lipoprotein(a) concentrations after single doses of the drug; lepodisiran is a short interfering RNA directed at hepatic synthesis of apolipoprotein(a), an essential component necessary for assembly of lipoprotein(a) particles. Design, Setting, and Participants: A single ascending-dose trial conducted at 5 clinical research sites in the US and Singapore that enrolled 48 adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater (or ≥30 mg/dL) between November 18, 2020, and December 7, 2021; the last follow-up visit occurred on November 9, 2022. Interventions: Participants were randomized to receive placebo or a single dose of lepodisiran (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg) administered subcutaneously. Main Outcomes and Measures: The primary outcome was the safety and tolerability of the single ascending doses of lepodisiran. The secondary outcomes included plasma levels of lepodisiran for 168 days after dose administration and changes in fasting lipoprotein(a) serum concentrations through a maximum follow-up of 336 days (48 weeks). Results: Of the 48 participants enrolled (mean age, 46.8 [SD, 11.6] years; 35% were women), 1 serious adverse event occurred. The plasma concentrations of lepodisiran reached peak levels within 10.5 hours and were undetectable by 48 hours. The median baseline lipoprotein(a) concentration was 111 nmol/L (IQR, 78 to 134 nmol/L) in the placebo group, 78 nmol/L (IQR, 50 to 152 nmol/L) in the 4 mg of lepodisiran group, 97 nmol/L (IQR, 86 to 107 nmol/L) in the 12-mg dose group, 120 nmol/L (IQR, 110 to 188 nmol/L) in the 32-mg dose group, 167 nmol/L (IQR, 124 to 189 nmol/L) in the 96-mg dose group, 96 nmol/L (IQR, 72 to 132 nmol/L) in the 304-mg dose group, and 130 nmol/L (IQR, 87 to 151 nmol/L) in the 608-mg dose group. The maximal median change in lipoprotein(a) concentration was -5% (IQR, -16% to 11%) in the placebo group, -41% (IQR, -47% to -20%) in the 4 mg of lepodisiran group, -59% (IQR, -66% to -53%) in the 12-mg dose group, -76% (IQR, -76% to -75%) in the 32-mg dose group, -90% (IQR, -94% to -85%) in the 96-mg dose group, -96% (IQR, -98% to -95%) in the 304-mg dose group, and -97% (IQR, -98% to -96%) in the 608-mg dose group. At day 337, the median change in lipoprotein(a) concentration was -94% (IQR, -94% to -85%) in the 608 mg of lepodisiran group. Conclusions and Relevance: In this phase 1 study of 48 participants with elevated lipoprotein(a) levels, lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations. The findings support further study of lepodisiran. Trial Registration: ClinicalTrials.gov Identifier: NCT04914546.

Angiotensin-(1-7) suppresses airway inflammation and airway remodeling via inhibiting ATG5 in allergic asthma.

BACKGROUND: Angiotensin (Ang)-(1-7) can reduce airway inflammation and airway remodeling in allergic asthma. Autophagy-related 5 (ATG5) has attracted wide attentions in asthma. However, the effects of Ang-(1-7) on ATG5-mediated autophagy in allergic asthma are unclear. METHODS: In this study, human bronchial epithelial cell (BEAS-2B) and human bronchial smooth muscle cell (HBSMC) were treated with different dose of Ang-(1-7) to observe changes of cell viability. Changes of ATG5 protein expression were measured in 10 ng/mL of interleukin (IL)-13-treated cells. Transfection of ATG5 small interference RNA (siRNA) or ATG5 cDNA in cells was used to analyze the effects of ATG5 on secretion of cytokines in the IL-13-treated cells. The effects of Ang-(1-7) were compared to the effects of ATG5 siRNA transfection or ATG5 cDNA transfection in the IL-13-treated cells. In wild-type (WT) mice and ATG5 knockout (ATG5-/-) mice, ovalbumin (OVA)-induced airway inflammation, fibrosis and autophagy were observed. In the OVA-induced WT mice, Ang-(1-7) treatment was performed to observe its effects on airway inflammation, fibrosis and autophagy. RESULTS: The results showed that ATG5 protein level was decreased with Ang-(1-7) dose administration in the IL-13-treated BEAS-2B and IL13-treated HBSMC. Ang-(1-7) played similar results to ATG5 siRNA that it suppressed the secretion of IL-25 and IL-13 in the IL-13-treated BEAS-2B cells, and inhibited the expression of transforming growth factor (TGF)-ß1 and α-smooth muscle actin (α-SMA) protein in the IL-13-treated HBSMC cells. ATG5 cDNA treatment significantly increased the secretion of IL-25 and IL-13 and expression of TGF-ß1 and α-SMA protein in IL-13-treated cells. Ang-(1-7) treatment suppressed the effects of ATG5 cDNA in the IL-13-treated cells. In OVA-induced WT mice, Ang-(1-7) treatment suppressed airway inflammation, remodeling and autophagy. ATG5 knockout also suppressed the airway inflammation, remodeling and autophagy. CONCLUSIONS: Ang-(1-7) treatment suppressed airway inflammation and remodeling in allergic asthma through inhibiting ATG5, providing an underlying mechanism of Ang-(1-7) for allergic asthma treatment.

Inclisiran in patients with prior myocardial infarction: A post hoc pooled analysis of the ORION-10 and ORION-11 Phase 3 randomised trials.

BACKGROUND AND AIMS: Among patients with prior myocardial infarction (MI), the risk of future ischaemic cardiovascular events is increased, and intensive lipid-lowering therapy (LLT) is indicated to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals. Here, the efficacy and safety of inclisiran, a small interfering ribonucleic acid, were evaluated in patients with or without prior MI from the pooled ORION-10 and ORION-11 Phase 3 trials. METHODS: Patients (n = 2636) were randomised 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on Day 1, Day 90, and 6-monthly thereafter over 18 months, along with background oral LLT, including statins. Of these, 1643 (62.3%) patients had an MI prior to randomisation, stratified as recent (>3 months to <1 year) or remote (≥1 year), and 993 (37.7%) patients were without a prior MI. The percentage change in LDL-C from baseline and safety were assessed. RESULTS: Baseline characteristics were well balanced across the treatment arms and MI strata. The mean (95% confidence interval) placebo-corrected LDL-C reductions from baseline to Day 510 with inclisiran were 52.6% (40.1, 65.1), 50.4% (47.0, 53.8), and 51.6% (47.4, 55.9) for recent, remote, and no prior MI, respectively. Corresponding time-adjusted LDL-C reductions were 50.0% (41.4, 58.7), 52.2% (49.8, 54.7), and 51.2% (48.1, 54.2). In each MI stratum, treatment-emergent adverse events (TEAEs) at the injection site (all mild to moderate) were observed more in inclisiran-treated patients than placebo, without an excess of other TEAEs. CONCLUSIONS: Inclisiran provided effective and consistent LDL-C lowering, irrespective of MI status.

Pharmacokinetics, safety, and tolerability of BMS-986263, a lipid nanoparticle containing HSP47 siRNA, in participants with hepatic impairment.

BMS-986263 is a retinoid-conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47 protein, a collagen-specific chaperone protein involved in fibrosis development. This is a phase I, open-label, two-part study evaluating pharmacokinetics and safety of BMS-986263 in participants with hepatic impairment (HI). Part 1 (n = 24) of this study enrolled two cohorts with mild and moderate HI and a separate cohort of age- and body mass index (BMI)-matched participants with normal hepatic function. Part 2 enrolled eight participants with severe HI and eight age- and BMI-matched participants with normal hepatic function. All participants received a single intravenous 90 mg BMS-986263 infusion. Compared with normal-matched participants, geometric mean area under the plasma concentration-time curve time zero to the time of the last quantifiable concentration (AUC(0-T) ) and AUC from zero to infinity (AUC(INF) ) of HSP47 siRNA were similar in participants with mild HI and 34% and 163% greater in those with moderate and severe HI, respectively, whereas the maximum plasma concentration was ~25% lower in mild and moderate HI groups but 58% higher in the severe HI group than in the normal group. Adverse events were reported by two of eight, four of eight, and three of eight participants with mild, moderate, or severe HI, respectively; none were reported in the normal-matched group. Overall, single-dose BMS-986263 was generally safe and well-tolerated and dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS-986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure-safety/efficacy relationship becomes available.

First clinical experiences with inclisiran in a real-world setting.

BACKGROUND AND OBJECTIVE: Inclisiran is the first-in-class small interfering RNA (siRNA) proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. In clinical trials inclisiran showed effective and sustained low-density lipoprotein cholesterol (LDL-C) reduction of ± 50 %. As data in clinical setting are scarce, we aim to investigate the efficacy and safety in clinical practice. METHODS: We describe a registry of consecutive patients who started with inclisiran at a lipid clinic of a university hospital. Patients were eligible if they fulfilled the reimbursement criteria in the Netherlands. Patients were included if they started with inclisiran as first line (group 1) or switched from PCSK9 monoclonal antibody (mAbs) to inclisiran (group 2). LDL-C levels were measured at 3 and 9 months after initiation of inclisiran. Median change of LDL-C levels was calculated on an individual and group level. RESULTS: We analysed 65 patients (36 women), median [25th percentile; 75th percentile] age of 63 [54; 68] years. Of these, 44 patients had both a 3 month and 9 month visit. At 3 months, patients who newly started inclisiran (group 1, n = 45) showed a LDL-C decrease of 38 [-49;-33] %. Patients who used statins as co-medication (n = 15) had a higher median LDL-C decrease compared to those without statin use (n=30; 45 % vs 38 %). However, patients who switched from mAbs to inclisiran (group 2, n = 20) had an increase in LDL-C of 38 [+4; +97] %. Adverse effects associated with inclisiran were mild and consisted of mild injection site reactions. Efficacy was slightly less whereas safety results were similar at 9 months. CONCLUSION: Our initial experience of inclisiran in a clinical setting showed less reduction in LDL-C levels compared to clinical trials but a similar safety profile. Moreover, patients who switched from PCSK9 mAbs to inclisiran generally showed an increase in LDL-C levels implying that inclisiran is less potent in LDL-C reduction compared to PCSK9 mAbs.

High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany. METHODS: Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration. RESULTS: Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%). CONCLUSION: In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.

The Societal Impact of Inclisiran in England: Evidence From a Population Health Approach.

OBJECTIVES: As first-in-class cholesterol-lowering small interfering ribonucleic acid, inclisiran provides effective reductions in low-density lipoprotein-cholesterol to achieve better cardiovascular (CV) health. We estimate the health and socioeconomic effects of introducing inclisiran according to a population health agreement in England. METHODS: Building on the inclisiran cost-effectiveness model, a Markov model simulates health gains in terms of avoided CV events and CV deaths because of add-on inclisiran treatment for patients aged 50 years and older with pre-existing atherosclerotic CV disease. These are translated into socioeconomic effects, defined as societal impact. To that end, we quantify avoided productivity losses in terms of paid and unpaid work productivity and monetize them according to gross value added. Furthermore, we calculate value chain effects for paid work activities, drawing on value-added multipliers based on input-output tables. The derived value-invest ratio compares avoided productivity losses against the increased healthcare costs. RESULTS: Our results show that 138 647 CV events could be avoided over a period of 10 years. The resulting societal impact amounts to £8.17 billion, whereas additional healthcare costs are estimated at £7.94 billion. This translates into a value-invest ratio of 1.03. CONCLUSIONS: Our estimates demonstrate the potential health and socioeconomic value of inclisiran. Thereby, we highlight the importance to treat CVD and illustrate the impact that a large-scale intervention can have on population health and the economy.

Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial.

INTRODUCTION: Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol. METHODS: ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577. FINDINGS: Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm. INTERPRETATION: Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran. FUNDING: Novartis Pharma.

Role of Tumor Necrosis Factor Receptor 1-Reactive Oxygen Species-Caspase 11 Pathway in Neuropathic Pain Mediated by HIV gp120 With Morphine in Rats.

BACKGROUND: Recent clinical research suggests that repeated use of opioid pain medications can increase neuropathic pain in people living with human immunodeficiency virus (HIV; PLWH). Therefore, it is significant to elucidate the exact mechanisms of HIV-related chronic pain. HIV infection and chronic morphine induce proinflammatory factors, such as tumor necrosis factor (TNF)α acting through tumor necrosis factor receptor I (TNFRI). HIV coat proteins and/or chronic morphine increase mitochondrial superoxide in the spinal cord dorsal horn (SCDH). Recently, emerging cytoplasmic caspase-11 is defined as a noncanonical inflammasome and can be activated by reactive oxygen species (ROS). Here, we tested our hypothesis that HIV coat glycoprotein gp120 with chronic morphine activates a TNFRI-mtROS-caspase-11 pathway in rats, which increases neuroinflammation and neuropathic pain. METHODS: Neuropathic pain was induced by repeated administration of recombinant gp120 with morphine (gp120/M) in rats. Mechanical allodynia was assessed using von Frey filaments, and thermal latency using hotplate test. Protein expression of spinal TNFRI and cleaved caspase-11 was examined using western blots. The image of spinal mitochondrial superoxide was examined using MitoSox Red (mitochondrial superoxide indicator) image assay. Immunohistochemistry was used to examine the location of TNFRI and caspase-11 in the SCDH. Intrathecal administration of antisense oligodeoxynucleotide (AS-ODN) against TNFRI, caspase-11 siRNA, or a scavenger of mitochondrial superoxide was given for antinociceptive effects. Statistical tests were done using analysis of variance (1- or 2-way), or 2-tailed t test. RESULTS: Intrathecal gp120/M induced mechanical allodynia and thermal hyperalgesia lasting for 3 weeks ( P < .001). Gp120/M increased the expression of spinal TNFRI, mitochondrial superoxide, and cleaved caspase-11. Immunohistochemistry showed that TNFRI and caspase-11 were mainly expressed in the neurons of the SCDH. Intrathecal administration of antisense oligonucleotides against TNFRI, Mito-Tempol (a scavenger of mitochondrial superoxide), or caspase-11 siRNA reduced mechanical allodynia and thermal hyperalgesia in the gp120/M neuropathic pain model. Spinal knockdown of TNFRI reduced MitoSox profile cell number in the SCDH; intrathecal Mito-T decreased spinal caspase-11 expression in gp120/M rats. In the cultured B35 neurons treated with TNFα, pretreatment with Mito-Tempol reduced active caspase-11 in the neurons. CONCLUSIONS: These results suggest that spinal TNFRI-mtROS-caspase 11 signal pathway plays a critical role in the HIV-associated neuropathic pain state, providing a novel approach to treating chronic pain in PLWH with opioids.