A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9.

PURPOSE: AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations. METHODS: This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks. RESULTS: The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%. CONCLUSIONS: Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development. TRIAL REGISTRATION: EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.

Moving Targets: Recent Advances in Lipid-Lowering Therapies

Statin therapy has delivered tremendous value to society by improving the burden of atherosclerotic cardiovascular disease. Nonetheless, atherosclerotic cardiovascular disease remains the leading cause of death globally. Technological advances such as in the field of genomics have revolutionized drug discovery and development and have revealed novel therapeutic targets to lower low-density lipoprotein cholesterol (LDL-C), as well as other detrimental lipids and lipoproteins. Therapeutic LDL-C lowering prevents atherosclerotic cardiovascular disease with an effect size proportional to absolute LDL-C reductions and time of exposure. This understanding supports the notion that reducing cumulative LDL-C exposure should be a key therapeutic target. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibiting monoclonal antibodies provides the possibility of reducing LDL-C to very low levels. Novel therapeutic platforms such as RNA inhibition present opportunities to combine robust lipid lowering with infrequent dosing regimens, introducing therapies with vaccine-like properties. The position of lipid-lowering therapies with targets other than LDL-C, such as Lp(a) [lipoprotein(a)], TRL (triglyceride-rich lipoproteins), and remnant cholesterol, will likely be determined by the results of ongoing clinical trials. Current evidence suggests that reducing Lp(a) or TRLs could attenuate atherosclerotic cardiovascular disease risk in specific categories of patients. This review provides an overview of the latest therapeutic developments, focusing on their mechanisms, efficacy, and safety.

Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Prespecified Secondary End Points in ORION 1.

BACKGROUND: The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction. The effects of inclisiran on other lipids are less well described. METHODS: ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens versus placebo. Participants with elevated low-density lipoprotein cholesterol despite receiving maximally tolerated statin therapy received a single-dose (200, 300, or 500 mg) or 2-dose starting regimen (100, 200, or 300 mg on days 1 and 90) of inclisiran or placebo. This prespecified analysis reports the percentage reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, very-low-density lipoprotein cholesterol, lipoprotein(a), triglycerides, HDL-C, and apo A1 at the primary efficacy time point (day 180) with mixed-effect models for repeated measures. Additional prespecified analyses report time course of changes from baseline at each visit to day 210, interindividual variation in response, and lipid goal attainment. RESULTS: The mean age of the 501 participants was 63 years, 65% were male, 69% had atherosclerotic cardiovascular disease, 73% used statins, and mean low-density lipoprotein cholesterol was 128 mg/dL. A single dose of inclisiran reduced apo B, non-HDL-C, and very-low-density lipoprotein cholesterol over 210 days. A second dose of inclisiran provided additional lowering of these lipids. At day 180, non-HDL-C was lowered dose-dependently: by 25% from 148±43 to 110±45 mg/dL in the 200-mg single-dose group and by 46% from 161±58 to 91±58 mg/dL in the 2-dose 300-mg group. For the same dosing regimens, apo B was reduced by 23% from 101±23 to 78±29 mg/dL and by 41% from 106±31 to 65±33 mg/dL ( P<0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non-HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non-HDL-C <100 and <130 mg/dL. CONCLUSIONS: Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting the synthesis of protease proprotein convertase subtilisin/kexin type 9 through siRNA may be a viable alternative to other approaches that target protease proprotein convertase subtilisin/kexin type 9. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02597127.

Proprotein convertase subtilisin/kexin type 9: from genetics to clinical trials.

PURPOSE OF REVIEW: This review describes the pivotal role of genetic insights and technologies in the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the rapid development of PCSK9 inhibitors - a revolutionary new class of lipid-lowering agents. RECENT FINDINGS: PCSK9 was discovered as a the third gene implicated in familial hypercholesterolemia. Population genetics studies, enabled by technological advances, were instrumental in validating PCSK9 as a therapeutic target. Monoclonal antibodies against PCSK9 were introduced in the clinic after an unprecedently rapid development path, in which clinical trial results confirmed that these drugs robustly lower cholesterol and improve clinical outcomes regardless of disease indication or background therapy. New strategies to PCSK9 inhibition are underway and have delivered promising preliminary results, including inhibition of PCSK9 synthesis by targeting the cellular gene expression machinery and vaccination. The future will tell whether directly targeting the genome through editing techniques will ultimately enable us to virtually eliminate many of the traditional CVD risk factors. SUMMARY: The extraordinary PCSK9 narrative highlights the opportunities offered by genetics-driven drug development and holds valuable lessons for future development programs.

How common are foot problems among individuals with diabetes? Diabetic foot ulcers in the Dutch population.

AIMS/HYPOTHESIS: Contemporary data on diabetic foot ulcer prevalence are scarce. Most studies were conducted in the 1990s, reporting incidence rates of 1.9-2.6%. Since then the prevalence of diabetes has doubled and the organisation of diabetes care has undergone major changes. Up-to-date data that quantify the occurrence of diabetic foot ulcers are required and could serve as baseline measures for future studies. METHODS: Individuals with diabetes (n = 81,793) were identified from the NIVEL (Netherlands institute for health services research) Primary Care Database, which contains data for standardised routine care and is representative of the Dutch population. The annual incidence rates of ulcers and other foot abnormalities were calculated using data collected between 2010 and 2013. To account for inaccuracies, incidence rates were calculated using: (1) only individuals with a documented foot examination; (2) all individuals; and (3) individuals with explicit documentation of present/absent foot ulceration. RESULTS: There were 412 individuals with documented ulceration during the registration period (0.50%). The annual incidence rate of foot ulcers was 0.34% (range 0.22-1.08%). Of those individuals with a documented foot examination, 14.6% had absent pedal pulsations, 17.3% had neuropathy and 10.1% had callus/pressure marks. CONCLUSIONS/INTERPRETATION: The annual incidence rate of foot ulcers in the current study was lower than previously reported. This observation could reflect the efficacy of screening practices and an increased awareness among professionals and patients. Nevertheless, approximately one in every five diabetic individuals had at least one identifiable risk factor on foot examination. This signifies the importance of preventive screening.

Heterogeneous impact of classic atherosclerotic risk factors on different arterial territories: the EPIC-Norfolk prospective population study.

AIMS: Particular atherosclerotic risk factors may differ in their association with atherosclerosis across vascular territories. Few studies have compared the associations between multiple risk factors and cardiovascular disease (CVD) manifestations in one population. We studied the strength of the associations between traditional risk factors including coronary artery disease (CAD), ischaemic and haemorrhagic stroke, abdominal aortic aneurysms (AAAs), and peripheral arterial disease (PAD). METHODS AND RESULTS: This analysis included 21 798 participants of the EPIC-Norfolk population study, without previous CVD. Events were defined as hospitalization or mortality, coded using ICD-10. The associations between the risk factors, such as low-density lipoprotein cholesterol, systolic blood pressure (SBP), and smoking, and the various CVD manifestations were compared using competing risk analyses. During 12.1 years, 3087 CVD events were recorded. The associations significantly differed across CVD manifestations. Low-density lipoprotein cholesterol was strongly associated with CAD [adjusted hazard rate (aHR) highest vs. lowest quartile 1.63, 95% CI 1.44-1.86]. Systolic blood pressure was a strong risk factor for PAD (aHR highest vs. lowest quartile 2.95, 95% CI 1.78-4.89) and ischaemic stroke (aHR highest vs. lowest quartile 2.48, 95% CI 1.55-3.97), but not for AAA. Smoking was strongly associated with incident AAA (aHR current vs. never 7.66, 95% CI 4.50-13.04) and PAD (aHR current vs. never 4.66, 95% CI 3.29-6.61), but not with haemorrhagic stroke. CONCLUSION: The heterogeneity in the risk factor-CVD associations supports the concept of pathophysiological differences between atherosclerotic CVD manifestations and could have implications for CVD prevention.

Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study.

Variable agreement exists between different lipoprotein (a) [Lp(a)] measurement methods, but their clinical relevance remains unclear. The predictive value of Lp(a) measured by two different assays [Randox and University of California, San Diego (UCSD)] was determined in 623 coronary artery disease (CAD) cases and 948 controls in a case-control study within the EPIC-Norfolk Prospective Population Study. Participants were divided into sex-specific quintiles, and by Lp(a) <50 versus ∼50 mg/dl, which represents the 80th percentile in northern European subjects. Randox and UCSD Lp(a) levels were strongly correlated; Spearman's correlation coefficients for men, women, and sexes combined were 0.905, 0.915, and 0.909, respectively (P< 0.001 for each). The >80th percentile cutoff values, however, were 36 mg/dl and 24 mg/dl for the Randox and UCSD assays, respectively. Despite this, Lp(a) levels were significantly associated with CAD risk, with odds ratios of 2.18 (1.58-3.01) and 2.35 (1.70-3.26) for people in the top versus bottom Lp(a) quintile for the Randox and UCSD assays, respectively. This study demonstrates that CAD risk is present at lower Lp(a) levels than the currently suggested optimal Lp(a) level of <50 mg/dl. Appropriate thresholds may need to be population and assay specific until Lp(a) assays are standardized and Lp(a) thresholds are evaluated broadly across all populations at risk for CVD and aortic stenosis.

Carotid arterial wall inflammation in peripheral artery disease is augmented by type 2 diabetes: a cross-sectional study.

BACKGROUND: Patients with peripheral artery disease (PAD) are at increased risk of secondary events, which is exaggerated in the presence of type 2 diabetes mellitus. Diabetes is associated with a systemic pro-inflammatory state. We therefore investigated the cumulative impact of PAD and type 2 diabetes on carotid arterial wall inflammation. As recent data suggest a detrimental role of exogenous insulin on cardiovascular disease, we also included a group of insulin users. RESULTS: 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) imaging showed increased carotid arterial wall inflammation, assessed as target-to-background ratio (TBR), in PAD patients without diabetes (PAD-only: n = 11, 1.97 ± 0.57) compared with matched controls (n = 12, 1.49 ± 0.57; p = 0.009), with a significant further TBR increase in PAD patients with type 2 diabetes (PAD-DM, n = 23, 2.90 ± 1, p = 0.033 vs PAD-only). TBR of insulin users (n = 12, 3.31 ± 1.14) was higher compared with patients on oral medication only (n = 11, 2.44 ± 0.76, p = 0.035), despite comparable PAD severity (Fontaine stages), BMI and CRP. Multivariate regression analysis showed that Hba1c and plasma insulin levels, but not dose of exogenous insulin, correlated with TBR. CONCLUSIONS: Concurrent diabetes significantly augments carotid arterial wall inflammation in PAD patients. A further increase in those requiring insulin was observed, which was associated with diabetes severity, rather than with the use of exogenous insulin itself.

PCSK9 inhibition: the way forward in the treatment of dyslipidemia.

Barely a decade after the discovery of the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and its recognition as a key player in cholesterol metabolism, PCSK9 inhibition is now considered an exciting approach in the reduction of residual risk of cardiovascular disease. The progress from PCSK9 discovery to the development of targeted treatment has been unprecedented in terms of scale and speed. The first suggestion of a link between PCSK9 and hypercholesterolemia was published in 2003; a decade later, two meta-analyses of clinical trials comparing anti-PCSK9 treatment to placebo or ezetimibe, including >10,000 hypercholesterolemic individuals, were published. Currently, three PCSK9 inhibitors are being evaluated in clinical outcome trials and the results will determine the future of these lipid-lowering therapies by establishing their clinical efficacy in terms of cardiovascular event reduction, safety, and the consequences of prolonged exposure to very low levels of LDL-cholesterol. Irrespective of their outcomes, the exceptionally rapid development of these drugs exemplifies how novel technologies, genetic validation, and rapid clinical progression provide the tools to expedite the development of new drugs.

Systemic wound care: a meta-review of cochrane systematic reviews.

Wound care is a classic example of a surgical realm with a great variation in care. The diversity in wounds and wound treatments, the limited amount of convincing evidence, and the diverging opinions among doctors and nurses involved in wound care contribute to this undesirable variation in care. For chronic wounds, such as arterial or venous ulcers, pressure sores, and diabetic foot ulcers, but also for acute wounds after surgery or trauma, international and national guidelines provide recommendations on diagnostic procedures and treatment options, but rely mostly on expert opinion. We present the available evidence from Cochrane systematic reviews for the systemic treatment (i.e., not prevention) of patients with wounds, as opposed to topical wound treatments. This evidence shows: - Venous ulcers: High-compression therapy is the classic and evidence-based treatment for treating venous ulcers. Oral pentoxifylline promotes ulcer healing with and without compression therapy. Oral zinc is not effective to heal venous ulcers. - Acute wounds: Recombinant human growth hormone accelerates healing of large burn wounds and donor sites, while high-carbohydrate feeding might reduce the risk of pneumonia. Linezolid is more effective than vancomycin for treating skin and soft tissue infections. Hyperbaric oxygen may help heal crush wounds and skin grafts. Therapeutic touch does not heal acute wounds. - Pressure sores: Air-fluidized and some low-tech devices appear effective for treating existing pressure ulcers. Oral zinc, protein, or vitamin C supplements seem ineffective. Also, evidence is lacking on the effectiveness of repositioning regimes as a treatment option. - Diabetic ulcers: Hyperbaric oxygen therapy and pressure-relieving devices may improve healing rates. - Arterial ulcers: Prostanoids and spinal cord stimulation may be effective in healing ischemic ulcers. Thus, fortunately, some high-level evidence exists for various local and systemic interventions in wound care. Caregivers should be aware of, and apply, the strongest evidence available. Only when all stakeholders (patients, physicians, wound care nurses, but also manufacturers and buyers) implement this available evidence will optimum quality of care for patients with wounds be ensured.

Recent failures in antiatherosclerotic drug development: examples from the thyroxin receptor agonist, the secretory phospholipase A2 antagonist, and the acyl coenzyme A: cholesterol acyltransferase inhibitor programs.

PURPOSE OF REVIEW: To review the published data related to the rise and fall of three different therapeutic approaches, which were investigated to lower cardiovascular disease (CVD) risk. RECENT FINDINGS: CVD remains a major burden of morbidity and mortality, despite therapeutic interventions. Novel strategies to address this residual risk are eagerly awaited, and a number of novel targets for therapy have been identified. Lipids and lipoproteins have been shown to play an eminent role in atherosclerosis progression, and as such, interventions that influence these biomarkers are crucial in CVD risk prevention. In recent years, however, clinical studies investigating the effect of novel lipid-modifying drugs on cardiovascular risk prevention have not always resulted in the anticipated beneficial outcome. Moreover, the development of therapies directed toward bioactive proteins acting at the crossroads of lipids and inflammation has also been disappointing. SUMMARY: In this review, we will specifically address the rationale, design, and results of the clinical trials investigating the effects of three of the failing therapies: the thyroxin receptor agonist, the secretory phospholipase A2 antagonist, and the acyl coenzyme A:cholesterol acyltransferase inhibitor.

Homozygous familial hypercholesterolemia in China: Genetic and clinical characteristics from a real-world, multi-center, cohort study.

BACKGROUND: There is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia. OBJECTIVE: To define the characteristics of phenotypic and genetic HoFH probands from mainland China. METHODS: We collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test. RESULTS: A total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH. CONCLUSIONS: This report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH.

Effects of Renal Impairment on the Pharmacokinetics, Efficacy, and Safety of Inclisiran: An Analysis of the ORION-7 and ORION-1 Studies.

OBJECTIVE: To investigate the pharmacodynamic properties of inclisiran, a small interfering RNA targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), in individuals with normal renal function and renal impairment (RI). PATIENTS AND METHODS: The analysis included participants with normal renal function and mild, moderate, and severe RI from the phase 1 ORION-7 renal study (n=31) and the phase 2 ORION-1 study (n=247) who received 300 mg of inclisiran sodium or placebo. RESULTS: In ORION-7, PCSK9 values were reduced at day 60 in the normal renal function group (68.1%±12.4%), mild RI group (74.2%±12.3%), moderate RI group (79.8%±4.9%), and severe RI group (67.9%±16.4%) (P<.001 vs placebo in all groups). Low-density lipoprotein cholesterol levels were significantly reduced versus placebo: normal renal function, 57.6%±10.7%; mild RI, 35.1%±13.5%; moderate RI, 53.1%±21.3%; severe RI, 49.2%±26.6% (P<.001 for all). In ORION-1, PCSK9 level reductions at day 180 were 48.3% to 58.6% in the 300-mg single-dose groups and 67.3% to 73.0% in the 300-mg 2-dose groups (P<.001 vs placebo in all groups). The corresponding low-density lipoprotein cholesterol level reductions were 35.7% to 40.2% in the 300-mg single-dose groups and 50.9% to 58.0% in the 300 mg 2-dose groups (P<.001 vs placebo in all groups). In ORION-7, exposure to inclisiran was proportionally greater in individuals with increasing RI; inclisiran was undetectable in plasma 48 hours after administration in any group. CONCLUSION: The pharmacodynamic effects and safety profile of inclisiran were similar in study participants with normal and impaired renal function. Dose adjustments of inclisiran are not required in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT02597127 and NCT03159416.

Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.

Importance: Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes. Objective: To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen. Design, Setting, and Participants: Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017. Interventions: One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo. Main Outcomes and Measures: Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year. Results: At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year. Conclusions and Relevance: Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing. Trial Registration: ClinicalTrials.gov identifier: NCT02597127.

Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program.

Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi. Phase I and II data show that inclisiran lowers low-density lipoprotein cholesterol levels on average by >50% with a duration of effect that enables twice-yearly dosing. Phases I, II and emerging Phase III data support inclisiran's safety, tolerability and risk-benefit profile. The ongoing ORION program includes Phase III trials that will provide robust evidence of inclisiran's safety and efficacy in individuals at high risk of atherosclerotic cardiovascular disease (ASCVD), including established ASCVD and familial hypercholesterolemia. In addition, the ORION-4 trial will assess the impact of inclisiran on cardiovascular outcomes in approximately 15,000 ASCVD subjects.

Inhibiting PCSK9 - biology beyond LDL control.

Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly from the liver, but the protein is also expressed in the pancreas, the kidney, the intestine and the central nervous system. Although PCSK9 modulates cholesterol metabolism by regulating LDL receptor expression in the liver, in vitro and in vivo studies have suggested that PCSK9 is involved in various other physiological processes. Although therapeutic PCSK9 inhibition could theoretically have undesired effects by interfering with these non-cholesterol-related processes, studies of individuals with genetically determined reduced PCSK9 function and clinical trials of PCSK9 inhibitors have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation. The clinical implications of PCSK9 functions beyond lipid metabolism in terms of wanted or unwanted effects of therapeutic PCSK9 inhibition therefore appear to be limited. The objective of this Review is to describe the physiological role of PCSK9 beyond the LDL receptor to provide a rational basis for monitoring the effects of PCSK9 inhibition as these drugs gain traction in the clinic.

PCSK9 inhibitors in clinical practice: Delivering on the promise?

BACKGROUND AND AIMS: In clinical trials, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors robustly lowered LDL-cholesterol (LDL-c) and had a favorable tolerability and safety profile. Based on these findings, PCSK9 inhibitors are incorporated in updates of clinical treatment guidelines. However, trial results do not necessarily predict the effectiveness under real-world conditions. The aim of the current study is to determine the efficacy and tolerability of PCSK9 inhibitors in routine outpatient care. METHODS: The cohort comprised all patients who were prescribed evolocumab or alirocumab at the outpatient clinic of a large university hospital in the Netherlands. Eligible patients required additional lipid-lowering despite maximally tolerated statin therapy and ezetimibe, or were statin intolerant. Data were systematically collected during routine outpatient visits. RESULTS: The study included 238 patients of whom 67.2% had familial hypercholesterolemia (FH) and 42.9% were statin intolerant. The mean LDL-c reduction was 55.0% from a baseline of 4.4 mmol/L. LDL-c goals were attained by 62.3% of patients. Side effects were reported by 15.5% of patients and 2.5% discontinued treatment. No meaningful differences in efficacy or tolerability were observed between patients with FH or statin intolerance, or across treatment regimens. CONCLUSIONS: The observed lipid reductions and side effects profile of PCSK9 inhibitors in a routine care setting were comparable to observations in clinical trials.