Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.

Comparison of low-density lipoprotein cholesterol equations in patients with dyslipidaemia receiving cholesterol ester transfer protein inhibition.

AIMS: Low-density lipoprotein (LDL-C) lowering is imperative in cardiovascular disease prevention. We aimed to compare accuracy of three clinically-implemented LDL-C equations in a clinical trial of cholesterol ester transfer protein (CETP) inhibition. METHODS AND RESULTS: Men and women aged 18-75 years with dyslipidaemia were recruited from 17 sites in the Netherlands and Denmark. Patients were randomly assigned to one of nine groups using various combinations of the CETP inhibitor TA-8995 (obicetrapib), statin therapy, and placebo. In pooled measurements over 12 weeks, we calculated LDL-C by the Friedewald, Martin/Hopkins, and Sampson equations, and compared values with preparative ultracentrifugation (PUC) LDL-C overall and with a special interest in the low LDL-C/high triglycerides subgroup. There were 242 patients contributing 921 observations. Overall median LDL-C differences between estimates and PUC were small: Friedewald, 0.00 (25th, 75th: -0.10, 0.08) mmol/L [0 (-4, 3) mg/dL]; Martin/Hopkins, 0.02 (-0.08, 0.10) mmol/L [1 (-3, 4) mg/dL]; and Sampson, 0.05 (-0.03, 0.15) mmol/L [2 (-1, 6) mg/dL]. In the subgroup with estimated LDL-C <1.8 mmol/L (<70 mg/dL) and triglycerides 1.7-4.5 mmol/L (150-399 mg/dL), the Friedewald equation underestimated LDL-C with a median difference versus PUC of -0.25 (-0.33, -0.10) mmol/L [-10 (-13, -4) mg/dL], whereas the median difference by Martin/Hopkins was 0.00 (-0.08, 0.10) mmol/L [0 (-3, 4) mg/dL] and by Sampson was -0.06 (-0.13, 0.00) mmol/L [-2 (-5, 0) mg/dL]. In this subgroup, the proportion of LDL-C observations <1.8 mmol/L (<70 mg/dL) that were correctly classified compared with PUC was 71.4% by Friedewald vs. 100.0% by Martin/Hopkins and 93.1% by Sampson. CONCLUSION: In European patients with dyslipidaemia receiving a CETP inhibitor, we found improved LDL-C accuracy using contemporary equations vs. the Friedewald equation, and the greatest accuracy was observed with the Martin/Hopkins equation. REGISTRATION: ClinicalTrials.gov, NCT01970215.

Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels.

Importance: Lipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities. Objectives: To assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses. Design, Setting, and Participants: A single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021. Interventions: Participants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously. Main Outcomes and Measures: The primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days. Results: Among 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were -20 (IQR, -61 to 3) nmol/L, -89 (IQR, -119 to -61) nmol/L, -185 (IQR, -226 to -163) nmol/L, -268 (IQR, -292 to -189) nmol/L, and -227 (IQR, -270 to -174) nmol/L, with maximal median percentage changes of -10% (IQR, -16% to 1%), -46% (IQR, -64% to -40%), -86% (IQR, -92% to -82%), -96% (IQR, -98% to -89%), and -98% (IQR, -98% to -97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration. Conclusions and Relevance: In this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA. Trial Registration: ClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35.

Cascade Screening for Familial Hypercholesterolemia in South Africa: The Wits FIND-FH Program.

OBJECTIVE: Due to gene founder effects, familial hypercholesterolemia (FH) has a prevalence of ≈1:80 in populations of Afrikaner ancestry and is a major contributor to premature atherosclerotic cardiovascular disease in South Africans of Jewish and Indian descent. No systematic program exists to identify these families. Furthermore, information regarding FH prevalence in Black Africans is sparse. The Wits FIND-FH program was initiated in late 2016 to address these issues. Approach and Results: Based on index subjects with definite or probable FH, first-degree relatives were contacted, informed consent obtained, and targeted medical history, physical examination, and blood samples collected. In patients with likely FH using the Simon Broome criteria, DNA analysis for LDLR (low-density lipoprotein receptor), APOB (apolipoprotein B), PCSK9 (proprotein convertase subtilisin/kexin type 9), and LDLRAP1 (LDLR adaptor protein 1) variants was analyzed by next-generation sequencing. Of the initial 700 subjects screened of whom 295 (42%) were index cases, 479 (68.4%) were clinically diagnosed with probable or definite FH. Genetic analysis confirmed 285 of 479 (59.5%) as having variants consistent with FH. Three subjects met the clinical diagnosis for homozygous FH, but DNA analysis revealed a further 34 patients, including 4 Black African subjects, with ≥2 FH-causing variants. CONCLUSIONS: Using phenotype cascade screening, the Wits FIND-FH program has screened an average of 30 subjects monthly of whom 68% had a clinical diagnosis of FH with ≈60% genetically confirmed. The program is identifying a small but growing number of Black South Africans with FH. Interestingly, 37 subjects (7.7%) who underwent DNA testing were found to have ≥2 FH-causing variants.

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia. METHODS: In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. RESULTS: The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).

Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label).

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis manifested by increased carotid intima-media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in children with HeFH. METHODS: Children with HeFH (age, 6-<18 years) and low-density lipoprotein cholesterol >4.9 mmol/L or >4.1 mmol/L in combination with other risk factors received rosuvastatin for 2 years, starting at 5 mg once daily, with uptitration to 10 mg (age, 6-<10 years) or 20 mg (age, 10-<18 years). Carotid IMT was assessed by ultrasonography at baseline and 12 and 24 months in all patients and in age-matched unaffected siblings. Carotid IMT was measured at 3 locations (common carotid artery, carotid bulb, internal carotid artery) in both the left and right carotid arteries. A linear mixed-effects model was used to evaluate differences in carotid IMT between children with HeFH and the unaffected siblings. P values were adjusted for age, sex, carotid artery site, and family relations. RESULTS: At baseline, mean±SD carotid IMT was significantly greater for the 197 children with HeFH compared with the 65 unaffected siblings (0.397±0.049 and 0.377±0.045 mm, respectively; P=0.001). During 2 years of follow-up, the change in carotid IMT was 0.0054 mm/y (95% confidence interval, 0.0030-0.0082) in children with HeFH and 0.0143 mm/y (95% confidence interval, 0.0095-0.0192) in unaffected siblings (P=0.002). The end-of-study difference in mean carotid IMT between children with HeFH and unaffected siblings after 2 years was no longer significant (0.408±0.043 and 0.402±0.042 mm, respectively; P=0.2). CONCLUSIONS: In children with HeFH who were ≥6 years of age, carotid IMT was significantly greater at baseline compared with unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid IMT in children with HeFH than untreated unaffected siblings. As a result, no difference in carotid IMT could be detected between the 2 groups after 2 years of rosuvastatin. These findings support the value of early initiation of statin treatment for low-density lipoprotein cholesterol reduction in children with HeFH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01078675.

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

BACKGROUND: In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODS: We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTS: A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONS: In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).

Evaluation of buprenorphine/naloxone dose and use of sedating supportive medication on treatment outcomes in veterans with opioid use disorder.

INTRODUCTION: This retrospective cohort study evaluated effects of buprenorphine/naloxone dose and concomitant use of selected sedating medications on treatment outcomes in patients with opioid use disorder. METHODS: Patients enrolled in the buprenorphine/naloxone clinic at the study institution from 2009 until April 2013 were included. There were no exclusion criteria. Part 1 assessed treatment failure within 6 months and time to treatment failure with buprenorphine doses >8 mg and ≤8 mg. Part 2 assessed for treatment failure within 6 months and time to treatment failure with use of selected sedating medications. Sedating medications were cyproheptadine, hydroxyzine, quetiapine, and trazodone. Treatment failure was defined as documentation of illicit opioid use per patient report, urine drug screen showing opioid use, or patient lost to follow-up. RESULTS: There were 132 patients included in this study, but 163 separate encounters due to multiple enrollments. Treatment failure was experienced within 6 months 51 times a patient was prescribed ≤8 mg (66.2%) and 26 times a patient was prescribed >8 mg (33.8%) (P = .0005). Average time to treatment failure was 5.1 months with ≤8 mg and 8.4 months with >8 mg. The 48% of patients who received sedating medications did not demonstrate any significant differences in treatment response at 6 months (P = .2746) or time to treatment failure (P = .2209). DISCUSSION: Doses of buprenorphine/naloxone >8 mg demonstrated better treatment response and prolonged time to treatment failure. Concomitant sedating medications did not have a statistically significant effect on treatment response or time to treatment failure.

Efficacy and safety of rosuvastatin therapy in children and adolescents with familial hypercholesterolemia: Results from the CHARON study.

OBJECTIVE: Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Guidelines recommend initiating statins early to reduce low-density lipoprotein cholesterol (LDL-C). Studies have evaluated rosuvastatin in children aged ≥10 years, but its efficacy and safety in younger children is unknown. METHODS: Children with HeFH and fasting LDL-C >4.92 mmol/L (190 mg/dL) or >4.10 mmol/L (>158 mg/dL) with other cardiovascular risk factors received rosuvastatin 5 mg daily. Based on LDL-C targets (<2.85 mmol/L [<110 mg/dL]), rosuvastatin could be uptitrated to 10 mg (aged 6-9 years) or 20 mg (aged 10-17 years). Treatment lasted 2 years. Changes in lipid values, growth, sexual maturation, and adverse events (AEs) were assessed. RESULTS: The intention-to-treat analysis included 197 patients. At 24 months, LDL-C was reduced by 43, 45, and 35% vs baseline in patients aged 6-9, 10-13, and 14-17 years, respectively (P < .001 for all groups). Most AEs were mild. Intermittent myalgia was reported in 11 (6%) patients and did not lead to discontinuation of rosuvastatin treatment. Serious AEs were reported by 9 (5%) patients, all considered unrelated to treatment by the investigators. No clinically important changes in hepatic biochemistry were reported. Rosuvastatin treatment did not appear to adversely affect height, weight, or sexual maturation. CONCLUSIONS: In HeFH patients aged 6-17 years, rosuvastatin 5-20 mg over 2 years significantly reduced LDL-C compared with baseline. Treatment was well tolerated, with no adverse effects on growth or sexual maturation.

Non-statin Treatments for Managing LDL Cholesterol and Their Outcomes.

PURPOSE: Over the past 3 decades reducing LDL-C has proven to be the most reliable and easily achievable modifiable risk factor to decrease the rate of cardiovascular morbidity and mortality. Statins are effective, but problems with their side effects, adherence, or LDL-C efficacy in some patient groups remain. Most currently available alternative lipid-modifying therapies have limited efficacy or tolerability, and additional effective pharmacologic modalities to reduce LDL-C are needed. METHODS: Recent literature on new and evolving LDL-C-lowering modalities in preclinical and clinical development was reviewed. FINDINGS: Several new therapies targeting LDL-C are in development. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a recently elucidated key regulator of plasma LDL-C, is the most promising and effective, with a number of approaches aimed at this target. The most advanced are monoclonal antibodies, which have demonstrated LDL-C reductions of ~60%, whether given alone or added to statins. Other PCSK9-targeted therapies in clinical development include adnectins and gene silencing techniques. Preclinical approaches involve vaccines, whereas a search remains for small molecule inhibitors. Other new pharmacologic approaches in Phase III clinical trials include a refocusing of cholesterol ester transfer protein inhibitors from primarily agents to increase HDL-C to their off-target effect on LDL-C and adenosine triphosphate citrate lyase inhibition. In earlier clinical development is new delivery of nicotinic acid-containing compounds. Additional agents are being developed as orphan indications expressly for patients with homozygous familial hypercholesterolemia, including peroxisome proliferator activated receptor-δ agonists, angiopoietin-like protein 3 inhibitors, and gene therapy. IMPLICATIONS: Monoclonal antibodies that inhibit PCSK9 were shown to be very effective reducers of LDL-C and well tolerated despite subcutaneous administration, and no significant safety issues have yet emerged during large Phase II and III trials. They have the potential to substantially impact further the risk of cardiovascular disease. A number of additional new, but less effective, oral LDL-C-lowering agents are also in various stages of development, including some which are targeted only to patients with homozygous familial hypercholesterolemia.

PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. FUNDING: Amgen Inc.