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.

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.

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week.

The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research. With these needs in mind, participants in a Cardiac Safety Research Consortium Think Tank proposed the development of international guidance in this area, together with improved quality assurance and analytical methods, to determine what biomarkers can reliably show. Participants recommended the development of systematic methods for sample collection, and the archiving of samples in all cardiovascular clinical trials (including creation of a biobank or repository). The academic and regulatory communities also agreed to work together to ensure that published information is fully and clearly expressed.

NaPi-IIb Inhibition for Hyperphosphatemia in CKD Hemodialysis Patients.

INTRODUCTION: Chronic kidney disease (CKD) has a prevalence of 9.1% globally, and frequently results in elevated serum phosphate, increasing cardiovascular morbidity and mortality risk in hemodialysis (HD) patients. DS-2330b, an oral NaPi-IIb inhibitor, reduced intestinal phosphate absorption in preclinical studies, but its effect in patients with CKD is unknown. This 2-part, randomized, placebo- and active-controlled, single- and repeated-dose, phase 1b study evaluated safety and efficacy of DS-2330b in patients with CKD on HD. METHODS: Part A, a 2-period, 2-way study, evaluated safety and pharmacokinetics of DS-2330b 250 mg in solution and tablet formulations. Part B assessed the safety of DS-2330b in solution (chosen based on results of part A) and its effect on serum phosphate. Patients were randomized to placebo 3 times daily (TID), DS-2330b 400 mg TID, DS-2330b 400 mg with sevelamer 1.6 g TID, and sevelamer 1.6 g with placebo TID for 14 days. Safety endpoints included adverse event (AE) monitoring. RESULTS: Six patients completed part A. Two patients experienced serious AEs considered unrelated to DS-2330b treatment. Thirty-two patients enrolled and completed part B. Serum phosphate mean change from baseline ± SD was -2.2±1.5 mg/dl versus -1.9 ± 1.1 mg/dl for DS-2330b monotherapy versus placebo. Patients receiving DS-2330b with sevelamer or sevelamer with placebo experienced the greatest serum phosphate decrease from baseline. Nine patients (28.1%) experienced ≥1 treatment-emergent AE (TEAE); 7 patients experienced drug-related TEAEs. The TEAE incidence was comparable between DS-2330b and control groups. CONCLUSIONS: DS-2330b, alone or in combination with sevelamer, was safe and well tolerated but did not demonstrate clinically meaningful efficacy in HD patients.

Safety and Pharmacokinetics of DS-1040 Drug-Drug Interactions With Aspirin, Clopidogrel, and Enoxaparin.

DS-1040, a novel low-molecular-weight inhibitor of activated thrombin-activatable fibrinolysis inhibitor, is under development for the treatment of thromboembolic diseases including venous thromboembolism and acute ischemic stroke. Here we describe the results of 3 studies that evaluated the safety and tolerability of DS-1040 along with the effect on DS-1040 pharmacokinetic (PK) parameters, when dosed alone or when coadministered with aspirin (NCT02071004), clopidogrel (NCT02560688), or enoxaparin in healthy subjects. Concomitant administration of single-dose DS-1040 with multiple-dose aspirin, multiple-dose clopidogrel, or single-dose enoxaparin, consistent with clinically relevant dose regimens, was safe and well tolerated with no serious treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, bleeding-related TEAEs, and no significant changes in coagulation parameters. DS-1040 did not prolong bleeding time when administered concomitantly with aspirin or clopidogrel. In the aspirin study, DS-1040 PK was evaluated following the concomitant administration with multiple-dose aspirin, where the plasma DS-1040 exposure (peak plasma concentration [Cmax ] and area under the concentration-time curve [AUCinf ]) was to be similar to the data previously published in the first-in-human study of DS-1040 in healthy subjects. The PK parameters of DS-1040 coadministered with clopidogrel were similar to those of DS-1040 alone, with small increases in geometric means for Cmax (7%) and AUClast (9%). When coadministered with enoxaparin, the PK parameters of DS-1040 were not affected (1.1% and 1.5% decreases in geometric means for Cmax and AUClast , respectively). Therefore, concomitant administration of DS-1040 and clopidogrel or enoxaparin did not demonstrate PK drug-drug interactions.

Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE): Protocol and preliminary data.

Chronic obstructive pulmonary disease (COPD) is a multisystem disease. Established comorbidities include cardiovascular disease, osteoporosis, loss of muscle mass and function, depression, and impaired quality of life. The natural history is not well understood. The Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE) is a longitudinal study of comorbidities in COPD. The primary aims are to delineate the progression and interrelationships of cardiovascular disease and associated comorbidities. Each year ARCADE aims to recruit 250 patients diagnosed with COPD and 50 comparators (free from respiratory disease). Assessments include spirometry, body composition, blood pressure, aortic stiffness (pulse wave velocity (PWV)), noninvasive measures of cardiac output, systemic inflammatory mediators, blood and urine biochemistry, and physical and health outcomes. These will be repeated at 2 and 5 years. In the first year of recruitment, 350 patients and 100 comparators were recruited. The reproducibility of aortic PWV, cardiac output, stroke volume, and cardiac index was evaluated and accepted in 30 patients free from overt cardiovascular disease. The preliminary data from ARCADE have demonstrated acceptable reproducibility of hemodynamic outcome measures. Further longitudinal data collection will increase knowledge of the progression and interactions between cardiovascular risk factors and other comorbidities in COPD.

An international matched cohort study of the contribution of metabolic impairments to subclinical atherosclerosis in United Kingdom and Jamaican African-Caribbeans.

BACKGROUND: A gradient of increased vascular risk exists across the African diaspora. We hypothesised that increased insulin resistance with environmental transition contributes to this risk. METHODS: The study was undertaken in 73 healthy African-Caribbeans in the UK and 151 age and sex matched African-Caribbeans in Jamaica. Body mass index (BMI), fasting insulin, insulin resistance, carotid intima media thickness (CIMT) and endothelium dependent vasodilatation (EDV) were compared. CIMT was measured ultrasonographically in the distal 1cm of both common carotid arteries. EDV was measured the absolute change from baseline in the Reflection index (RI) of the digital volume pulse during intravenous infusion of albuterol (DeltaRI(ALB)). RESULTS: UK African-Caribbeans had greater CIMT (mean difference 0.124 [95% C.I. 0.075-0.173] mm, p<0.0001) and decreased EDV (mean difference in DeltaRI(ALB) 5.1 [95% C.I. 2.5-7.6] percentage points, p<0.0001). This was associated with higher insulin concentrations (mean difference 1.6 [95% C.I. 1.3-4.1] microU/mL, p=0.038) and greater HOMA score (2.8 versus 2.0; p=0.035) despite no significant differences in BMI (28.8 versus 27.6; p=0.168) or the waist to hip ratio (0.86 versus 0.85; p=0.188). HOMA scores correlated positively with CIMT (r=0.35, p=0.01) and negatively with DeltaRI(ALB) (r=-0.17; p=0.02) in UK, but not in Jamaican, African-Caribbeans. A significant interaction was seen between HOMA and UK domicile for CIMT (p<0.0001) and between fasting insulin and UK domicile for DeltaRI(ALB) (p<0.0001). CONCLUSIONS: Increased insulin resistance, associated with living in a nutritionally enriched environment, may contribute to early subclinical atherosclerosis in UK African-Caribbeans.

Assessment of endothelial function: comparison of the pulse wave response to beta 2-adrenoceptor stimulation with flow mediated dilatation.

AIMS: To assess the reproducibility of the digital pulse wave response to beta(2)-adrenoreceptor stimulation and to determine if an attenuated response to beta(2)-adrenoceptor stimulation is associated with impaired flow mediated dilatation (FMD). METHODS: Subjects (n = 20) with endothelial dysfunction (ED), were compared with healthy control subjects (n = 20). Change in reflection index (Delta RI) of the digital volume pulse in response to salbutamol (SALB, 5 microg min(-1) i.v) and to nitroglycerin (NTG, 5 microg min(-1) i.v) was used to assess endothelium-dependent (Delta RI(SALB)) and endothelium-independent (Delta RI(NTG)) pressure wave reflection. Delta RI(SALB) was assessed on two occasions to examine reproducibility. High resolution ultrasound of the brachial artery was used to measure FMD and also dilation to NTG (NTGD). RESULTS: The mean difference in Delta RI(SALB) between two visits was -0.2%, with SD of the difference 4.9%. Both Delta RI(SALB) and FMD were impaired in subjects with ED compared with values in control subjects (5.0 +/- 0.7 vs. 11.3 +/- 1.2%, mean values +/- SEM, P < 0.01 and 4.2 +/- 0.6 vs. 7.5 +/- 0.8%, P < 0.02 for Delta RI(SALB) and FMD, respectively), whereas Delta RI(NTG) and NTGD were similar in the two groups. Delta RI(SALB) was correlated with FMD (r = 0.44, P < 0.01) and had 88% sensitivity and 79% specificity to detect abnormal (FMD < 4%). CONCLUSIONS: The pulse wave response to a beta(2)-adrenoceptor agonist correlates with FMD and has high sensitivity and specificity in detecting abnormal endothelial function as defined by FMD. However, FMD is the preferred test to detect effects of interventions on endothelial function.

The vascular effects of metabolic impairment clusters in subjects of different ethnicities.

BACKGROUND: Although metabolic syndrome affects vascular function, the impact of individual impairments and their clustering is unclear. OBJECTIVE: To assess the vascular impact of metabolic impairments before they reach treatment thresholds in different ethnic groups. METHODS: Metabolic variables, inflammatory markers, endothelium dependent vasodilatation (EDV) and carotid intima media thickness (CIMT) were measured in population samples of 82 Caucasians and 78 matched Afro-Caribbeans with no vascular disease. Insulin resistance was assessed using homeostasis model assessment (HOMA-IR). EDV was measured as the change in the height of the inflection point of the digital volume pulse following intravenous infusion of 5 mcg/min of albuterol (DeltaRIDeltaLB). Regression models were used to investigate the independent effects of metabolic impairment clusters and their interaction with ethnicity on EDV and CIMT. RESULTS: HOMA-IR (2.4-3.8, p < 0.0001), IL-6 levels (1.1-2.8 pg/mL, p = 0.02) and CIMT (0.71-0.83 mm, p = 0.009) increased whereas in DeltaRIBASELINE (77.6-72.9 percentage points, p < 0.0001) and DeltaRIDeltaLB (15.5-7.1 percentage points, p < 0.0001) decreased with the number of metabolic impairments present. DeltaRIDeltaLB decreased by 1.6 (95% CI 0.2-3.7) percentage points and CIMT increased by 0.06 (95% CI 0.02-0.10) mm for each metabolic impairment present after adjusting for age, gender, ethnicity and HOMA-IR. There were significant interactions between Afro-Caribbean ethnicity and metabolic impairments for IL-6 (p = 0.037) and DeltaRIDeltaLB (p = 0.002). CONCLUSIONS: Clustering of metabolic impairments is associated with inflammatory activation, impaired EDV and increased CIMT even before reaching treatment thresholds for individual impairments. This effect was more marked in Afro-Caribbean subjects.

The role of inheritance and environment in predisposition to vascular disease in people of African descent.

OBJECTIVES: This study sought to compare vascular reactivity and carotid intima media thickness (CIMT) between Afro-Caribbean people in the United Kingdom (UK) and the West Indies and Afro-Caribbean and Caucasian people in the UK. BACKGROUND: Attenuated vascular reactivity and increased CIMT in black patients is seen as evidence for predisposition to vascular disease, but no comparisons exist between Afro-Caribbean people in different settings, which can provide insight into non-inherited determinants of increased ethnic susceptibility. METHODS: A representative community sample of 81 healthy Afro-Caribbean people and 101 Caucasian people in the UK was compared with 197 matched Afro-Caribbean people in Jamaica. Small vessel reactivity was assessed by measuring the absolute change from baseline in the reflection index (RI) of the digital volume pulse during intravenous infusion of albuterol (5 microg/min, DeltaRI(ALB)) and glyceryl trinitrate (5 microg/min, DeltaRI(GTN)). The CIMT was measured ultrasonographically in the distal 1 cm of the common carotid artery. RESULTS: Mean DeltaRI(ALB) was 4.2 percentage points (95% confidence interval [CI], 2.3 to 6.1, p < 0.001) lower in UK Afro-Caribbean people compared with Jamaican Afro-Caribbean people and 2.6 percentage points (95% CI, 0.4 to 4.7, p = 0.02) lower compared with Caucasian people, after adjusting for vascular risk profile. Adjusted mean CIMT of UK Afro-Caribbean people was 0.13 mm (95% CI, 0.08 to 0.17, p < 0.001) greater compared with Jamaican Afro-Caribbean people and 0.05 mm (95% CI, 0.01 to 0.10, p = 0.02) greater compared with Caucasian people. CONCLUSIONS: Healthy UK Afro-Caribbean people have greater and Jamaican Afro-Caribbean people have less impairment of vascular reactivity and intima media thickness compared with UK Caucasian people, suggesting that potentially modifiable environmental interactions may contribute to excess vascular disease in Afro-Caribbean people.

Ethnic differences in arterial responses and inflammatory markers in Afro-Caribbean and Caucasian subjects.

OBJECTIVE: Small vessel disease is more common in Afro-Caribbeans than Caucasians. We investigated underlying differences in metabolic, inflammatory, and vascular responses that may predispose Afro-Caribbeans to small vessel pathology. METHODS AND RESULTS: Seventy-eight Afro-Caribbeans aged 35-75 years, with no vascular disease or medications, were compared with 82 matched Caucasians for metabolic variables, fasting insulin, interleukin 6, tumor necrosis factor (TNF) alpha, and cytoplasmic repressor protein levels. Carotid intima media thickness (CIMT) was measured ultrasonographically. Small vessel function was assessed by measuring the absolute change from baseline in the reflectance index (RI) of the digital volume pulse during IV infusion of albuterol (5 microg/min, DeltaRIALB) and glyceryl tri nitrate (5 microg/min, DeltaRIGTN). Large artery elasticity was measured as the stiffness index (SI) and derived from the time to pulse wave reflection adjusted for subject height. Afro-Caribbeans had significantly higher diastolic blood pressure (80.3 versus 77.6 mm Hg; P=0.033), fasting insulin (14.0 versus 10.6 microU/mL; P=0.026), TNF-alpha (6.7 versus 4.3; pg/mL; P=0.001), and interleukin 6 (2.3 versus 1.5 pg/mL; P=0.036) levels compared with Caucasians. CIMT was greater (0.81+/-0.20 versus 0.75+/-0.18 mm; P=0.02) and small vessel reactivity attenuated (mean DeltaRIALB 6.8+/-8.0% versus 12.3+/-8.%; P<0.0001) in Afro-Caribbeans, but their large artery elasticity (mean index of large artery stiffness 9.9 versus 9.7 m/s; P=0.48) was comparable with Caucasians. CIMT was independently associated with an index of large artery stiffness (beta=0.03; P=0.002) in Caucasians but not in Afro-Caribbeans. There were independent relationships among Afro-Caribbean ethnicity, TNF-alpha, and insulin levels. CONCLUSIONS: Selective impairment of small artery function may contribute to excess small vessel disease in Afro-Caribbeans.