-
1.
Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial.
Deedwania, P, Murphy, SA, Scheen, A, Badariene, J, Pineda, AL, Honarpour, N, Keech, AC, Sever, PS, Pedersen, TR, Sabatine, MS, et al
JAMA cardiology. 2021;(2):139-147
-
-
Free full text
-
Abstract
IMPORTANCE The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk. OBJECTIVE To investigate outcomes with evolocumab in patients with and without MetS. DESIGN, SETTING, AND PARTICIPANTS The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. INTERVENTIONS Patients were randomized to evolocumab or placebo. MAIN OUTCOMES AND MEASURES The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. RESULTS Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 [18-44] mg/dl; P < .001). For the primary end point, the hazard ratios (95% CI) with evolocumab vs placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (P for interaction = .39). For the key secondary end point, the corresponding hazard ratios (95% CIs) were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (P for interaction = .23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS. CONCLUSIONS AND RELEVANCE Patients with atherosclerotic cardiovascular disease and MetS have substantial residual risk of cardiovascular events despite statin therapy. Evolocumab significantly reduced low-density lipoprotein cholesterol and cardiovascular risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease and MetS is safe and efficacious to reduce residual cardiovascular risk. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01764633.
-
2.
Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus.
Casey, KA, Smith, MA, Sinibaldi, D, Seto, NL, Playford, MP, Wang, X, Carlucci, PM, Wang, L, Illei, G, Yu, B, et al
Arthritis & rheumatology (Hoboken, N.J.). 2021;(3):459-471
Abstract
OBJECTIVE Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo. METHODS Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. RESULTS Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05). CONCLUSION These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.
-
3.
Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.
Salama, C, Han, J, Yau, L, Reiss, WG, Kramer, B, Neidhart, JD, Criner, GJ, Kaplan-Lewis, E, Baden, R, Pandit, L, et al
The New England journal of medicine. 2021;(1):20-30
-
-
Free full text
-
Abstract
BACKGROUND Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).
-
4.
Biologic Treatment in Combination with Lifestyle Intervention in Moderate to Severe Plaque Psoriasis and Concomitant Metabolic Syndrome: Rationale and Methodology of the METABOLyx Randomized Controlled Clinical Trial.
Pinter, A, Schwarz, P, Gerdes, S, Simon, JC, Saalbach, A, Rush, J, Melzer, N, Kramps, T, Häberle, B, Reinhardt, M
Nutrients. 2021;(9)
Abstract
Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients' health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.
-
5.
Effect of alirocumab on coronary plaque in patients with coronary artery disease assessed by optical coherence tomography.
Gao, F, Wang, ZJ, Ma, XT, Shen, H, Yang, LX, Zhou, YJ
Lipids in health and disease. 2021;(1):106
Abstract
BACKGROUND Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have been demonstrated to produce significantly greater reduction in LDL cholesterol levels and cardiovascular events than standard statin therapy. However, evidence on the impact of PCSK9 inhibitors on coronary plaque composition and morphology is limited. METHODS In this open-label randomized study, eligible patients with intermediate coronary lesions and elevated LDL cholesterol values were randomized to either alirocumab 75 mg Q2W plus statin (atorvastatin 20 mg/day or rosuvastatin 10 mg/day) therapy or standard care. Optical coherence tomography (OCT) assessments for target lesions were obtained at baseline and at 36 weeks of follow-up. RESULTS LDL cholesterol levels were significantly decreased in both the alirocumab and standard care arms, whereas the absolute reduction in LDL cholesterol was significantly greater in patients treated with alirocumab (1.72 ± 0.51 vs. 0.96 ± 0.59, P < 0.0001). Compared with standard care, the addition of alirocumab to statins was associated with significantly greater increases in minimum fibrous cap thickness (18.0 [10.8-29.2] μm vs 13.2 [7.4-18.6] μm; P = 0.029), greater increases in minimum lumen area (0.20[0.10-0.33] mm2 vs 0.13 [0.12-0.24] mm2; P = 0.006) and a greater diminution in maximum lipid arc (15.1̊ [7.8-24.5] vs. 8.4̊ [2.0-10.5]; P = 0.008). CONCLUSIONS The addition of alirocumab to statins can not only provide additional LDL cholesterol lowering effects but also have a potential role in promoting a more stable plaque phenotype. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04851769 . Registered 2 Mar 2019.
-
6.
Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer.
Keenan, TE, Guerriero, JL, Barroso-Sousa, R, Li, T, O'Meara, T, Giobbie-Hurder, A, Tayob, N, Hu, J, Severgnini, M, Agudo, J, et al
Nature communications. 2021;(1):5563
Abstract
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.
-
7.
Epithelial Cell Biomarkers Are Predictive of Response to Biologic Agents in Crohn's Disease.
Osterman, MT, VanDussen, KL, Gordon, IO, Davis, EM, Li, K, Simpson, K, Ciorba, M, Glover, SC, Abraham, B, Guo, X, et al
Inflammatory bowel diseases. 2021;(5):677-685
-
-
Free full text
-
Abstract
BACKGROUND Therapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohn's disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ) and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis, with respect to response to VDZ. METHOD Ileal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST. In a 5-center academic retrospective cohort of CD patients, ileal MVL was analyzed to determine its predictive value for response to VDZ. Correlation between ileal MVL and IEC pyroptosis was determined, and the discriminant ability of the combination of 2 biomarkers to VDZ was examined. RESULTS Clinical response in UST was significantly higher than placebo (65% vs 39%; P = 0.03), with patients with normal MVL (>1.7 µm) having the greatest therapeutic effect: 85% vs 20% (P = 0.02). For VDZ, clinical response with MVL of 1.35 to 1.55 µm was 82% vs 44% (<1.35 µm) and 40% (>1.55 µm; P = 0.038). There was no correlation between ileal MVL and IEC pyroptosis. The combination criteria of ileal pyroptosis <14 positive cells/1000 IECs or MVL of 1.35 to 1.55 µm could identify 84% of responders and 67% of nonresponders (P = 0.001). CONCLUSION Ileal MVL was predictive of response to UST and VDZ in prospective and retrospective CD cohorts. It was independent of ileal IEC pyroptosis, and combination of the 2 biomarkers enhanced the discriminate ability of responders from nonresponders to VDZ.
-
8.
Effects of the PCSK9 antibody alirocumab on coronary atherosclerosis in patients with acute myocardial infarction: a serial, multivessel, intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography imaging study-Rationale and design of the PACMAN-AMI trial.
Zanchin, C, Koskinas, KC, Ueki, Y, Losdat, S, Häner, JD, Bär, S, Otsuka, T, Inderkum, A, Jensen, MRJ, Lonborg, J, et al
American heart journal. 2021;:33-44
Abstract
BACKGROUND The risk for cardiovascular adverse events after acute myocardial infarction (AMI) remains high despite potent medical treatment including low-density lipoprotein cholesterol (LDL-C) lowering with statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies substantially reduce LDL-C when added to statin. Alirocumab, a monoclonal antibody to PCSK9, reduces major adverse cardiovascular events after AMI. The effects of alirocumab on coronary atherosclerosis including plaque burden, plaque composition and fibrous cap thickness in patients presenting with AMI remains unknown. AIMS To determine the effect of LDL-C lowering with alirocumab on top of high-intensity statin therapy on intravascular ultrasound (IVUS)-derived percent atheroma volume (PAV), near-infrared spectroscopy (NIRS)-derived maximum lipid core burden index within 4 mm (maxLCBI4 mm) and optical coherence tomography (OCT)-derived fibrous cap thickness (FCT) in patients with AMI. METHODS In this multicenter, double-blind, placebo-controlled trial, 300 patients with AMI (ST-elevation or non-ST-elevation myocardial infarction) were randomly assigned to receive either biweekly subcutaneous alirocumab (150 mg) or placebo beginning <24 hours after the acute event as add-on therapy to rosuvastatin 20 mg. Patients undergo serial IVUS, NIRS and OCT in the two non-infarct related arteries at baseline (at the time of treatment of the culprit lesion) and at 52 weeks. The primary endpoint, change in IVUS-derived PAV, and the powered secondary endpoints, change in NIRS-derived maxLCBI4 mm, and OCT-derived minimal FCT, will be assessed 52 weeks post randomization. SUMMARY The PACMAN-AMI trial will determine the effect of alirocumab on top of high-intensity statin therapy on high-risk coronary plaque characteristics as assessed by serial, multimodality intracoronary imaging in patients presenting with AMI. CLINICAL TRIAL REGISTRATION NCT03067844.
-
9.
Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis.
Verweyen, EL, Pickering, A, Grom, AA, Schulert, GS
Arthritis & rheumatology (Hoboken, N.J.). 2021;(7):1334-1340
-
-
Free full text
-
Abstract
OBJECTIVE Canakinumab is a human anti-interleukin-1β (anti-IL-1β) blocking agent that effectively neutralizes IL-1β-mediated signaling for treatment of systemic juvenile idiopathic arthritis (JIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there are currently no validated clinical or immunologic predictors of response. We undertook this study to characterize distinct gene signatures for treatment response and nonresponse to canakinumab in systemic JIA patients. METHODS We performed a secondary analysis of whole-blood gene expression microarrays using blood samples obtained from healthy controls and systemic JIA patients at baseline and on day 3 after canakinumab treatment (GEO accession no. GSE80060). Patients were considered strong clinical responders if they met the ACR90 response (exhibited ≥90% improvement in the American College of Rheumatology [ACR] JIA response criteria; nonresponders were those who met ACR30 [exhibiting ≤30% improvement in the ACR JIA response criteria]). A random-effects model with patient identity as the random variable was used for differential expression analysis. RESULTS We identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to nonresponders, mediated by up-regulation of neutrophil- and IL-1-associated genes and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identified a signature including up-regulated CD163 expression that was associated with canakinumab nonresponse. Intriguingly, canakinumab treatment induced either up- or down-regulation of type I interferon (IFN) genes, independent of clinical response. CONCLUSION Here, we identify a gene signature in systemic JIA patients prior to receiving treatment that distinguishes strong responders to canakinumab from nonresponders. Further prospective studies are needed to assess the utility of these insights for treatment decisions in systemic JIA and to track the association of up-regulated type I IFN signatures with systemic JIA complications.
-
10.
IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.
Ridker, PM, Devalaraja, M, Baeres, FMM, Engelmann, MDM, Hovingh, GK, Ivkovic, M, Lo, L, Kling, D, Pergola, P, Raj, D, et al
Lancet (London, England). 2021;(10289):2060-2069
Abstract
BACKGROUND IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction. METHODS RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117. FINDINGS Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were -66·2% for the 7·5 mg group, -77·7% for the 15 mg group, and -87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. INTERPRETATION Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. FUNDING Novo Nordisk.