9 research outputs found
Immunogenicity of a first dose of mRNA- or vector-based SARS-CoV-2 vaccination in dialysis patients: a multicenter prospective observational pilot study
Background!#!Dialysis patients are at risk for lower SARS-CoV-2-vaccine immunogenicity than the normal population. We assessed immunogenicity to a first mRNA- or vector-based SARS-CoV-2-vaccination dose in dialysis patients.!##!Methods!#!In a multicenter observational pilot study, 2 weeks after a first vaccination (BNT162b2/Pfizer-BioNTech [Comirnaty] or ChAdOx1 nCoV-19/Oxford-Astra-Zeneca [Vaxzevria]), hemodialysis patients (N = 23), peritoneal dialysis patients (N = 4) and healthy staff (N = 14) were tested for SARS-CoV-2-spike IgG/IgM, Nucleocapsid-protein-IgG-antibodies and plasma ACE2-receptor-binding-inhibition capacity. Hemodialysis patients who had had prior COVID-19 infection (N = 18) served as controls. Both response to first SARS-CoV-2 vaccination and IgG spike-positivity following prior COVID-19 infection were defined as SARS-CoV-2 spike IgG levels ≥ 50 AU/mL.!##!Results!#!Vaccination responder rates were 17.4% (4/23) in hemodialysis patients, 100% (4/4) in peritoneal dialysis patients and 57.1% (8/14) in staff (HD vs. PD: p = 0.004, HD vs. staff: p = 0.027). Among hemodialysis patients, type of vaccine (Comirnaty N = 11, Vaxzevria N = 12, 2 responders each) did not appear to influence antibody levels (IgG spike: Comirnaty median 0.0 [1.-3. quartile 0.0-3.8] versus Vaxzevria 4.3 [1.6-20.1] AU/mL, p = 0.079). Of responders to the first dose of SARS-CoV-2 vaccination among hemodialysis patients (N = 4/23), median IgG spike levels and ACE2-receptor-binding-inhibition capacity were lower than that of IgG spike-positive hemodialysis patients with prior COVID-19 infection (13/18, 72.2%): IgG spike: median 222.0, 1.-3. quartile 104.1-721.9 versus median 3794.6, 1.-3. quartile 793.4-9357.9 AU/mL, p = 0.015; ACE2-receptor-binding-inhibition capacity: median 11.5%, 1.-3. quartile 5.0-27.3 versus median 74.8%, 1.-3. quartile 44.9-98.1, p = 0.002.!##!Conclusions!#!Two weeks after their first mRNA- or vector-based SARS-CoV-2 vaccination, hemodialysis patients demonstrated lower antibody-related response than peritoneal dialysis patients and healthy staff or unvaccinated hemodialysis patients following prior COVID-19 infection
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APABETALONE, A SELECTIVE BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR, REDUCES SERUM FGF23 IN CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE PATIENTS
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BET PROTEIN INHIBITION AND COGNITION: A PRE-SPECIFIED SUBSTUDY OF THE BETONMACE PHASE 3 TRIAL EVALUATING APABETALONE IN PATIENTS WITH DIABETES AND ACUTE CORONARY SYNDROME
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Apabetalone lowers serum alkaline phosphatase and improves cardiovascular risk in patients with cardiovascular disease.
BACKGROUND AND AIMS:In patients with cardiovascular disease, considerable residual risk remains despite evidence-based secondary prevention measures. Alkaline phosphatase (ALP) has been suggested as a modifiable cardiovascular risk factor. We sought to determine whether cardiovascular risk reduction by the bromodomain and extra-terminal (BET) protein inhibitor apabetalone is associated with the concomitant lowering of serum ALP. METHODS:In a post-hoc analysis of 795 patients with established coronary heart disease and statin treatment, who participated in phase 2 placebo-controlled trials of apabetalone, we determined the effect of assigned treatment for up to 24 weeks on the incidence of major adverse cardiovascular events (MACE) and serum ALP. RESULTS:Baseline ALP (median 72 U/L) predicted MACE (death, non-fatal myocardial infarction, coronary revascularization, or hospitalization for cardiovascular causes), independent of high-sensitivity C-reactive protein (hsCRP), sex, age, race, study, cardiovascular risk factors, chronic kidney disease (CKD), liver function markers and treatment allocation (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.19-2.16, p = 0.002). Mean placebo-corrected decreases in ALP from baseline were 9.2% (p < 0.001) after 12-14 weeks and 7.7% (p < 0.001) after 24-26 weeks of apabetalone treatment. In the apabetalone group, a 1-SD reduction in ALP was associated with a HR for MACE of 0.64 (95% CI 0.46-0.90, p = 0.009). CONCLUSIONS:Serum ALP predicts residual cardiovascular risk, independent of hsCRP, established cardiovascular risk factors and CKD, in patients with cardiovascular disease on statin treatment. Apabetalone lowers serum ALP, which was associated with a lower risk of cardiovascular events. Whether the beneficial cardiovascular effects of apabetalone are causally related to ALP reduction remains undetermined
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APABETALONE, AN INHIBITOR OF BET PROTEINS, IMPROVES CARDIOVASCULAR RISK AND REDUCES ALKALINE PHOSPHATASE IN BOTH CVD PATIENTS AND PRIMARY HUMAN CELL CULTURE SYSTEMS
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APABETALONE, A BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR, REDUCES ALKALINE PHOSPHATASE IN CVD PATIENTS, IN MICE, AND IN CELL CULTURE SYSTEMS
Abstract
Background and Aims
Elevated serum alkaline phosphatase (ALP) independently predicts major adverse cardiac events (MACE) by contributing to vascular calcification and endothelial dysfunction arising in chronic kidney disease (CKD) and cardiovascular disease (CVD). Apabetalone is an orally active inhibitor of bromodomain and extraterminal (BET) proteins – epigenetic readers that modulate gene expression involved in vascular inflammation and calcification. Here we examined apabetalone’s effects on ALP post-hoc in recent clinical trials, then performed mechanistic studies into apabetalone’s impact on tissue non-specific ALP (TNALP) expression in mice and cell culture.
Method
Serum ALP was determined in CVD patients in phase 2 trials (3 month ASSERT and 6 month SUSTAIN & ASSURE) and in the phase 3 BETonMACE CVD outcomes trial, including subpopulations with CKD (eGFR<60 mL/min/1.73m2). Apabetalone’s effect on expression of TNALP (gene symbol ALPL) was examined in mice, cultured primary human hepatocytes (PHH), HepaRG, HepG2, vascular smooth muscle cells (VSMCs), and vascular endothelial cells by real-time PCR. TNALP protein levels were assessed by immunoblots and flow cytometry. ALP enzyme activity was measured in enzymatic assays.
Results
In phase 2 trials, baseline serum ALP independently predicted MACE (hazard ratio [HR] 1.6, 95% CI 1.2-2.2, p=0.001). In the 3 month ASSERT trial, apabetalone dose dependently reduced serum ALP (p<0.001 vs placebo). Prominent reductions in ALP were apparent in patients on apabetalone (n=331) vs placebo (n=166) in combined analysis of the ASSURE & SUSTAIN trials (median % change -11 vs -3.2; p<0.001). In the subset with CKD, patients on apabetalone (n=69) had greater reduction in serum ALP than placebo (n=22; p=0.008). Strikingly, ALP reductions in phase 2 correlated with reduction in MACE (HR 0.58, 95% CI 0.44-0.77, p<0.001). Consistent with phase 2, BETonMACE saw serum ALP reduced by 6.8 U/L with apabetalone (n=1082) vs placebo (n=1070; p<0.001) at 24 weeks. At the conclusion of BETonMACE, fewer MACE occurred in the CKD subgroup with apabetalone (n=124) vs placebo (n=164; HR 0.50 95% CI 0.26-0.96 p=0.032). Neither apabetalone nor statins that control low-density lipoprotein cholesterol inhibited recombinant TNALP enzyme activity, implying that decreased serum ALP activity in patients reflected reduction in TNALP production rather than inhibition of the enzyme.
Liver-derived TNALP accounts for ≈50% of circulating ALP. In the liver of mice on high fat diet, apabetalone or JQ1 (BET inhibitors with different chemical scaffolds) reduced Alpl mRNA (p<0.001) with corresponding trends in TNALP activity. In PHH, HepaRG, & HepG2 cells, apabetalone dose dependently suppressed ALPL expression by 60-80%. In HepG2 cells, apabetalone reduced TNALP protein (>55%, p<0.001), enzyme activity (> 40%; p<0.001), and % of TNALP positive cells (15-30%; p<0.001). MZ1, which promotes degradation of BET proteins, downregulated ALPL / TNALP similar to apabetalone. In VSMCs, apabetalone or JQ1 suppressed ALPL gene expression, TNALP protein levels, and enzyme activity, leading to decreases in extracellular calcium deposition. In addition, apabetalone downregulated ALPL expression in human aortic, umbilical vein, and brain microvascular endothelial cells by 50-70%.
Conclusion
Apabetalone lowers serum ALP in clinical trials, which is consistent with reduced hepatic production of TNALP - the most abundant ALP isoform. Further, apabetalone downregulates ALPL gene expression in vascular cell types while reducing calcification. Together, BET-dependent epigenetic modulation of ALP by apabetalone can affect several pathogenetic processes, and thereby improve cardiovascular outcomes. This study provides insights to the CVD event reductions observed in the CKD subpopulation in the BETonMACE Phase 3 trial
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