ABSTRACT
BACKGROUND: The VICTORIA trial (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) demonstrated that, in patients with high-risk heart failure, vericiguat reduced the primary composite outcome of cardiovascular death or heart failure hospitalization relative to placebo. The hazard ratio for all-cause mortality was 0.95 (95% CI, 0.84-1.07). In a prespecified analysis, treatment effects varied substantially as a function of baseline NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, with survival benefit for vericiguat in the lower NT-proBNP quartiles (hazard ratio, 0.82 [95% CI, 0.69-0.97]) and no benefit in the highest NT-proBNP quartile (hazard ratio, 1.14 [95% CI, 0.95-1.38]). An economic analysis was a major secondary objective of the VICTORIA research program. METHODS: Medical resource use data were collected for all VICTORIA patients (N=5050). Costs were estimated by applying externally derived US cost weights to resource use counts. Life expectancy was projected from patient-level empirical trial survival results with the use of age-based survival modeling methods. Quality-of-life adjustments were based on prospectively collected EQ-5D-based utilities. The primary outcome was the incremental cost-effectiveness ratio, comparing vericiguat with placebo, assessed from the US health care sector perspective over a lifetime horizon. Cost-effectiveness was estimated using the total VICTORIA cohort, both with and without interaction between treatment and baseline NT-proBNP. RESULTS: Life expectancy modeling results varied according to whether the observed heterogeneity of treatment effect by baseline NT-proBNP values was incorporated into the modeling. Including the interaction term, the vericiguat arm had an estimated quality-adjusted life expectancy of 4.56 quality-adjusted life-years (QALYs) compared with 4.13 QALYs for placebo (incremental discounted QALY, 0.43). Without the treatment heterogeneity/interaction term, vericiguat had 4.50 QALYs compared with 4.33 QALYs for placebo (incremental discounted QALY, 0.17). Incremental discounted costs (vericiguat minus placebo) were $28 546 with the treatment interaction and $20 948 without it. Corresponding incremental cost-effectiveness ratios were $66 509 per QALY allowing for treatment heterogeneity and $124 512 without heterogeneity. CONCLUSIONS: Vericiguat use in the VICTORIA trial met criteria for intermediate value, but the incremental cost-effectiveness ratio estimates were sensitive to whether the analysis accounted for observed NT-proBNP treatment effect heterogeneity. The cost-effectiveness of vericiguat was driven by the projected incremental life expectancy among patients in the lowest 3 quartiles of NT-proBNP. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.
Subject(s)
Heart Failure , Heterocyclic Compounds, 2-Ring , Humans , Cost-Benefit Analysis , Stroke Volume , Heart Failure/diagnosis , Heart Failure/drug therapy , Heterocyclic Compounds, 2-Ring/therapeutic use , Natriuretic Peptide, BrainABSTRACT
BACKGROUND: The effect of vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received intravenous diuretic therapy is unclear. METHODS: In this phase 3, randomized, double-blind, placebo-controlled trial, we assigned 5050 patients with chronic heart failure (New York Heart Association class II, III, or IV) and an ejection fraction of less than 45% to receive vericiguat (target dose, 10 mg once daily) or placebo, in addition to guideline-based medical therapy. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure. RESULTS: Over a median of 10.8 months, a primary-outcome event occurred in 897 of 2526 patients (35.5%) in the vericiguat group and in 972 of 2524 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P = 0.02). A total of 691 patients (27.4%) in the vericiguat group and 747 patients (29.6%) in the placebo group were hospitalized for heart failure (hazard ratio, 0.90; 95% CI, 0.81 to 1.00). Death from cardiovascular causes occurred in 414 patients (16.4%) in the vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06). The composite of death from any cause or hospitalization for heart failure occurred in 957 patients (37.9%) in the vericiguat group and in 1032 patients (40.9%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P = 0.02). Symptomatic hypotension occurred in 9.1% of the patients in the vericiguat group and in 7.9% of the patients in the placebo group (P = 0.12), and syncope occurred in 4.0% of the patients in the vericiguat group and in 3.5% of the patients in the placebo group (P = 0.30). CONCLUSIONS: Among patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who received vericiguat than among those who received placebo. (Funded by Merck Sharp & Dohme [a subsidiary of Merck] and Bayer; VICTORIA ClinicalTrials.gov number, NCT02861534.).
Subject(s)
Heart Failure/drug therapy , Heterocyclic Compounds, 2-Ring/therapeutic use , Pyrimidines/therapeutic use , Administration, Oral , Aged , Cardiovascular Diseases/mortality , Chronic Disease , Double-Blind Method , Female , Follow-Up Studies , Heart Failure/physiopathology , Heterocyclic Compounds, 2-Ring/adverse effects , Hospitalization/statistics & numerical data , Humans , Hypotension/chemically induced , Incidence , Male , Middle Aged , Pyrimidines/adverse effects , Soluble Guanylyl Cyclase/metabolism , Stroke Volume , Syncope/chemically induced , Ventricular Dysfunction, Left/drug therapyABSTRACT
Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review, we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for 4 new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The 4 new therapeutic classes discussed are ARNIs, SGLT2 (sodium-glucose cotransporter 2) inhibitors, soluble guanylate cyclase stimulators, and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances was informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2 inhibitors is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades and may lead to rethinking or expanding our current conceptual models for HFrEF.
Subject(s)
Heart Failure/drug therapy , Heart Failure/physiopathology , Stroke Volume , Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Biphenyl Compounds/therapeutic use , Clinical Trials, Phase III as Topic , Drug Combinations , Drug Development , Enzyme Activators/therapeutic use , Heterocyclic Compounds, 2-Ring/therapeutic use , Humans , Models, Biological , Natriuretic Peptides/metabolism , Neprilysin/antagonists & inhibitors , Pyrimidines/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Soluble Guanylyl Cyclase/metabolism , Urea/analogs & derivatives , Urea/therapeutic use , Valsartan/therapeutic use , Ventricular Remodeling/drug effects , Ventricular Remodeling/physiologyABSTRACT
The significant morbidity and mortality associated with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function. This pathway is disrupted in HF resulting in decreased protection against myocardial injury. The sGC activator cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and then reduced NO levels, but this comes at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, and then exert a more physiological action. The phase 3 VICTORIA trial found that vericiguat is safe and effective in patients with HFrEF and recent HF decompensation. Therefore, adding vericiguat may be considered in individual patients with HFrEF, particularly those at higher risk of HF hospitalization; the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF is currently unknown.
Subject(s)
Heart Failure , Heterocyclic Compounds, 2-Ring , Aminobutyrates , Biphenyl Compounds , Cyclic GMP/metabolism , Heterocyclic Compounds, 2-Ring/therapeutic use , Humans , Nitric Oxide/metabolism , Pyrimidines , Soluble Guanylyl Cyclase/metabolism , Soluble Guanylyl Cyclase/therapeutic use , Stroke Volume/physiologyABSTRACT
BACKGROUND: Over the last years, several trials offered new evidence on heart failure (HF) treatment. DESIGN AND RESULTS: For HF with reduced left ventricular ejection fraction, type 2 sodium-glucose cotransporter inhibitors, aside from sacubitril-valsartan, demonstrated extraordinary efficacy in ameliorating patients' prognosis. Some new molecules (eg vericiguat, omecamtiv mecarbil and ferric carboxymaltose) correct iron deficiency and have shown to be capable of furthering reducing the burden of HF hospitalisation. Finally, there is new evidence on the possible therapeutic approaches of HF patients with mid-range or preserved left ventricular ejection fraction. CONCLUSIONS: This review aimed to revise the main novelties in the field of HF therapy and focus on how the daily clinical approach to patient treatment is changing.
Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Cardiotonic Agents/therapeutic use , Heart Failure/drug therapy , Hospitalization/statistics & numerical data , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Vasodilator Agents/therapeutic use , Aminobutyrates/therapeutic use , Biphenyl Compounds/therapeutic use , Drug Combinations , Ferric Compounds/therapeutic use , Heart Failure/complications , Heart Failure/physiopathology , Heterocyclic Compounds, 2-Ring/therapeutic use , Humans , Iron Deficiencies/complications , Iron Deficiencies/drug therapy , Maltose/analogs & derivatives , Maltose/therapeutic use , Pyrimidines/therapeutic use , Stroke Volume/physiology , Urea/analogs & derivatives , Urea/therapeutic use , Valsartan/therapeutic use , Ventricular RemodelingABSTRACT
BACKGROUND: Sacubitril/valsartan, vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials on heart failure with reduced ejection fraction (HFrEF). METHODS: We compared the treatment arms (sacubitril/valsartan, vericiguat, and SGLT2i) with the respective control arms (standard-of-care [SOC]) through a network meta-analysis of the phase 3 trials (PARADIGM-HF, VICTORIA, DAPA-HF, EMPEROR-Reduced), a phase 2 trial on vericiguat and the HFrEF subgroup of DECLARE-TIMI 58. RESULTS: There was a trend towards decreased risk of cardiovascular (CV) death or HF hospitalization with SGLT2i than sacubitril/valsartan (HR 0.92, 95% CI 0.81 to 1.05) and vericiguat (HR 0.83, 95% CI 0.73 to 0.94). A non-significant effect of SGLT2i on CV mortality compared to sacubitril/valsartan (HR 1.04, 95% CI 0.88 to 1.24) and vericiguat (HR 0.88, 95% CI 0.63 to 1.22) was found. SGLT2i demonstrated the greatest effect on HF hospitalization (HR 0.69, 95% CI 0.62 to 0.77) over the SOC, as well as a significant benefit over vericiguat (HR 0.77, 95% CI 0.66 to 0.89), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.75 to 1.02). SGLT2i were ranked as the most effective therapy, followed by sacubitril/valsartan and vericiguat. CONCLUSIONS: Based on an indirect comparison, SGLT2i therapy is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or vericiguat. The risk of HF hospitalization does not differ significantly between patients on SGLT2i or sacubitril/valsartan, while dapagliflozin is superior to vericiguat. REGISTRATION NUMBER: PROSPERO ID 186351.
Subject(s)
Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Biphenyl Compounds/therapeutic use , Heart Failure/drug therapy , Heterocyclic Compounds, 2-Ring/therapeutic use , Pyrimidines/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Valsartan/therapeutic use , Aminobutyrates/administration & dosage , Aminobutyrates/adverse effects , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin Receptor Antagonists/adverse effects , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/adverse effects , Clinical Trials, Phase III as Topic , Drug Combinations , Heart Failure/mortality , Heterocyclic Compounds, 2-Ring/administration & dosage , Heterocyclic Compounds, 2-Ring/adverse effects , Hospitalization/statistics & numerical data , Humans , Network Meta-Analysis , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Randomized Controlled Trials as Topic , Sodium-Glucose Transporter 2 Inhibitors/administration & dosage , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Stroke Volume , Valsartan/administration & dosage , Valsartan/adverse effectsABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disease with high morbidity. Omarigliptin is a novel antidiabetic drug that inhibits dipeptidyl peptidase-4 and alleviates inflammation and insulin resistance. In the present study, the anti-inflammatory and antioxidative stress property of omarigliptin will be investigated to explore the potential therapeutic effects of omarigliptin on NAFLD in mice models. A high-fat diet (HFD) was used to induce a NAFLD model in mice. Hematoxylin-eosin staining and detection on the concentrations of total cholesterol (TC) and triglyceride (TG) were used to evaluate lipid accumulation of the liver tissues. Liver function was evaluated by measuring aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase. The insulin resistance index, the concentration of glucose, and insulin in the serum were determined. The levels of malondialdehyde and superoxide dismutase activities were detected to access the oxidative stress state. The concentrations of interleukin (IL)-1α, IL-6, and CXCL1 were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to determine the expression levels of nuclear factor kappa B (NF-κB) p65 and SIRT1 in the liver tissues. Significant elevated body weight and liver weight, marked macrovesicular steatosis combined with hepatocellular ballooning on the liver tissues, accumulated TC and TG concentrations, damaged liver function, increased oxidative stress, and elevated production of inflammatory factors were all induced with an HFD and significantly reversed by treatment with omarigliptin. Also, the activated NF-κB signaling pathway, as well as suppressed SIRT1 expression level, were significantly reversed by omarigliptin. Omarigliptin protected against NAFLD by ameliorating oxidative stress and inflammation.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Heterocyclic Compounds, 2-Ring/therapeutic use , Inflammation/prevention & control , Non-alcoholic Fatty Liver Disease/prevention & control , Oxidative Stress/drug effects , Pyrans/therapeutic use , Animals , Diet, High-Fat , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Heterocyclic Compounds, 2-Ring/pharmacology , Male , Mice , Non-alcoholic Fatty Liver Disease/metabolism , Pyrans/pharmacologyABSTRACT
Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET-inhibiting drugs on the expression of oncogenes such as c-Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2-M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775-induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775-induced DNA double-strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET-inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , DNA Breaks, Double-Stranded/drug effects , DNA End-Joining Repair/drug effects , Lung Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azepines/pharmacology , Azepines/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/genetics , Cell Line, Tumor , DNA-Binding Proteins/antagonists & inhibitors , Drug Synergism , Female , Gene Knockdown Techniques , Heterocyclic Compounds, 2-Ring/pharmacology , Heterocyclic Compounds, 2-Ring/therapeutic use , Humans , Lung Neoplasms/pathology , Mice , Piperazines/pharmacology , Piperazines/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyridazines , Pyrimidinones/pharmacology , Pyrimidinones/therapeutic use , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Triazoles/pharmacology , Triazoles/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE OF REVIEW: The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the American College of Cardiology 2020 Virtual Scientific Session (ACC.20)/World Cardiology Congress (WCC). RECENT FINDINGS: The studies reviewed include clinical trials on the efficacy and safety of alirocumab (Study in Participants with Homozygous Familial Hypercholesterolemia [ODYSSEY HoFH]) and evinacumab in the treatment of homozygous familial hypercholesterolemia (HoFH); Evaluating the Efficacy of E-cigarettes for Smoking Cessation (E3); the use of renal denervation in the treatment of hypertension (SPYRAL HTN-OFF MED PIVOTAL); and the assessment of vericiguat in the treatment of heart failure (A Study of Vericiguat in Participants with Heart Failure with Reduce Ejection Fraction [VICTORIA]). In addition, results from the pooled analysis of phase III trials on inclisiran and secondary analysis examining eicosapentaenoic acid levels and cardiovascular outcomes from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) were included. Finally, we discuss studies examining the use of polygenic risk score with low density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) on lifetime cardiovascular risk. The studies presented at the ACC.20/WCC represent notable contributions in the field of CVD prevention.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Cholesterol, LDL/blood , Denervation/methods , Eicosapentaenoic Acid/analogs & derivatives , Electronic Nicotine Delivery Systems , Heart Failure/drug therapy , Heterocyclic Compounds, 2-Ring/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , Hypertension/blood , Hypertension/surgery , Kidney/surgery , Pyrimidines/therapeutic use , Smoking Cessation/methods , Adolescent , Adult , Aged , Aged, 80 and over , Child , Eicosapentaenoic Acid/therapeutic use , Female , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , United States , Young AdultABSTRACT
Chronic obstructive pulmonary disease (COPD) is one of the most prevalent and severe diseases worldwide with high societal and health care costs. The pathogenesis of COPD is very complicated, and no curative treatment is available. Cellular senescence promotes the development of COPD. Type II alveolar epithelial cells (AECII) play a momentous role in lung tissue repair and maintenance of alveolar homeostasis. Sirtuin 1 (SIRT1), an antiaging molecule involved in the response to chronic inflammation and oxidative stress, regulates many pathophysiological changes including stress resistance, apoptosis, inflammation, and cellular senescence. This study aimed to investigate whether the pharmacological SIRT1 activator SRT2104 protects against AECII senescence in rats with emphysema. Our findings confirmed that SRT2104 administration reduced the pathological characteristics of emphysema and improved lung function parameters, including pulmonary resistance, pulmonary dynamic compliance, and peak expiratory flow. Moreover, SRT2104 treatment upregulated the expression of surfactant proteins A and C, SIRT1, and forkhead box O 3a (FoxO3a), decreased senescence-associated-ß-galactosidase (SA-ß-gal) activity, increased SIRT1 deacetylase activity, and downregulated the levels of p53 and p21. Therefore, SRT2104 administration protected against AECII senescence in rats with emphysema via SIRT1/FoxO3a and SIRT1/p53 signaling pathways and may provide a novel potential therapeutic strategy for COPD.
Subject(s)
Alveolar Epithelial Cells/drug effects , Cellular Senescence/drug effects , Heterocyclic Compounds, 2-Ring/therapeutic use , Lung Injury/prevention & control , Pulmonary Emphysema/complications , Pulmonary Emphysema/pathology , Alveolar Epithelial Cells/pathology , Animals , Disease Models, Animal , Lung Injury/etiology , Lung Injury/pathology , Male , Rats , Rats, Sprague-DawleyABSTRACT
Importance: Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life. Objective: To assess the efficacy of the oral soluble guanylate cyclase stimulator vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ). Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019. Interventions: Patients were randomized to receive vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1. Main Outcomes and Measures: The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks. Results: Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d vericiguat and placebo groups was -1.5 (95% CI, -5.5 to 2.5; P = .47) and between the 10-mg/d vericiguat and placebo groups was -0.5 (95% CI, -4.6 to 3.5; P = .80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 295.0 m and 311.8m , 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d vericiguat and placebo groups was -5.5 m (95% CI, -19.7 m to 8.8 m; P = .45) and between the 10-mg/d vericiguat and placebo groups was -1.8 m (95% CI, -16.2 m to 12.6 m; P = .81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d vericiguat group, 4.2% in the 10-mg/d vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively. Conclusions and Relevance: Among patients with HFpEF and recent decompensation, 24-week treatment with vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ. Trial Registration: ClinicalTrials.gov Identifier: NCT03547583.
Subject(s)
Exercise Tolerance/drug effects , Heart Failure/drug therapy , Heterocyclic Compounds, 2-Ring/therapeutic use , Pyrimidines/therapeutic use , Quality of Life , Administration, Oral , Aged , Double-Blind Method , Female , Guanylate Cyclase/metabolism , Heart Failure/physiopathology , Heterocyclic Compounds, 2-Ring/administration & dosage , Heterocyclic Compounds, 2-Ring/adverse effects , Hospitalization , Humans , Least-Squares Analysis , Male , Middle Aged , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Stroke Volume , Treatment Failure , Walk TestABSTRACT
Janus kinase inhibition is promising in the treatment of RA, with already two oral drugs marketed. New compounds are under investigation that are more selective for Janus kinase 1 or Janus kinase 3. Phase II results for filgotinib, upadacitinib, peficitinib and decernotinib are reviewed showing almost consistently a fast dose-dependent clinical improvement similar to already approved drugs tofacitinib and baricitinib. I will reflect on the most frequently reported dose-dependent adverse events and laboratory changes. Some are similar for all drugs of this class, some are more specific for a certain drug, but all may influence future treatment effectiveness in daily practice. This implies the need for a critical evaluation of phase III trials, and eventually trials specifically powered for conclusions on the safety profile and registries once these drugs become marketed. These innovative drugs also need head-to-head trials versus biologics or in-class as well as specific strategy studies to determine their optimal future use.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Janus Kinase Inhibitors/therapeutic use , Adamantane/analogs & derivatives , Adamantane/therapeutic use , Azetidines/therapeutic use , Heterocyclic Compounds, 2-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 3/antagonists & inhibitors , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Piperidines/therapeutic use , Purines , Pyrazoles , Pyridines/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Sulfonamides/therapeutic use , Treatment Outcome , Triazoles/therapeutic use , Valine/analogs & derivatives , Valine/therapeutic useABSTRACT
AIMS: To characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of the once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin in healthy subjects and patients with type 2 diabetes mellitus, and use these models to support the dosing recommendation for patient labelling including patients with renal impairment. METHODS: PK and PD were assessed from a total of 9827 omarigliptin concentrations collected from 1387 healthy subjects and patients participating in Phase 1, 2 and 3 studies examining single- or multiple-dose weekly administration of omarigliptin at doses ranging from 0.25 to 400 mg. Population PK and PD analyses were performed using nonlinear mixed effect modelling. RESULTS: A semi-mechanistic 2-compartment model with linear unbound clearance and concentration-dependent binding of omarigliptin to the DPP-4 enzyme in both the central and peripheral compartments adequately described omarigliptin PK. Key covariates on omarigliptin PK included reduced unbound clearance with renal impairment. A direct effect sigmoid maximum inhibitory efficacy model adequately described the relationship between omarigliptin plasma concentrations and DPP-4 inhibition. These models supported the current Japan label instructions that the approved omarigliptin 25-mg once-weekly dose be halved in patients with severe renal impairment and in those with end-stage renal disease. Also, if patients missed a dose, the next dose of omarigliptin should be taken as soon as remembered up to and including the day before the next scheduled dose. No other clinically important covariates were identified. CONCLUSION: The models in the present analysis adequately described PK and PD characteristics of omarigliptin and supported the dosing and administration section of the omarigliptin label.
Subject(s)
Diabetes Mellitus, Type 2/blood , Dipeptidyl-Peptidase IV Inhibitors/blood , Heterocyclic Compounds, 2-Ring/blood , Hypoglycemic Agents/blood , Kidney Failure, Chronic/blood , Models, Biological , Pyrans/blood , Renal Insufficiency/blood , Blood Glucose/analysis , Clinical Trials as Topic , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/blood , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dose-Response Relationship, Drug , Drug Administration Schedule , Heterocyclic Compounds, 2-Ring/administration & dosage , Heterocyclic Compounds, 2-Ring/therapeutic use , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/drug therapy , Pyrans/administration & dosage , Pyrans/therapeutic use , Renal Insufficiency/complications , Renal Insufficiency/drug therapyABSTRACT
Increasing evidence suggests that Ras-related in brain 7 (Rab7), an endosome-localized small GTPase contributes to cerebral ischemic brain injury. In the present study, we investigated the role of Rab7 in ischemic stroke-induced formation of astrogliosis and glial scar. Rats were subjected to transient middle cerebral artery occlusion (tMCAO); the rats were injected with the Rab7 receptor antagonist CID1067700 (CID). Primary astrocytes were subjected to an oxygen and glucose deprivation and reoxygenation (OGD/Re) procedure; CID was added to the cell culture media. We found that Rab7 was significantly elevated over time in both the in vivo and in vitro astrocytic injury models, and administration of CID significantly down-regulated the glial scar markers such as glial fibillary acidic protein (GFAP), neurocan and phosphacan. Moreover, administration of CID significantly attenuated the brain atrophy and improved neurologic deficits in tMCAO rats, and protected astrocytes against OGD/Re-induced injury. Further, CID downregulated the protein levels of Lamp1 and active cathepsin B in astrocytes after OGD/Re or tMCAO injury; CID inhibited the co-localization of cathepsin B and Rab7, Lamp1 and Rab7; CID decreased OGD/Re-induced increase in lysosomal membrane permeability and blocked OGD/Re-induced release of cathepsin B from the lysosome into the cytoplasm in astrocytes. Taken together, these results suggest that Rab7 is involved in ischemic stroke-induced formation of astrogliosis and glial scar. CID administration attenuates brain atrophy and improves neurologic deficits and inhibits astrogliosis and glial scar formation after ischemic stroke via reducing the activation and release of cathepsin B from the lysosome into the cytoplasm.
Subject(s)
Atrophy/drug therapy , Brain/drug effects , Gliosis/drug therapy , Heterocyclic Compounds, 2-Ring/therapeutic use , Infarction, Middle Cerebral Artery/drug therapy , Neuroprotective Agents/therapeutic use , Thiourea/analogs & derivatives , rab GTP-Binding Proteins/antagonists & inhibitors , Animals , Astrocytes/drug effects , Astrocytes/pathology , Brain/pathology , Cathepsin B/metabolism , Chondroitin Sulfate Proteoglycans/metabolism , Glial Fibrillary Acidic Protein/metabolism , Lysosomal Membrane Proteins/metabolism , Lysosomes/metabolism , Male , Neurocan , Rats, Sprague-Dawley , Receptor-Like Protein Tyrosine Phosphatases, Class 5/metabolism , Thiourea/therapeutic use , rab GTP-Binding Proteins/metabolism , rab7 GTP-Binding ProteinsABSTRACT
Oncogenic activation of protein kinase BRAF drives tumor growth by promoting mitogen-activated protein kinase (MAPK) pathway signaling. Because oncogenic mutations in BRAF occur in â¼2-7% of lung adenocarcinoma (LA), BRAF-mutant LA is the most frequent cause of BRAF-mutant cancer mortality worldwide. Whereas most tumor types harbor predominantly the BRAFV600E-mutant allele, the spectrum of BRAF mutations in LA includes BRAFV600E (â¼60% of cases) and non-V600E mutant alleles (â¼40% of cases) such as BRAFG469A and BRAFG466V The presence of BRAFV600E in LA has prompted clinical trials testing selective BRAF inhibitors such as vemurafenib in BRAFV600E-mutant patients. Despite promising clinical efficacy, both innate and acquired resistance often result from reactivation of MAPK pathway signaling, thus limiting durable responses to the current BRAF inhibitors. Further, the optimal therapeutic strategy to block non-V600E BRAF-mutant LA remains unclear. Here, we report the efficacy of the Raf proto-oncogene serine/threonine protein kinase (RAF) inhibitor, PLX8394, that evades MAPK pathway reactivation in BRAF-mutant LA models. We show that PLX8394 treatment is effective in both BRAFV600E and certain non-V600 LA models, in vitro and in vivo. PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAFV600E that promotes vemurafenib-insensitive MAPK pathway signaling. We further show that acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor. Our study provides a biological rationale and potential polytherapy strategy to aid the deployment of PLX8394 in lung cancer patients.
Subject(s)
Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , MAP Kinase Signaling System/drug effects , Mutation/genetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Enzyme Activation/drug effects , Female , Gene Knockdown Techniques , Heterocyclic Compounds, 2-Ring/adverse effects , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Heterocyclic Compounds, 2-Ring/pharmacology , Heterocyclic Compounds, 2-Ring/therapeutic use , Humans , Lung Neoplasms/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice, SCID , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Mas , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUNDS/AIMS: Bromodomain-containing protein 4 (BRD4) overexpression participates in prostate cancer progression by enhancing the transcriptional activity and expression of several key oncogenes. AZD5153 is a novel BRD4 inhibitor. METHODS: Prostate cancer cells were treated with AZD5153. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by [H3] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling was tested by Western blotting assay. The nude mice PC-3 xenograft model was applied to test AZD5153's activity in vivo. RESULTS: AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show that AKT could be the primary resistance factor of AZD5153. Pharmacological inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was further enhanced with co-treatment of the AKT specific inhibitor MK-2206. CONCLUSION: Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells.
Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Heterocyclic Compounds, 2-Ring/pharmacology , Piperazines/pharmacology , Administration, Oral , Animals , B-Cell Lymphoma 3 Protein , Cell Cycle Checkpoints/drug effects , Cell Cycle Proteins , Cyclin D1/genetics , Cyclin D1/metabolism , Down-Regulation/drug effects , Heterocyclic Compounds, 2-Ring/administration & dosage , Heterocyclic Compounds, 2-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Male , Mice , Mice, Nude , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Piperazines/administration & dosage , Piperazines/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Pyrazoles , Pyridazines , RNA Interference , RNA, Small Interfering/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Cells, CulturedABSTRACT
The development of novel anti-papillary thyroid carcinoma agents is urgent. AZD5153 is a novel and specific Bromodomain-containing protein 4 (BRD4) inhibitor. Here, we show that AZD5153 dose-dependently inhibited survival, proliferation and cell cycle progression in TPC-1â¯cells and primary human thyroid carcinoma cells. Yet, it was non-cytotoxic to the primary thyroid epithelial cells. AZD5153 induced caspase-3/-9 and apoptosis activation in TPC-1â¯cells and primary cancer cells. Its cytotoxicity in TPC-1â¯cells was significantly attenuated with co-treatment of the caspase inhibitors. BRD4 expression was elevated in TPC-1 and primary human thyroid carcinoma cells, but was low in the thyroid epithelial cells. BRD4-regulated proteins, including c-Myc, Bcl-2 and cyclin D1, were significantly downregulated following AZD5153 treatment in TPC-1 and primary cancer cells. In vivo, oral administration of AZD5153 at well-tolerated doses significantly inhibited TPC-1 xenograft growth in severe combined immunodeficient (SCID) mice. BRD4-dependent proteins, Myc, Bcl-2 and cyclin D1, were also downregulated in AZD5153-treated tumor tissues. Collectively, the results suggest that targeting BRD4 by AZD5153 inhibits human thyroid carcinoma cell growth in vitro and in vivo.
Subject(s)
Heterocyclic Compounds, 2-Ring/therapeutic use , Nuclear Proteins/antagonists & inhibitors , Piperazines/therapeutic use , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/pathology , Transcription Factors/antagonists & inhibitors , Administration, Oral , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Cycle Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Female , Heterocyclic Compounds, 2-Ring/administration & dosage , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Male , Mice, SCID , Middle Aged , Nuclear Proteins/metabolism , Piperazines/administration & dosage , Piperazines/pharmacology , Pyrazoles , Pyridazines , Transcription Factors/metabolism , Xenograft Model Antitumor AssaysABSTRACT
AIM: To compare the efficacy and safety of the once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin or once-daily DPP-4 inhibitor sitagliptin in patients with type 2 diabetes (T2DM) and inadequate glycaemic control on metformin. MATERIALS AND METHODS: Patients with T2DM with a glycated haemoglobin (HbA1c) concentration ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500 mg/d) were randomized in a double-blind manner to receive omarigliptin 25 mg once weekly (n = 322) or sitagliptin 100 mg once daily (n = 320). The primary analysis assessed whether omarigliptin was non-inferior to sitagliptin in reducing HbA1c at week 24, based on the criterion of having an upper bound of the 95% confidence interval (CI) about the difference less than the non-inferiority bound of 0.3%. RESULTS: The mean baseline HbA1c was 7.5% in both groups. After 24 weeks, the least squares (LS) mean change in HbA1c from baseline was -0.47% in the omarigliptin group and -0.43% in the sitagliptin group, with a between-group difference of -0.03% (95% CI -0.15, 0.08). This result met the prespecified criterion for declaring non-inferiority. The LS mean change from baseline in fasting plasma glucose and the percentage of patients with HbA1c <7.0% or <6.5% at week 24 were similar in the two treatment groups. There were no notable differences in adverse events and the incidence of symptomatic hypoglycaemia was low and similar in the groups. CONCLUSIONS: In patients with T2DM and inadequate glycaemic control on metformin, the addition of omarigliptin 25 mg once weekly or sitagliptin 100 mg once daily led to similar improvements in glycaemic control. Both agents were generally well tolerated with a low incidence of hypoglycaemia.