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CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag.
Basso-Valentina, F, Levy, G, Varghese, LN, Oufadem, M, Neven, B, Boussard, C, Balayn, N, Marty, C, Vainchenker, W, Plo, I, et al
Blood. 2021;(6):480-485
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Abstract
Congenital amegakaryocytic thrombocytopenia (CAMT) is a severe inherited thrombocytopenia due to loss-of-function mutations affecting the thrombopoietin (TPO) receptor, MPL. Here, we report a new homozygous MPL variant responsible for CAMT in 1 consanguineous family. The propositus and her sister presented with severe thrombocytopenia associated with mild anemia. Next-generation sequencing revealed the presence of a homozygous MPLR464G mutation resulting in a weak cell-surface expression of the receptor in platelets. In cell lines, we observed a defect in MPLR464G maturation associated with its retention in the endoplasmic reticulum. The low cell-surface expression of MPLR464G induced very limited signaling with TPO stimulation, leading to survival and reduced proliferation of cells. Overexpression of a myeloproliferative neoplasm-associated calreticulin (CALR) mutant did not rescue trafficking of MPLR464G to the cell surface and did not induce constitutive signaling. However, it unexpectedly restored a normal response to eltrombopag (ELT), but not to TPO. This effect was only partially mimicked by the purified recombinant CALR mutant protein. Finally, the endogenous CALR mutant was able to restore the megakaryocyte differentiation of patient CD34+ cells carrying MPLR464G in response to ELT.
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Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.
Pivonello, R, Bancos, I, Feelders, RA, Kargi, AY, Kerr, JM, Gordon, MB, Mariash, CN, Terzolo, M, Ellison, N, Moraitis, AG
Frontiers in endocrinology. 2021;:662865
Abstract
INTRODUCTION/PURPOSE Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). MATERIALS AND METHODS A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%). RESULTS 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred. CONCLUSIONS The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.
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Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
McCann, KJ, Yadav, M, Alishahedani, ME, Freeman, AF, Myles, IA
PloS one. 2021;(3):e0248011
Abstract
Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.
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Phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of teneligliptin monotherapy in Chinese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise.
Ji, L, Ma, J, Lu, W, Liu, J, Zeng, J, Yang, J, Li, W, Zhang, X, Xiao, X, Takayanagi, G, et al
Journal of diabetes investigation. 2021;(4):537-545
Abstract
AIMS/INTRODUCTION Although the efficacy of teneligliptin, a highly selective dipeptidyl peptidase-4 inhibitor, has been amply studied for the treatment of type 2 diabetes, no clinical trials of teneligliptin have been carried out in China. We evaluated the efficacy and safety of teneligliptin monotherapy compared with a placebo in Chinese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. MATERIALS AND METHODS This multicenter, randomized, double-blind, placebo-controlled, parallel-group study, carried out at 42 sites, enrolled type 2 diabetes patients with glycosylated hemoglobin 7.0 to <10.0% and fasting blood glucose <270 mg/dL. Patients were randomly assigned, in a 1:1 ratio, to treatment with 20 mg teneligliptin or a placebo (n = 127, each) administered orally once daily before breakfast for 24 weeks. Change in glycosylated hemoglobin from baseline to week 24 was the primary efficacy end-point. Safety was assessed by the incidence of adverse events and adverse drug reactions. RESULTS The least square mean (LSM) change in glycosylated hemoglobin from baseline to week 24 was -0.95% with teneligliptin versus -0.14% with a placebo, yielding an LSM difference (teneligliptin vs placebo) of -0.80% (P < 0.0001). For the secondary end-point, from baseline to week 24, the LSM change in fasting blood glucose was -21.9 mg/dL with teneligliptin versus -1.4 mg/dL with a placebo, yielding an LSM difference (teneligliptin vs placebo) of -20.5 mg/dL (P < 0.0001). The adverse event and adverse drug reaction incidence rates, including hypoglycemia, were similar in both groups. CONCLUSIONS At 24 weeks, teneligliptin was generally well tolerated and effective in Chinese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise.
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Efficacy and safety of teneligliptin added to metformin in Chinese patients with type 2 diabetes mellitus inadequately controlled with metformin: A phase 3, randomized, double-blind, placebo-controlled study.
Ji, L, Li, L, Ma, J, Li, X, Li, D, Meng, B, Lu, W, Sun, J, Liu, Y, Takayanagi, G, et al
Endocrinology, diabetes & metabolism. 2021;(2):e00222
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Abstract
INTRODUCTION We evaluated the efficacy and safety of teneligliptin compared with placebo when added to metformin therapy in Chinese patients with type 2 diabetes inadequately controlled with metformin monotherapy. METHODS This multicentre, randomized, double-blind, placebo-controlled, parallel-group study enrolled type 2 diabetes patients with glycosylated haemoglobin (HbA1c) 7.0%-<10.0% and fasting plasma glucose (FPG) <270 mg/dl, receiving a stable metformin dose ≥1000 mg/day. Teneligliptin 20 mg or placebo was administered orally once daily (qd) before breakfast for 24 weeks. The primary efficacy end-point was change in HbA1c from baseline to Week 24. Safety end-points included the incidence of adverse events (AEs). RESULTS The least square mean (LSM) change from baseline (standard error [SE]) was -0.72 (0.07) (95% confidence intervals [CI], -0.87, -0.58) for teneligliptin and -0.01 (0.07) (95% CI, -0.16, 0.13) for placebo. The differences (LSM ± SE) between the placebo and teneligliptin groups in HbA1c and FPG were -0.71% ± 0.11% (p < .0001) and -16.5 ± 4.7 mg/dl (p = .0005), respectively. Teneligliptin yielded significant changes in HbA1c (-0.81%; p < .0001) and FPG (-22.2 mg/dl; p < .0001) at Week 12. At Week 24, more patients achieved HbA1c <7.0% with teneligliptin (41.7%) compared with placebo (16.1%; p < .0001). Treatment-emergent AE incidence was similar with teneligliptin (58.9%) and placebo (68.3%); upper respiratory tract infection, hyperuricaemia and hyperlipidaemia were the most common AEs. CONCLUSIONS Teneligliptin 20 mg qd for 24 weeks added to ongoing metformin treatment significantly decreased HbA1c and FPG levels compared with placebo in Chinese type 2 diabetes patients. The combination was safe and tolerable.
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Phase 1 Study Evaluating the Effects of the Proton Pump Inhibitor Rabeprazole and Food on the Pharmacokinetics of Lorlatinib in Healthy Participants.
Xu, H, O'Gorman, MT, Nepal, S, James, LP, Ginman, K, Pithavala, YK
Clinical pharmacology in drug development. 2021;(11):1395-1404
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Abstract
Lorlatinib is approved worldwide as treatment for anaplastic lymphoma kinase-positive and c-ros oncogene 1-positive non-small cell lung cancer. The objectives of this phase 1, open-label crossover study (NCT02569554) in healthy adult participants were to determine (1) the effects of the proton pump inhibitor (PPI) rabeprazole on lorlatinib pharmacokinetics (PK), (2) the effects of a high-fat meal on lorlatinib PK, and (3) the relative bioavailability of an oral solution to tablet formulation of lorlatinib under fasted conditions. Participants were followed on-study for ≥50 days after the first dose of lorlatinib. Participants received treatments over 4 periods, with a washout of ≥10 days between consecutive lorlatinib doses. Twenty-seven participants were enrolled and received lorlatinib, and all were assessed for PK and safety. Results showed no effect of multiple doses of rabeprazole on the total plasma exposure of a single oral dose of lorlatinib 100-mg tablets. The results also indicated that a high-fat meal had no effect on lorlatinib PK after a single 100-mg oral dose. In addition, the relative bioavailability of lorlatinib oral solution compared with lorlatinib tablets was complete (approximately 108%). The safety profile of lorlatinib was consistent with that reported in previous studies, and most treatment-related adverse events were mild to moderate. These data indicate that lorlatinib can be administered with drugs that modify gastric acid, including PPIs, without restriction. These results also confirm that lorlatinib can be administered regardless of food intake.
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Educational Impact on Apixaban Adherence in Atrial Fibrillation (the AEGEAN STUDY): A Randomized Clinical Trial.
Montalescot, G, Brotons, C, Cosyns, B, Crijns, HJ, D'Angelo, A, Drouet, L, Eberli, F, Lane, DA, Besse, B, Chan, A, et al
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(1):61-71
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Abstract
INTRODUCTION Adherence to non-vitamin-K oral anticoagulants (NOACs) may be lower than to vitamin K antagonists because NOACs do not require routine monitoring. OBJECTIVE We assessed the impact of an educational program on adherence and persistence with apixaban in patients with non-valvular atrial fibrillation (NVAF). METHODS Patients with NVAF eligible for NOACs with one or more stroke risk factor (prior stroke/transient ischemic attack, age ≥ 75 years, hypertension, diabetes, or symptomatic heart failure) were randomized (1:1) to standard of care (SOC) or SOC with additional educational (information booklet, reminder tools, virtual clinic access). The primary outcome was adherence to apixaban (2.5 or 5 mg twice daily) at 24 weeks. Patients receiving the educational program were re-randomized (1:1) to continue the program for 24 further weeks or to switch to secondary SOC. Implementation adherence and persistence were reassessed at 48 weeks. RESULTS In total, 1162 patients were randomized (SOC, 583; educational program, 579). Mean implementation adherence ± standard deviation (SD) at 24 weeks was 91.6% ± 17.1 for SOC and 91.9% ± 16.1 for the educational program arm; results did not differ significantly between groups at any time-point. At 48 weeks, implementation adherence was 90.4% ± 18.0, 90.1% ± 18.6, and 89.3% ± 18.1 for continued educational program, SOC, and secondary SOC, respectively; and corresponding persistence was 86.1% (95% confidence interval [CI] 81.3-89.7), 85.2% (95% CI 81.5-88.2), and 87.8% (95% CI 83.4-91.1). Serious adverse events were similar across groups. CONCLUSION High implementation adherence and persistence with apixaban were observed in patients with NVAF receiving apixaban. The educational program did not show additional benefits. CLINICAL TRIAL REGISTRATION This study is registered at ClinicalTrials.gov [NCT01884350].
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Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease.
Frölich, L, Wunderlich, G, Thamer, C, Roehrle, M, Garcia, M, Dubois, B
Alzheimer's research & therapy. 2019;(1):18
Abstract
BACKGROUND There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD. Efficacy and safety of BI 409306 was analysed in two phase II proof-of-concept clinical trials in cognitive impairment associated with prodromal AD (study 1) and mild AD (study 2). METHODS Two multicentre, double-blind, parallel-group, randomised controlled phase II studies were conducted (North America/Europe). Following study run-in, eligible subjects were randomised to one of four oral doses of BI 409306 (10-50 mg daily) or placebo (1:1:1:1:2 ratio) for 12 weeks. The primary efficacy endpoint was the change from baseline in Neuropsychological Test Battery (NTB) total z-score after 12 weeks' treatment. Secondary efficacy assessments included change from baseline in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog11) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; mild cognitive impairment [MCI] version for prodromal patients) after 12 weeks' treatment. Safety and tolerability assessments included adverse event reporting and vital sign monitoring. Change from baseline in NTB total z-score (primary endpoint) and CDR-SB were analysed using the restricted maximum likelihood-based mixed-effects model with repeated measurement. An analysis of covariance model was used to assess other secondary endpoints. RESULTS Four hundred fifty-seven patients were randomised (study 1 for prodromal AD, N = 128; study 2 for mild AD, N = 329); 427 (93.4%) completed. A prespecified pooled analysis of the primary endpoint revealed no significant changes in NTB total composite z-score at week 12 in the BI 409306 treatment groups compared with placebo, with similar findings observed in the individual studies. The analysis of all secondary endpoints, including pooled analysis of CDR-SB and ADAS-Cog11, ADCS-MCI-ADL (study 1), ADCS-ADL (study 2), also gave no indication of a treatment benefit for BI 409306, compared with placebo. BI 409306 was well tolerated. CONCLUSIONS Overall, the data do not demonstrate efficacy of BI 409306 in improving cognition in patients with prodromal and mild AD. BI 409306 is well tolerated. TRIAL REGISTRATION ClinicalTrials.gov, NCT02240693 and NCT02337907 . Registered 15 September 2014 and 09 January 2015, respectively.
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Effectiveness and Safety of Apixaban versus Warfarin as Outpatient Treatment of Venous Thromboembolism in U.S. Clinical Practice.
Weycker, D, Li, X, Wygant, GD, Lee, T, Hamilton, M, Luo, X, Vo, L, Mardekian, J, Pan, X, Burns, L, et al
Thrombosis and haemostasis. 2018;(11):1951-1961
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Abstract
In the AMPLIFY clinical trial, apixaban was non-inferior to warfarin plus subcutaneous enoxaparin bridge therapy in the treatment of acute venous thromboembolism (VTE) and was associated with significantly less bleeding. This study evaluated their comparative effectiveness and safety in routine clinical practice. A matched-cohort design and data from four U.S. private health care claims databases were employed. Study population comprised patients who initiated outpatient treatment with apixaban versus warfarin (plus parenteral anticoagulant bridge therapy) within 30 days of their initial VTE episode; apixaban and warfarin patients were matched on age, characteristics of VTE episode, study database and propensity score. Major bleeding, clinically relevant non-major (CRNM) bleeding and recurrent VTE during the 180-day (maximum) follow-up period were compared using shared frailty models. During mean follow-up of 143 days among apixaban patients (n = 17,878) and 152 days among warfarin patients (n = 17,878), incidence proportions for apixaban versus warfarin, respectively, were 1.7% versus 2.3% for major bleeding, 7.0% versus 9.4% for CRNM bleeding and 2.3% versus 2.9% for recurrent VTE. In shared frailty models, risks of major bleeding (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.64-0.87), CRNM bleeding (HR = 0.77, 95% CI = 0.71-0.83) and recurrent VTE (HR = 0.80, 95% CI = 0.70-0.91) were lower for apixaban versus warfarin. In this large-scale evaluation of VTE patients receiving outpatient treatment with apixaban or warfarin in U.S. clinical practice, risks of major bleeding, CRNM bleeding and recurrent VTE were significantly lower among patients who received apixaban.
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Factors associated with non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with new-onset atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II).
Steinberg, BA, Shrader, P, Thomas, L, Ansell, J, Fonarow, GC, Gersh, BJ, Hylek, E, Kowey, PR, Mahaffey, KW, O'Brien, EC, et al
American heart journal. 2017;:40-47
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BACKGROUND Several non-vitamin K antagonist oral anticoagulant (NOAC) alternatives to warfarin are available for stroke prevention in atrial fibrillation (AF). We aimed to describe the factors associated with selection of NOACs versus warfarin in patients with new onset AF. METHODS The ORBIT-AF II study is a national, US, prospective, observational, cohort study of anticoagulation treatment in patients with AF receiving NOACs or warfarin in the United States from 2013 to 2016. We measured factors associated with oral anticoagulant selection in 4,670 patients recently diagnosed with AF. RESULTS At baseline, 1,169 (25%) patients were started on warfarin and 3,501 (75%) on NOACs: of these latter, 259 (6%) were started on dabigatran, 1858 (40%) on rivaroxaban, and 1384 (30%) on apixaban. Those receiving NOACs were slightly younger patients (median age 71 vs 72, P<.0001); were less likely to have prior stroke (5.3% vs 8.6%; P<.0001) or prior bleeding (2.7% vs 4.4%; P=.005); had better kidney function (mean estimated glomerular filtration rate 91 mL/min vs 80 mL/min, P<.0001); and had fewer patients at high stroke risk (CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age ≥75years, Diabetes mellitus, Prior stroke, transient ischemic attack {TIA}, or thromboembolism,Vascular disease, Age 65-74years, Sex category {female}] ≥2 in 86% vs 93%; P<.0001). In multivariable analysis, factors associated with NOAC selection versus warfarin included renal function, prior stroke or valve replacement, rhythm control AF management strategy, treatment by a cardiologist, and higher patient education level. CONCLUSIONS In contemporary clinical practice, up to three-fourths of patients with new-onset AF are now initially treated with a NOAC for stroke prevention. Those selected for NOAC treatment had lower stroke and bleeding risk profiles, were more likely treated by cardiologists, and had higher socioeconomic status. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01701817.