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Pooled Resistance Analysis in Patients with Hepatitis C Virus Genotype 1 to 6 Infection Treated with Glecaprevir-Pibrentasvir in Phase 2 and 3 Clinical Trials.
Krishnan, P, Pilot-Matias, T, Schnell, G, Tripathi, R, Ng, TI, Reisch, T, Beyer, J, Dekhtyar, T, Irvin, M, Xie, W, et al
Antimicrobial agents and chemotherapy. 2018;(10)
Abstract
Over 2,200 patients infected with hepatitis C virus (HCV) genotypes (GT) 1 to 6, with or without cirrhosis, who were treatment naive or experienced to interferon, ribavirin, and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight registrational phase 2 and 3 clinical studies. High rates of sustained virologic response at 12 weeks postdosing (SVR12) were achieved with a <1% virologic failure (VF) rate. The prevalence of baseline polymorphisms (BPs) in NS3 at amino acid position 155 or 168 was low (<3%) in patients infected with GT1, GT2, GT3, GT4, and GT6, while 41.9% of the GT5-infected patients had NS3-D168E; BPs were not detected at position 156 in NS3. The prevalence of NS5A-BPs was high across genotypes, driven by common polymorphisms at amino acid position 30 or 31 in GT2, 58 in GT4, and 28 in GT6. The prevalence of NS5A T/Y93 polymorphisms was 5.5% in GT1, 4.9% in GT3, and 12.5% in GT6. Consistent with the activity of glecaprevir and pibrentasvir against most amino acid polymorphisms in vitro, BPs in NS3 and/or NS5A did not have an impact on treatment outcome for patients infected with GT1 to GT6, with the exception of treatment-experienced GT3-infected patients treated for 12 weeks, for whom a 16-week regimen of glecaprevir/pibrentasvir was required to achieve SVR12 rates of ≥95%. Among the 22 patients experiencing VF, treatment-emergent substitutions were detected in NS3 in 50% of patients and in NS5A in 82% of patients, frequently as a combination of substitutions that conferred resistance to glecaprevir and/or pibrentasvir. The glecaprevir/pibrentasvir regimen, when the recommended durations are used, allows for a pan-genotypic treatment option without the need for baseline resistance testing.
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Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study.
Scheltens, P, Hallikainen, M, Grimmer, T, Duning, T, Gouw, AA, Teunissen, CE, Wink, AM, Maruff, P, Harrison, J, van Baal, CM, et al
Alzheimer's research & therapy. 2018;(1):107
Abstract
BACKGROUND PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests. METHODS This was a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability and efficacy of PQ912 800 mg twice daily (bid) for 12 weeks in subjects with mild cognitive impairment or mild dementia due to AD. The 120 enrolled subjects were treatment-naïve at the start of the study, had confirmed AD biomarkers in their cerebrospinal fluid at screening and had a Mini Mental State Examination score between 21 and 30. After 1 week of treatment with 400 mg bid, patients were up-titrated to 800 mg bid for 11 weeks. Patients were randomized 1:1 to either PQ912 or placebo. The primary composite endpoints were to assess safety and tolerability based on the number of patients who discontinued due to (serious) adverse events (safety), and based on dose adjustment during the treatment period and/or nonadherence to randomized treatment (tolerability). All randomized subjects who took at least one dose of the study treatment or placebo were used for safety analyses. RESULTS There was no significant difference between treatments in the number of subjects with (serious) adverse events, although there were slightly more patients with a serious adverse event in the PQ912 group compared to placebo. More subjects treated with PQ912 discontinued treatment due to adverse events, mostly related to gastrointestinal and skin/subcutaneous tissue disorders. PQ912 treatment resulted in a significant reduction in glutaminyl cyclase activity, which resulted in an average target occupancy of > 90%. A significant reduction of theta power in the EEG frequency analysis and a significant improvement in the One Back test of our Neuropsychological Test Battery was observed. The exploratory biomarker readouts, neurogranin for synaptic toxicity and YKL-40 as a marker of inflammation, appear to be sensitive enough to serve as efficacy markers in the next phase 2b study. CONCLUSIONS The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching > 50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study. TRIAL REGISTRATION Clinicaltrials.gov, NCT 02389413 . Registered on 17 March 2015.
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Efficacy and Safety of Lomitapide in Japanese Patients with Homozygous Familial Hypercholesterolemia.
Harada-Shiba, M, Ikewaki, K, Nohara, A, Otsubo, Y, Yanagi, K, Yoshida, M, Chang, Q, Foulds, P
Journal of atherosclerosis and thrombosis. 2017;(4):402-411
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Abstract
AIM: There is an unmet need in Japan for more optimal lipid-lowering therapy (LLT) for patients with homozygous familial hypercholesterolemia (HoFH) who respond inadequately to available drug therapies and/or apheresis, to achieve goals of low-density lipoprotein cholesterol (LDL-C) reduction by 50% or to <100 mg/dL. METHODS In this study, Japanese patients with HoFH on stable LLT and diet were treated with lomitapide, initiated at 5 mg/day and escalated to maximum tolerated dose (up to 60 mg/day) over 14 weeks. The primary efficacy endpoint was mean percentage change from baseline to Week 26 in LDL-C. Secondary endpoints included changes in other lipid parameters and safety throughout the 56-week study (including follow-up). RESULTS Nine patients entered the efficacy phase of the study and, of these, eight completed 56 weeks. Mean LDL-C was reduced by 42% (p<0.0001) at 26 weeks, from 199 mg/dL (95% CI: 149-250) at baseline to 118 mg/dL (95% CI: 70-166). A 50% reduction in LDL-C and LDL-C <100 mg/dL was achieved by five and six of nine patients, respectively, at 26 weeks. After 56 weeks, LDL-C was reduced by 38% (p=0.0032) from baseline. Significant reductions in non-HDL-C, VLDL-C, triglycerides, and apolipoprotein B were also reported at Week 26. There were no new safety signals and, similar to previous studies, gastrointestinal adverse events were the most common adverse events. CONCLUSION Lomitapide, added to ongoing treatment with other LLTs, was effective in rapidly and significantly reducing the levels of LDL-C and other atherogenic apolipoprotein B-containing lipoproteins in adult Japanese patients with HoFH.
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SELIMETRY-a multicentre I-131 dosimetry trial: a clinical perspective.
Wadsley, J, Gregory, R, Flux, G, Newbold, K, Du, Y, Moss, L, Hall, A, Flanagan, L, Brown, SR
The British journal of radiology. 2017;(1073):20160637
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Abstract
Treatment options for patients with thyroid cancer that is no longer sensitive to iodine therapy are limited. Those treatments which currently exist are associated with significant toxicity. The SELIMETRY trial (EudraCT No 2015-002269-47) aims to investigate the role of the MEK inhibitor Selumetinib in resensitizing advanced iodine refractory differentiated thyroid cancer to radioiodine therapy. Patients deemed to have sufficient iodine uptake in previously iodine refractory lesions after 4 weeks of Selumetinib therapy will be given an empirical activity of 5.5 GBq I-131, and response to therapy will be assessed. The trial presents an opportunity to investigate the dosimetric aspects of radioiodine therapy for advanced thyroid cancer. Patients will undergo serial I-123 single-photon emission CT (SPECT)/CT scans following Selumetinib therapy to determine whether there has been a change in the degree of iodine uptake to justify further I-131 therapy, and to allow dosimetric calculations to predict absorbed dose to target lesions following therapy. Patients receiving I-131 therapy will undergo a further series of post-therapy SPECT/CT scans to allow dosimetric calculations. We describe the challenges in setting up a multicentre trial in a relatively underinvestigated field, describing the work that has been carried out to calibrate and validate measurements to ensure that standardized image data are collected at each site. We hope that this trial will lead to individualization and optimization of therapy for patients with advanced thyroid cancer and that the ground work carried out in setting up a network of centres capable of standardized molecular radiotherapy dosimetry will lead to further clinical trials in this field.
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Characterization of Hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885.
Wong, KA, Worth, A, Martin, R, Svarovskaia, E, Brainard, DM, Lawitz, E, Miller, MD, Mo, H
Antimicrobial agents and chemotherapy. 2013;(12):6333-40
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GS-5885 is a novel hepatitis C virus (HCV) NS5A inhibitor. In a 3-day monotherapy study in treatment-naive genotype 1a (GT1a) and GT1b HCV-infected subjects, median viral load reductions ranged from 2.3 to 3.3 log10 HCV RNA IU/ml across dosing cohorts (1, 3, 10, 30, or 90 mg once daily). Here, we report viral sequencing and phenotypic analysis of clinical isolates from this study. Detection of baseline NS5A amino acid substitutions at positions 28, 30, 31, or 93 in GT1a was associated with a reduced treatment response. In the GT1b cohort, Y93H was detected in 100% of subjects at day 4 or 14. In the Gt1a cohort, population sequencing detected NS5A resistance-associated mutations at day 4 or 14 for 3/10 subjects at the 1-mg dose and for all subjects dosed at ≥3 mg. A subset of mutants that confer a low level of reduced susceptibility to GS-5885 was not detected by population sequencing at the 30- and 90-mg doses. Subject-derived M28T, Q30R, L31M, and Y93C mutations all conferred >30-fold reductions in GS-5885 and daclatasvir susceptibilities in vitro. Site-directed NS5A mutants also showed reduced susceptibility to GS-5885. However, all NS5A mutants tested remained fully susceptible to other classes of direct-acting antivirals (DAAs), interferon alpha, and ribavirin. Importantly, the nonoverlapping resistance profile and high potency of GS-5885 support its further development with other direct-acting antivirals for the treatment of chronic HCV. (This study has been registered at ClinicalTrials.gov under registration number NCT01193478.).
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Pharmacometric characterization of dabigatran hemodialysis.
Liesenfeld, KH, Staab, A, Härtter, S, Formella, S, Clemens, A, Lehr, T
Clinical pharmacokinetics. 2013;(6):453-62
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BACKGROUND Hemodialysis has been shown to be a useful method of decreasing dabigatran plasma levels in situations that require rapid elimination of this thrombin inhibitor. However, there is currently no clinical recommendation for the accelerated/optimized elimination of dabigatran via hemodialysis (e.g., flow rates, filter type, duration of dialysis). OBJECTIVES The primary objective of the present work was to characterize, via pharmacometric methods, the effects of different blood flow rates in hemodialysis on the pharmacokinetics of dabigatran, using data from a dedicated phase I dialysis study of end-stage renal disease (ESRD) patients. In addition, the effects of various clinically relevant hemodialysis settings were evaluated by simulation to assess their potential use in non-ESRD situations. METHODS Seven patients with ESRD were investigated in an open-label, fixed-sequence, two-period comparison trial. A population pharmacokinetic model was developed to fit the data and then used for various simulations. Data analyses were performed using NONMEM(®), Berkeley Madonna, or SAS. RESULTS The pharmacokinetics of dabigatran were best described by a two-compartment model with first-order absorption and a lag time. In addition to total body clearance in ESRD subjects, a first-order dialysis clearance was implemented which was greater than zero during hemodialysis and zero during the interdialytic periods. The relationship between the dialysis clearance and the blood flow rate was best described by the Michaels function. Simulations showed that varying clinically relevant dialysis settings such as filter properties or flow rates had only minor effects. Dialysis duration had the strongest impact on dabigatran plasma concentration. The observed geometric mean redistribution effect after hemodialysis was low (<16 %). The final model was successfully evaluated through the prediction of plasma concentrations from a case report undergoing dialysis. CONCLUSIONS This analysis allowed the influences of various hemodialysis parameters on the dabigatran plasma concentration to be predicted in detail for the first time. Dialysis duration was identified as having the strongest impact on the reduction in dabigatran plasma concentration. The model developed here can potentially serve as a tool to provide guidance when considering the use of hemodialysis in patients who have received dabigatran.
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Beneficial cardiometabolic actions of telmisartan plus amlodipine therapy in elderly patients with poorly controlled hypertension.
Bekki, H, Yamamoto, K, Sone, M, Homma, T, Nakata, M, Nohara, M, Fukami, K, Okuda, S, Yamagishi, S
Clinical cardiology. 2011;(4):261-5
Abstract
BACKGROUND There is a growing body of evidence that blood pressure (BP) level is one of the major determinants of cardiovascular morbidity and mortality in individuals, including elderly people. However, to achieve a target BP level in the elderly is more difficult compared with patients aged <65 years. Current guidelines recommend combination drug therapy with different modes of action for the treatment of elderly patients with moderate hypertension (HT). However, the optimal combination regimen is not well established in elderly HT. HYPOTHESIS We hypothesized that combination therapy of telmisartan plus amlodipine would exert favorable cardiometabolic actions in elderly HT. METHODS Seventeen elderly patients with essential HT who failed to achieve a target home BP level with treatment of 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan for at least 2 months were enrolled. Then the patients were assigned to replace their valsartan or candesartan with 40 mg telmisartan. The subjects were instructed to measure their own BP at home every day during the study periods. RESULTS Replacement of valsartan or candesartan by telmisartan in amlodipine-treated elderly hypertensive patients showed a significant reduction in morning home systolic BP and evening home systolic and diastolic BP at 12 weeks. Switching to telmisartan significantly increased serum adiponectin level. CONCLUSIONS Our present study suggests that combination therapy with telmisartan plus amlodipine may exert more beneficial cardiometabolic effects in elderly patients with HT compared with valsartan or candesartan plus amlodipine treatment.
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Office and ambulatory blood pressure control with a fixed-dose combination of candesartan and hydrochlorothiazide in previously uncontrolled hypertensive patients: results of CHILI CU Soon.
Mengden, T, Hübner, R, Bramlage, P
Vascular health and risk management. 2011;:761-9
Abstract
BACKGROUND Fixed-dose combinations of candesartan 32 mg and hydrochlorothiazide (HCTZ) have been shown to be effective in clinical trials. Upon market entry we conducted a noninterventional study to document the safety and effectiveness of this fixed-dose combination in an unselected population in primary care and to compare blood pressure (BP) values obtained during office measurement (OBPM) with ambulatory blood pressure measurement (ABPM). METHODS CHILI CU Soon was a prospective, noninterventional, noncontrolled, open-label, multicenter study with a follow-up of at least 10 weeks. High-risk patients aged ≥18 years with previously uncontrolled hypertension were started on candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ. OBPM and ABPM reduction and adverse events were documented. RESULTS A total of 4131 patients (52.8% male) with a mean age of 63.0 ± 11.0 years were included. BP was 162.1 ± 14.8/94.7 ± 9.2 mmHg during office visits at baseline. After 10 weeks of candesartan 32 mg/12.5 mg or 25 mg HCTZ, mean BP had lowered to 131.7 ± 10.5/80.0 ± 6.6 mmHg (P < 0.0001 for both comparisons). BP reduction was comparable irrespective of prior or concomitant medication. In patients for whom physicians regarded an ABPM to be necessary (because of suspected noncontrol over 24 hours), ABP at baseline was 158.2/93.7 mmHg during the day and 141.8/85.2 mmHg during the night. At the last visit, BP had significantly reduced to 133.6/80.0 mmHg and 121.0/72.3 mmHg, respectively, resulting in 20.8% being normotensive over 24 hours (<130/80 mmHg). The correlation between OBPM and ABPM was good (r = 0.589 for systolic BP and r = 0.389 for diastolic BP during the day). Of those who were normotensive upon OBPM, 35.1% had high ABPM during the day, 49.3% were nondippers, and 3.4% were inverted dippers. Forty-nine adverse events (1.19%) were reported, of which seven (0.17%) were regarded as serious. CONCLUSION Candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ is safe and effective for further BP lowering irrespective of prior antihypertensive drug class not being able to control BP.
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A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens.
Hainsworth, JD, Cebotaru, CL, Kanarev, V, Ciuleanu, TE, Damyanov, D, Stella, P, Ganchev, H, Pover, G, Morris, C, Tzekova, V
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2010;(10):1630-6
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INTRODUCTION AZD6244 (ARRY-142886) is a potent, selective MEK inhibitor. This study aimed to evaluate the efficacy and safety of AZD6244 versus pemetrexed as second- or third-line treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS In this randomized phase II study, patients received either 100 mg oral AZD6244 free-base suspension twice daily or 500 mg/m(2) intravenous pemetrexed once every 3 weeks after pretreatment with a corticosteroid, folic acid, and vitamin B12. The primary end point of the study was the disease progression event count. RESULTS Eighty-four patients were randomized. Disease progression events were experienced by 28 (70%) and 26 (59%) patients in the AZD6244 and pemetrexed groups, respectively. Median progression-free survival was not statistically significantly different between the AZD6244 and pemetrexed groups (67 versus 90 days, respectively; hazard ratio 1.08, two-sided 80% confidence interval = 0.75-1.54; p = 0.79). Two patients in the AZD6244 group had a best response to treatment of partial response. In the pemetrexed group, one patient achieved a complete response and one patient a partial response. Dermatitis acneiform, diarrhea, nausea, and vomiting were the most frequently reported adverse events with AZD6244, compared with fatigue, anemia, nausea, anorexia, and dermatitis acneiform with pemetrexed. CONCLUSIONS Oral AZD6244 showed clinical activity as second- or third-line therapy for patients with advanced NSCLC. In an unselected NSCLC population, there is no suggestion that AZD6244 monotherapy offers any advantage over standard treatment with pemetrexed. Based on preclinical data and recent clinical observations, further development of AZD6244 in NSCLC should focus on BRAF or RAS mutation-positive patients and/or AZD6244-based combination regimens.
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Long-term antiproteinuric effect of dual renin-angiotensin system blockade.
Robles, NR, Fernandez Carbonero, E, Romero, B, Sánchez Casado, E, Cubero, JJ
Cardiovascular therapeutics. 2009;(2):101-7
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We evaluated the long-term changes on overt proteinuria induced by dual blockade of the renin-angiotensin system (RAS). Dual blockade was produced by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an angiotensin converting enzyme (ACE) inhibitor in proteinuric patients. A total of 28 patients (19 men and 9 women) with proteinuria higher than 1 g/24 h were enrolled in this trial of treatment with the ARB candesartan (from 4 up to 32 mg daily) added to existing treatment with an ACE inhibitor. At 6, 12, 24, and 36 months, we evaluated proteinuria in 24-h urinary collections, office blood pressure (BP), plasmatic creatinine (Cr), serum potassium (K), and 24 h urine collection creatinine clearance (CrC). During monoblockade of the RAS by ACE inhibitor treatment, albuminuria was 2.94 +/- 1.92 mg/24 h; BP was 137/76 mmHg; K+ was 4.8 +/- 0.5 mmol/l, Cr was 1.76 +/- 0.67 mg/dL, and CrC was 62 +/- 31.9 mL/min. After 6 months, dual blockade of the RAS albuminuria was 2.18 +/- 2.29 mg/24 h (P < 0.01 vs. baseline) and BP was 133/75 mmHg (not significant). At 36 months, albuminuria was 2.21 +/- 2.20 mg/24 h (P < 0.05 vs. baseline); BP was 133/73 mmHg (not significant). CrC was not changed along the follow up. A small increment of Cr was detected at 24 months (2.11 +/- 1.06 mg/mL, P < 0.05). The antiproteinuric effect of dual renin-angiotensin system blockade combining candesartan and ACE inhibitors remain after 36 months without losing its initial effect. Blood pressure changes seem not to explain this long-term antiproteinuric effect.