Aims
Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR‐CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT). While ATTR‐ACT was not designed ...for a dose‐specific assessment, further analysis from ATTR‐ACT and its long‐term extension study (LTE) can guide determination of the optimal dose.
Methods and results
In ATTR‐ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR‐ACT could enrol in the LTE (with placebo‐treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high‐dose tafamidis. All‐cause mortality was assessed in ATTR‐ACT combined with the LTE (median follow‐up 51 months). In ATTR‐ACT, the combination of all‐cause mortality and cardiovascular‐related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All‐cause mortality vs. placebo was reduced with tafamidis 80 mg Cox hazards model (95% confidence interval): 0.690 (0.487–0.979), P = 0.0378 and 20 mg 0.715 (0.450–1.137), P = 0.1564. The mean (standard error) change in N‐terminal pro‐B‐type natriuretic peptide from baseline to Month 30 was −1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR‐ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg 0.700 (0.501–0.979), P = 0.0374. Incidence of adverse events in both tafamidis doses were comparable to placebo.
Conclusion
Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular‐related hospitalizations in patients with ATTR‐CM. The longer‐term survival data and the lack of dose‐related safety concerns support tafamidis 80 mg as the optimal dose.
Clinical Trial Registration: ClinicalTrials.gov NCT01994889; NCT02791230.
Design of ATTR‐ACT and the LTE and reduction in all‐cause mortality with tafamidis 80 mg/61 mg compared with tafamidis 20 mg
In this randomized, controlled, phase 3 trial of tafamidis for transthyretin amyloid cardiomyopathy, tafamidis was associated with lower all-cause mortality and lower rates of cardiovascular-related ...hospitalizations and decline in functional capacity and quality of life.
In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial, tafamidis significantly reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid ...cardiomyopathy (ATTR-CM). ATTR-CM is associated with a significant burden of disease; further analysis of patient-reported quality of life will provide additional data on the efficacy of tafamidis. In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial, 441 adult patients with ATTR-CM were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or placebo for 30 months, with pooled tafamidis (80 mg and 20 mg) compared with placebo. Change in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) domain scores, EQ-5D-3L scores, and patient global assessment, were prespecified exploratory end points. A greater proportion of patients improved KCCQ-OS score at month 30 with tafamidis (41.8%) versus placebo (21.4%). Tafamidis significantly reduced the decline in all 4 KCCQ-OS domains (p <0.0001 for all), and in EQ-5D-3L utility (0.09 confidence interval 0.05 to 0.12; p <0.0001) and EQ visual analog scale (9.11 confidence interval 5.39 to 12.83; p <0.0001) scores at month 30 versus placebo. A larger proportion of tafamidis-treated patients reported their patient global assessment improved at month 30 (42.3% vs 23.8% with placebo). In conclusion, tafamidis effectively reduced the decline in patient-reported outcomes, providing further insight into its efficacy in health-related quality of life in patients with ATTR-CM.
In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in ...patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure HF, arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT.
Clinical trial registration ClinicalTrials.gov: NCT01994889.
Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), this study aimed to determine whether there is a differential effect between variant transthyretin amyloidosis ...(ATTRv) and wild-type transthyretin (ATTRwt).
ATTR-CM is a progressive, fatal disorder resulting from mutations in the ATTRv or the deposition of denatured ATTRwt.
In pre-specified analyses from ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), baseline characteristics, all-cause mortality, and change from baseline to month 30 in 6-min walk test distance and Kansas City Cardiomyopathy Questionnaire Overall Summary score were compared in patients with ATTRwt and ATTRv.
There were 335 patients with ATTRwt (201 tafamidis, 134 placebo) and 106 with ATTRv (63 tafamidis, 43 placebo) enrolled in ATTR-ACT. Patients with ATTRwt (vs. ATTRv) had less advanced disease at baseline and a lower rate of disease progression over the study. The reduction in all-cause mortality with tafamidis compared with placebo was not different between ATTRwt (hazard ratio: 0.706 95% confidence interval (CI): 0.474 to 1.052; p = 0.0875) and ATTRv (hazard ratio: 0.690 95% CI: 0.408 to 1.167; p = 0.1667). Tafamidis was associated with a similar reduction (vs. placebo) in the decline in 6-min walk test distance in ATTRwt (mean ± SE difference from placebo, 77.14 ± 10.78; p < 0.0001) and ATTRv (79.61 ± 29.83 m; p = 0.008); and Kansas City Cardiomyopathy Questionnaire Overall Summary score in ATTRwt (12.72 ± 2.10; p < 0.0001) and ATTRv (18.18 ± 7.75; p = 0.019).
Pre-specified analyses from ATTR-ACT confirm the poor prognosis of untreated ATTRv-related cardiomyopathy compared with ATTRwt, but show the reduction in mortality and functional decline with tafamidis treatment is similar in both disease subtypes. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy ATTR-ACT; NCT01994889).
The purpose of this work is to develop a mathematical model of energy balance and body weight regulation that can predict species-specific response to common pre-clinical interventions. To this end, ...we evaluate the ability of a previously published mathematical model of mouse metabolism to describe changes in body weight and body composition in rats in response to two short-term interventions. First, we adapt the model to describe body weight and composition changes in Sprague-Dawley rats by fitting to data previously collected from a 26-day caloric restriction study. The calibrated model is subsequently used to describe changes in rat body weight and composition in a 23-day cannabinoid receptor 1 antagonist (CB1Ra) study. While the model describes body weight data well, it fails to replicate body composition changes with CB1Ra treatment. Evaluation of a key model assumption about deposition of fat and fat-free masses shows a limitation of the model in short-term studies due to the constraint placed on the relative change in body composition components. We demonstrate that the model can be modified to overcome this limitation, and propose additional measurements to further test the proposed model predictions. These findings illustrate how mathematical models can be used to support drug discovery and development by identifying key knowledge gaps and aiding in the design of additional experiments to further our understanding of disease-relevant and species-specific physiology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tafamidis, a non‐nonsteroidal anti‐inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20‐mg ...capsules, is approved in more than 40 countries worldwide for the treatment of adults with early‐stage symptomatic ATTR polyneuropathy. This agent, administered as an 80‐mg, once‐daily dose (4 × 20‐mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild‐type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61‐mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single‐center, open‐label, randomized, 2‐period, 2‐sequence, crossover, multiple‐dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61‐mg free acid capsules (test) and tafamidis meglumine 80‐mg (4 × 20‐mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0‐106.8) for area under the concentration‐time profile over the dosing interval and 94.1 (89.1‐99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80‐125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.
Duchenne muscular dystrophy (DMD) is a disabling and life-threatening, X-linked recessive disorder caused by mutations in dystrophin. Natural history studies can inform the disease characteristics of ...DMD, and data from these studies can be used to plan and design clinical trials and as external controls for long-term studies. We report 12-month results from the largest natural history study of individuals with DMD in China receiving standard of care treatment.
This ongoing, multicentre, prospective, single-cohort study (ClinicalTrials.gov: NCT03760029) was conducted in Chinese male participants with DMD (ambulatory aged <6 years Group 1; n = 99; ambulatory aged ≥6 years Group 2; n = 177, and non-ambulatory of any age Group 3; n = 36. The follow-up period is ≥24 months, with some participants followed for 30 months. The primary endpoint was time to clinical milestones due to DMD disease progression, and motor, pulmonary, and cardiac function. Secondary endpoints were quality of life (QoL) assessments.
Mean (standard deviation SD) age at screening was 3.4 (1.2), 8.6 (2.0), 12.3 (2.7) and 7.4 (3.5) years in Groups 1, 2, 3 and total respectively. Mean (SD) North Star Ambulatory Assessment (NSAA) total score at baseline was 21.2 (5.8) in Group 1 and 19.5 (8.3) in Group 2 and 20.0 (7.7) in ambulatory total. Overall, the time to clinical milestones due to DMD disease progression was consistent with previous findings, in which loss of ambulation occurred at 13 years. There was a trend towards a decline over 12 months in NSAA and timed motor function from age 6 years, with the greatest reductions observed thereafter. There were no consistent trends in measures of QoL, although participants of any age generally had poorer outcomes at Month 12 versus their domain scores at baseline.
This study improves the understanding of DMD progression according to the current standards of care in the Chinese DMD population and may inform selected endpoints and patient populations in clinical trials.
Pfizer Inc.
Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and ...cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.
A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists.
A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the ...treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (Ki’s⩽1nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R Ki value by 25-fold over a 24-h time-period.
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