Best practice considerations for nonclinical in vivo cardiovascular telemetry studies in non-rodent species: Delivering high quality QTc data to support ICH E14/S7B Q&As.

The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a "double negative" nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical "double negative" data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&As. Subject matter experts from both Pharma and CROs have collaborated to recommend best practices for more robust nonclinical cardiovascular telemetry studies in non-rodent species, with input from clinical and regulatory experts. The aim was to increase consistency and harmonization across the industry and to ensure delivery of high quality nonclinical QTc data to meet the proposed sensitivities defined within the revised ICH E14/S7B Q&As guideline (Q&As 5.1 and 6.1). The detailed best practice recommendations presented here cover the design and execution of the safety pharmacology cardiovascular study, including optimal methods for acquiring, analyzing, reporting, and interpreting the resulting QTc and pharmacokinetic data to allow for direct comparison to clinical exposures and assessment of safety margin for QTc prolongation.

Lack of an Effect of Supratherapeutic Dose of Venlafaxine on Cardiac Repolarization in Healthy Subjects.

This single-center, randomized, 3-way crossover thorough QT study evaluated the effect of steady-state supratherapeutic venlafaxine (Effexor) on cardiac repolarization. Fifty-four healthy adults received double-blinded extended-release venlafaxine 450 mg/d and placebo and open-label positive-control moxifloxacin 400 mg. The postdose QT intervals corrected for heart rate using the Fridericia formula (QTcF) were assessed on day 14 with an analysis of covariance using a mixed-effects model. At each time, the upper bound of the 2-sided 90%CI for time-matched least-squares (LS) mean difference between venlafaxine and placebo did not exceed the predefined cutoff of 10 milliseconds; the highest 90%CI upper bound was 5.8 milliseconds 24 hours postdose, demonstrating the lack of effect of venlafaxine on the QTc interval (primary objective). Assay sensitivity was established because the lower bound of the 2-sided 90%CI for LS mean difference in QTcF between moxifloxacin and placebo was 7.413 milliseconds on day 14 (postdose 3 hours). The exposure-response analysis demonstrated no evidence of increase in QTcF with increase in venlafaxine and desvenlafaxine concentrations. Also, supratherapeutic venlafaxine was found to be safe and well tolerated. Overall, the results demonstrated the lack of significant prolongation of the QTc interval with supratherapeutic venlafaxine 450 mg/d.

Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story.

Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.

Modeling of Survival and Frequency of Cardiovascular-Related Hospitalization in Patients with Transthyretin Amyloid Cardiomyopathy Treated with Tafamidis.

INTRODUCTION: ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) demonstrated the efficacy and safety of tafamidis in transthyretin amyloid cardiomyopathy (ATTR-CM). Model-based analyses from ATTR-ACT can examine predictor effects on dose-response/exposure-response relationships. METHODS: Parametric hazard distributions were developed for all-cause mortality and frequency of cardiovascular-related hospitalization. Time-to-event models were fitted to survival data, and repeated time-to-event models were fitted to hospitalization data. Disease-specific characteristics were assessed as baseline predictors of event hazards. RESULTS: There were 441 patients in this analysis. At month 30, 70.5% (tafamidis) and 57.1% (placebo) of patients were alive, with 154/441 deaths reported; 495 cardiovascular-related hospitalizations occurred. The cumulative risk of death was 42.1% (95% confidence interval [CI] 24.2-58.0) lower with tafamidis than with placebo, regardless of New York Heart Association (NYHA) class; significant predictors of decreased risk were genotype (wild-type), greater 6-Minute Walk Test (6MWT) distance, higher left ventricular ejection fraction (LVEF), and lower blood urea nitrogen (BUN) and N-terminal pro-B-type natriuretic peptide concentrations. The average cumulative risk of cardiovascular-related hospitalization up to 30 months was 40.8% (95% CI 31.0-49.7) lower with tafamidis in NYHA class I/II patients. Significant predictors of reduced risk were greater 6MWT distance, higher LVEF, and lower BUN and troponin I concentrations. CONCLUSIONS: Tafamidis reduced cumulative mortality and hospitalization risk versus placebo in patients with ATTR-CM. Baseline predictors of outcome were consistent with the cardiovascular nature of the disease and suggested that earlier treatment may improve outcomes. CLINICAL TRIALS. GOV IDENTIFIER: NCT01994889 (date of registration: November 26, 2013).

Population pharmacokinetic modelling and simulation of tafamidis in healthy subjects and patients with transthyretin amyloidosis.

AIMS: Since the first approval for transthyretin amyloid polyneuropathy patients, new formulations and different strength of tafamidis have been developed and tested in a different population (transthyretin amyloid cardiomyopathy). The objective of this analysis was to develop a unified population pharmacokinetic (PK) model of tafamidis, which can describe the PK of various different formulations in healthy subjects as well as patients with TTR amyloidosis, and to understand effects of intrinsic and extrinsic factors on the PK variability. METHODS: Pooled data from 23 clinical studies (17 Phase 1 and 6 Phase 2/3 studies) were used for the analysis. The plasma concentration-time data were analysed using a nonlinear mixed effects modelling methodology. Covariate analysis was performed using a stepwise covariate model building procedure. RESULTS: The final model was a 2-compartment model with first-order absorption and elimination coupled with an absorption lag time for nonsolution formations. Body weight, food and tafamidis formulations were incorporated as structural covariates on PK parameters. Covariate analysis further identified age ≥65 years (14.5% decrease) and moderate hepatic impairment effects (57.6% increase) on apparent clearance and transthyretin amyloid polyneuropathy effect (17.3% decrease) on F. However, model-based clinical trial simulation results indicated that tafamidis steady-state exposure changes were not clinically meaningful under the tested conditions. CONCLUSIONS: The unified population PK model of tafamidis was developed based on 23 studies. Subsequent clinical trial simulations indicated that no significant changes in tafamidis exposure necessitating a dose modification are expected due to either extrinsic or intrinsic factors. The model was used to support labelling statements for dose recommendations in special populations.

Predictors of Systemic Exposure to Topical Crisaborole: A Nonlinear Regression Analysis.

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Results from 2 randomized, double-blind, vehicle-controlled phase 3 studies showed that twice-daily crisaborole in children and adults with mild to moderate atopic dermatitis was efficacious and well tolerated. Initial pharmacokinetics (PK) studies of crisaborole indicated absorption with measurable systemic levels of crisaborole. The current analysis was conducted to correlate steady-state systemic exposure parameters with ointment dose and identify covariates impacting PK parameters in healthy participants and patients with atopic dermatitis or psoriasis. A nonlinear regression analysis was conducted using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUCss ] and maximum concentration [Cmax,ss ]). PK data were available from 244 participants across 6 clinical studies (AUCss , N = 239; Cmax,ss , N = 241). Disease condition had the greatest impact on slope in both models, corresponding to 2.5-fold higher AUCss and Cmax,ss values at a given ointment dose in patients with atopic dermatitis or psoriasis relative to healthy participants. Disease severity, race/ethnicity, and sex had marginal effects on AUCss and Cmax,ss . Systemic exposures were similar across age groups ≥2 years of age when the same percentage of body surface area (%BSA) was treated. Predictive performance plots for AUCss and Cmax,ss for different age groups demonstrated that the models adequately describe the observed data. Model predictions indicated that systemic exposure to crisaborole in pediatric patients (2-17 years) is unlikely to exceed systemic exposure in adults (≥18 years), even at the highest possible ointment dose corresponding to a %BSA of 90.

The Bioequivalence of Tafamidis 61-mg Free Acid Capsules and Tafamidis Meglumine 4 × 20-mg Capsules in Healthy Volunteers.

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.

Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.

The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.

Evaluation of QT Liability for PF-05251749 in the Presence of Potential Circadian Rhythm Modification.

PF-05251749 is a dual inhibitor of casein kinase 1 δ/ε, key regulators of circadian rhythm. As a result of its mechanism of action, PF-05251749 may also change the heart rate corrected QT (QTc) circadian rhythm, which may confound detection of drug-induced QTc prolongation. In this analysis, a nonlinear mixed effect model including a multioscillator function was developed in addition to fitting the prespecified linear mixed effect concentration-QTc model, to identify QTc liability of PF-05251749 in the presence of potential circadian rhythm change. The modeling results suggested lack of clinically meaningful QTc prolongation (upper bound of 90% confidence interval for ∆∆QTc < 10 milliseconds) and that the drug-induced QTc circadian rhythm change was not present. However, simulation results indicated that inference of drug-induced QTc prolongation could be misleading if the drug effect on QTc circadian rhythm is not properly addressed. The modeling and simulation results suggest that prespecification of the concentration-QTc model should be reconsidered for drugs with circadian rhythm modulation potential.

A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects.

The effect of steady-state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single-center, randomized, 3-way crossover, double-blind, placebo- and moxifloxacin-controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12-lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed-effect model with sequence, period, treatment, time, and treatment-by-time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure-response was assessed using linear mixed-effect modeling. Fifty-four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10-millisecond significance threshold at the 4-hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635-11.666]). In the exposure-response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P < .0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady-state 400-mg/day dose.

Who do we discharge from renal clinic and what does it mean for primary care?

BACKGROUND: It is unclear whether discharging patients from renal clinic to primary care is safe. AIM: To determine the characteristics, primary care monitoring and renal outcomes of patients discharged from renal clinic. DESIGN AND SETTING: A retrospective study of 2236 adults discharged from a tertiary renal clinic between 2013-2018. METHOD: Patient demographics, primary renal disease, laboratory results and timeline dates were collected from the renal IT system. Timing of blood tests, renal progression, needing dialysis and patient survival were analysed. Reasons for discharge and cause of disease progression were reviewed in patients developing new estimated glomerular filtration rate <20 ml/min/1.73 m2. RESULTS: Patients were older (median age 75; interquartile range 63-84) with non-progressive, seemingly non-proteinuric renal disease. Median time to repeat blood test post-discharge was 75 days with 90% tested within 12 months. Sixty-six percent saw an improvement in kidney function post-discharge and only 13% had a decline of >10 ml/min/1.73 m2. Only 132 patients (6%) developed new advanced chronic kidney disease (estimated glomerular filtration rate < 20 ml/min/1.73 m2) of whom 40% were palliative, 36% had developed acute kidney injury and 23% discharged for failing to attend clinic. One hundred and thirty-four patients (6%) were referred back to nephrology and eight started dialysis of whom six were discharged for failure to attend clinic. CONCLUSION: Most discharged patients are low risk of progressive renal disease and need infrequent monitoring. Non-adherent patients discharged for failing to attend appear to be at risk of poor outcomes and new strategies are needed to better support this population.

Cardiac risk assessment based on early Phase I data and PK-QTc analysis is concordant with the outcome of thorough QTc trials: an assessment based on eleven drug candidates.

Cardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection-union test (IUT). ICH E14 Q&A (R3) (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf) allows for analysis of the PK-QTc relationship using early Phase I data to assess QTc liability. In this paper, we compared the cardiac risk assessment based on the early Phase I analysis with that from a thorough QTc study across eleven drug candidate programs, and demonstrate that the conclusions are largely the same. The early Phase I analysis is based upon a linear mixed effect model with known covariance structure (Dosne et al. in Stat Med 36(24):3844-3857, 2017). The treatment effect was evaluated at the supratherapeutic Cmax as observed in the thorough QTc study using a non-parametric bootstrap analysis to generate 90% confidence intervals for the treatment effect, and implementation of the standardized methodology in R and SAS software yielded consistent results. The risk assessment based on the concentration-response analysis on the early Phase I data was concordant with that based on the standard analysis of the thorough QTc study for nine out of the eleven drug candidates. This retrospective analysis is consistent with and supportive of the conclusion of a previous prospective analysis by Darpo et al. (Clin Pharmacol Ther 97(4):326-335, 2015) to evaluate whether C-QTc analysis can detect QTc effects in a small study with healthy subjects.

Impact of Phase 1 study design on estimation of QT interval prolongation risk using exposure-response analysis.

The International Council for Harmonisation (ICH) guidelines have been revised allowing for modeling of concentration-QT (C-QT) data from Phase I dose-escalation studies to be used as primary analysis for QT prolongation risk assessment of new drugs. This work compares three commonly used Phase I dose-escalation study designs regarding their efficiency to accurately identify drug effects on QT interval through C-QT modeling. Parallel group design and 4-period crossover designs with sequential or interleaving cohorts were evaluated. Clinical trial simulations were performed for each design and across different scenarios (e.g. different magnitudes of drug effect, QT variability), assuming a pre-specified linear mixed effect (LME) model for the relationship between drug concentration and change from baseline QT (ΔQT). Analyses suggest no systematic bias in either the predictions of placebo-adjusted ΔQT (ΔΔQT) or the LME model parameter estimates across all evaluated designs. Additionally, false negative rates remained similar and adequately controlled across all evaluated designs. However, compared to the crossover designs, the parallel design had significantly less power to correctly exclude a clinically significant QT effect, especially in the presence of substantial intercept inter-individual variability. In such cases, parallel design is associated with increased uncertainty around ΔΔQT prediction, mainly attributed to the uncertainty around the estimation of the treatment-specific intercept in the model. Throughout all the evaluated scenarios, the crossover design with interleaving cohorts had consistently the best performance characteristics. The results from this investigation will further facilitate informed decision-making during Phase I study design and the interpretation of the associated C-QT modeling output.

Systemic Tofacitinib Concentrations in Adult Patients With Atopic Dermatitis Treated With 2% Tofacitinib Ointment and Application to Pediatric Study Planning.

Atopic dermatitis is a chronic eczematous, pruritic, inflammatory skin condition affecting children and adults. Tofacitinib is a Janus kinase inhibitor. The efficacy, safety, and pharmacokinetics of 2% tofacitinib ointment twice daily have been evaluated in a 4-week phase 2a multisite randomized, double-blind, vehicle-controlled, parallel-group study (NCT02001181) in adult patients with mild to moderate atopic dermatitis and 2% to 20% body surface area (BSA) involvement. Tofacitinib ointment demonstrated significantly greater efficacy versus vehicle for all efficacy end points and had an acceptable safety profile. Predose and postdose pharmacokinetic samples were collected in week 2 and week 4. The objective of this analysis was to assess if predicted mean tofacitinib concentrations with topical application at higher treated BSA across age groups would exceed relevant concentration thresholds based on oral doses of tofacitinib. In this analysis, the pharmacokinetic concentrations were characterized using a linear mixed-effects model. The model was used to predict concentrations for adults with higher (>20%) treatable BSA. Adult concentrations were used to extrapolate concentrations to a pediatric population (2 to 17 years) using allometric principles. The predicted systemic concentrations for 2% tofacitinib ointment in both adult and pediatric populations at treated BSA ≤50% for a mild to moderate atopic dermatitis population did not exceed those reported for the 10th percentile of observed oral tofacitinib 5-mg twice-daily doses in patients with moderate to severe plaque psoriasis. The methodology described will enable analysis and prediction of systemic concentrations for topical agents.

Correction to: Scientific white paper on concentration-QTc modeling.

The original version of this article unfortunately contained an error in Equation 1 under the section "Pre-specified linear mixed effects model". The correct equation has given below.

Scientific white paper on concentration-QTc modeling.

The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies. Topics included are: important study design features in a phase 1 study; modeling objectives and approach; exploratory plots; the pre-specified linear mixed effects model; general principles for model development and evaluation; and expectations for modeling analysis plans and reports. The recommendations are based on current best modeling practices, scientific literature and personal experiences of the authors. These recommendations are expected to evolve as their implementation during drug development provides additional data and with advances in analytical methodology.

Lack of Effect of Rivipansel on QTc Interval in Healthy Adult African American Male Subjects.

Rivipansel is a pan-selectin inhibitor in phase 3 development for the treatment of vaso-occlusive crises in patients with sickle cell disease. This single-dose, randomized, 3-period, 3-treatment (400 mg moxifloxacin open-label, 4 g rivipansel-blinded, and placebo-blinded) crossover study evaluated the effect of rivipansel on the QT/QTc interval in 48 healthy male African American subjects (age, 21-53 years; weight, 60-115 kg). Time-matched, placebo-adjusted change from baseline QT interval using Fridericia's correction method (QTcF) was determined using a repeated-measures mixed-effects model. The highest upper bound of the 2-sided 90% confidence interval (CI) for QTcF change was 3.22 milliseconds 3 hours postdose. Moxifloxacin showed the anticipated QTcF effect, indicating that the study had adequate sensitivity to detect changes in the QTcF interval. The study concluded that no QTcF effect was demonstrated with rivipansel compared with placebo, as the upper bound of the 2-sided 90%CI was less than 10 milliseconds at all times. Exposure-response modeling for rivipansel concentrations and change from baseline in QTcF data corroborated a lack of effect with rivipansel compared with placebo. Single doses of rivipansel 4 g by intravenous infusion over 20 minutes were well tolerated in this study.

Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.

Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis.