Clinical measures in transthyretin familial amyloid polyneuropathy.

INTRODUCTION: This observational, cross-sectional, single-center study aimed to identify instruments capable of measuring disease progression in transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: The relationship between disease stage and Neuropathy Impairment Score-Lower Limbs (NIS-LL) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score was assessed in 61 (stages 1-3) patients with TTR-FAP (V30M variant) and 16 healthy controls. Composite measures of large- and small-nerve fiber function, and modified body mass index (mBMI) were also assessed. RESULTS: Ordinal-based NIS-LL and Norfolk QOL-DN scores discriminated between disease stages (P < 0.0001 for NIS-LL and Norfolk QOL-DN). Longer disease duration correlated with worse NIS-LL and Norfolk QOL-DN. Karnofsky performance score declined progressively by disease stage. Composite measures of nerve fiber function differentiated stage 1 from stage 2 disease. The mBMI declined with advancing disease. CONCLUSIONS: NIS-LL, Norfolk QOL-DN score, composite endpoints of nerve fiber function, and mBMI are valid, reliable measures of TTR-FAP severity. Muscle Nerve 55: 323-332, 2017.

Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.

The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A-retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K(d)s ~2 nM and ~200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.

Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy.

The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire is an instrument to assess QOL in diabetic polyneuropathy. The objective of this observational, cross-sectional study in 61 patients with V30M transthyretin familial amyloid polyneuropathy (TTR-FAP) and 16 healthy volunteers was to validate the Norfolk QOL-DN for assessment of QOL in TTR-FAP. Comparisons were conducted to identify the best items to discriminate disease stages and assess which individual Norfolk domains (symptoms, large fiber, small fiber, autonomic, and activities of daily living) would be most affected by disease stage. Analysis of individual items revealed a significant pattern of discrimination among disease stages (p < 0.001). Total QOL scores increased (indicating worsening) with duration of symptoms, with a steeper increase observed earlier in the course of disease. Significant correlations were observed between each Norfolk domain and other measures of neurological function. Limitations include cross-sectional study design, low patient numbers in this rare disease, and the ordinal-based character of the metric used; future areas to explore include item response theory approaches such as Rasch analysis. These results suggest the Norfolk QOL-DN is a reliable indicator of the impact of disease severity on QOL in patients with TTR-FAP.

Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1-2/3-6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1-2/3-6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7-53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 103  mm3 with palovarotene 10/5 mg; 1.3 × 103  mm3 with palovarotene 5/2.5 mg; 18.0 × 103  mm3 with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes.

BACKGROUND: Transthyretin (TTR) amyloidosis is a progressive systemic disorder caused by misfolded TTR monomers that cumulatively deposit in the heart and systemically as amyloid. METHODS AND RESULTS: This phase 2 open-label trial evaluated the stabilization of TTR tetramers using 20 mg of tafamidis daily at week 6 (primary end point), month 6, and month 12, as well as safety of tafamidis treatment and efficacy with respect to progression of TTR amyloid cardiomyopathy. Thirty-one wild-type patients (median age, 76.7 years; 93.5% men) with a median disease duration of 55.6 months and mild to moderate heart failure (96.8%; New York Heart Association, classes I-II) were enrolled. Thirty of 31 patients (96.8%) achieved TTR stabilization after 6 weeks and 25 of 28 patients (89.3%) after 12 months. After 12 months of treatment, 3 patients discontinued prematurely, 2 patients died, 7 patients were hospitalized because of cardiovascular events, 20 of 28 patients demonstrated preserved New York Heart Association classification status, but 15 of 31 (48.4%) patients had clinical progression (eg, admission for cardiac failure, atrial fibrillation, and syncope). N-terminal prohormone brain natriuretic peptide levels did not increase significantly over time, troponin I and troponin T increased moderately, and no consistent clinically relevant changes were seen in echocardiographic cardiac assessments. Tafamidis treatment was generally well tolerated although 7 of 31 patients had bouts of diarrhea. CONCLUSIONS: Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated. The absence of significant changes in most biochemical and echocardiographic parameters suggests that further evaluation of tafamidis in TTR amyloid cardiomyopathy is warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00694161.

Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis.

This phase II, open-label, single-treatment arm study evaluated the pharmacodynamics, efficacy, and safety of tafamidis in patients with non-Val30Met transthyretin (TTR) amyloidosis. Twenty-one patients with eight different non-Val30Met mutations received 20 mg QD of tafamidis meglumine for 12 months. The primary outcome, TTR stabilization at Week 6, was achieved in 18 (94.7%) of 19 patients with evaluable data. TTR was stabilized in 100% of patients with non-missing data at Months 6 (n = 18) and 12 (n = 17). Exploratory efficacy measures demonstrated some worsening of neurological function. However, health-related quality of life, cardiac biomarker N-terminal pro-hormone brain natriuretic peptide, echocardiographic parameters, and modified body mass index did not demonstrate clinically relevant worsening during the 12 months of treatment. Tafamidis was well tolerated. In conclusion, our findings suggest that tafamidis 20 mg QD effectively stabilized TTR associated with several non-Val30Met variants.

Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy.

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.

Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial.

OBJECTIVES: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. RESULTS: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. CONCLUSIONS: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.

Pressure-volume relationships in patients with transthyretin (ATTR) cardiac amyloidosis secondary to V122I mutations and wild-type transthyretin: Transthyretin Cardiac Amyloid Study (TRACS).

BACKGROUND: ATTR cardiac amyloidosis can result from a mutated variant of transthyretin (eg, V122I) or wild-type variant (ATTRwt). We evaluated pressure-volume (PV) indices at baseline and over time to further characterize abnormal pump function in these subjects. METHODS AND RESULTS: Twenty-nine subjects (18 with ATTRwt and 11 with ATTRm (V122I) had 2-dimensional echocardiograms with complete Doppler measures at baseline and every 6 months for up to 2 years. PV indices were derived from echocardiographic measures of ventricular volume coupled with sphygmomanometer-measured pressure and Doppler estimates of filling pressure. The end-systolic and end-diastolic PV relations and the area between them as a function of end-diastolic pressure, the isovolumic PV area (PVA(iso)), were calculated. Clinical, demographic, and PV indices were compared between V122I and ATTRwt subjects and between survivors and nonsurvivors at baseline and over time. Cox proportional hazards model identified correlates for mortality. Stroke volume decline was associated with alterations in ventricular-vascular coupling and a decrease in ventricular capacitance with significant decrement in ejection fraction (56±12% to 48±14%, P=0.0001) over 18 months. PVA(iso) was lower in V122I subjects compared with wild-type at baseline and declined over time. Twelve (41%) subjects died or underwent a cardiac transplant after a mean follow-up of 478 days (range, 31 to 807). Multivariable survival analysis demonstrated that initial ejection fraction (a measure of ventricular-vascular coupling) <50% was associated with increased mortality (hazard ratio, 6.6; 95% confidence interval, 1.1 to 40.3). CONCLUSIONS: In ATTR cardiac amyloidosis secondary to a V122I mutation and wild-type transthyretin, PV analysis reveals alterations that are associated with reductions in the ability of the ventricle to perform work and, ultimately, with reduced survival in these subjects.