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

Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS)

n/

Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%-92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, -3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, -6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, -5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807)

Amyloid polyneuropathy caused by wild-type transthyretin

IntroductionAmyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene.MethodsWe describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis.ResultsThe diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elderly patients with cardiomyopathy, but a few cases of polyneuropathy have been reported.ConclusionsThis entity is especially noteworthy in light of emerging treatment options for hereditary transthyretin amyloidosis, which are likely to also be beneficial in wild-type disease

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

Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS):14-year update

Abstract Background Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs. Methods Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021). Results This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation. Conclusions This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease. ClinicalTrials.gov Identifier: NCT00628745.http://deepblue.lib.umich.edu/bitstream/2027.42/173793/1/13023_2022_Article_2359.pd

Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

BACKGROUND: The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. METHODS: HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months. RESULTS: HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10−12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. CONCLUSIONS: Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile

A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers

Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population