Cardiovascular Burden of the V142I Transthyretin Variant.

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

Amyloidogenicity assessment of transthyretin gene variants.

OBJECTIVE: Hereditary transthyretin-mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the transthyretin-gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineation of these into pathogenic or non-pathogenic is highly desirable but hampered by low frequency and penetrance. We thus sought to characterize their amylogenic potential by an unbiased in vitro approach. METHODS: Thioflavin T and turbidity assays were used to compare the potential of mammalian cell expressed wt-transthyretin and 12 variant proteins (either variants of uncertain significance, benign, pathogenic) to aggregate and produce amyloid fibrils in vitro. As proof of principle, the assays were applied to transthyretin-Ala65Val, a variant that was newly detected in a family with peripheral neuropathy and amyloid deposits in biopsies. In silico analysis was performed to compare the position of the benign and pathogenic variants. RESULTS: Transthyretin-Ala65Val showed a significantly higher amyloidogenic potential than wt-transthyretin, in both turbidity- and Thioflavin T-assays, comparable to known pathogenic variants. The other eight tested variants did not show an increased amyloidogenic potential. In silico structural analysis further confirmed differences between pathogenic and benign variants in position and interactions. INTERPRETATION: We propose a biochemical approach to assess amyloidogenic potential of transthyretin variants. As exemplified by transthyretin-Ala65Val, data of three assays together with histopathology clearly demonstrates its amyloidogenicity.

Immunohistochemical Assessment of Transthyretin Association with Colorectal Adenocarcinoma.

BACKGROUND: To explore the association of transthyretin (TRR) with colorectal cancer (CRC) development and progression. METHODS: This study was conducted on 12 normal colorectal tissue samples, 15 colorectal adenomas, and 39 colorectal adenocarcinoma tissue specimens. TTR expression was assessed by immunohistochemistry, and the results were correlated to clinicopathological characteristics of CRC patients. RESULTS: TTR staining was detected in 16.7% (2/12) of normal colon tissues, 46.7% (7/15) of colorectal adenomas, and 89.7% (35/39) of colorectal adenocarcinoma tissues. TTR staining scores in normal colon tissues, adenoma, and adenocarcinoma were 0.58, 2.27, and 5.40, respectively. G3 grade adenocarcinoma had a higher TTR staining score compared with G2 and G1 grades (8.40, p = 0.0009). Lower TTR expression was significantly associated with metastasis (p = 0.043). CONCLUSIONS: TTR expression is positively correlated with adenoma to CRC progression. Thus, TTR has the potential to serve as a predictive marker in CRC.

The patient journey toward a diagnosis of hereditary transthyretin (ATTRv) amyloidosis.

BACKGROUND: Despite emerging treatments for hereditary transthyretin (ATTRv) amyloidosis, the disease is often misdiagnosed, with reported diagnostic delays of up to several years. Knowledge of the patient journey leading up to diagnosis may help to promote earlier intervention. The study's objective was to examine patient clinical characteristics and healthcare utilization prior to ATTRv amyloidosis diagnosis. METHODS: Patients ≥ 18 years and newly diagnosed with ATTRv amyloidosis identified in IBM® MarketScan® Commercial and Medicare Supplemental data using a claims-based algorithm as follows: diagnosis required ≥ 1 medical claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9; excludes light chain and wild type) during identification (ID) period (1/1/2016-12/31/2017), and ≥ 1 occurrence of qualifying criteria during 2011-2017: ≥ 15 days diflunisal use without > 30-day gap, liver transplant, or claim with specific codes E85.1 or E85.2. The index date was defined as the date of first claim with amyloidosis diagnosis code in ID period. Patients had continuous enrollment ≥ 5 years pre-index date (look-back period). Occurrence of selected comorbid conditions and symptoms and healthcare utilization (testing, emergency department visits and hospitalization) measured during the look-back period; demographics, physician specialty, and Charlson comorbidity index (CCI) measured 1 year pre-index. Patients with an ICD-9/10 amyloidosis code during the look-back period were excluded. An ATTRv-free reference cohort was created from a random sample of enrollees who lacked any diagnosis of amyloidosis and matched 3:1 to ATTRv patients on age, gender, and region to provide reference values; same index and enrollment requirement as match. RESULTS: For the 141 qualifying patients with ATTRv and 423 matched controls, mean (standard deviation) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for ATTRv cohort was 2.7 (3.0) versus 1.1 (1.9) among controls. Selected comorbidities, testing, visits, and hospitalization were common among patients with ATTRv during the look-back period with higher rates versus controls. CONCLUSIONS: Patients with ATTRv amyloidosis experience multiple neurological, cardiovascular, and other clinical manifestations, testing, and hospitalization prior to diagnosis. Occurrence of potential markers of illness is most common in the year before diagnosis.

Immunogenicity Assessment of Inotersen, a 2'-O-(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety.

Inotersen (TEGSEDI™) is a 2'-O-(2-methoxyethyl)-modified antisense oligonucleotide, intended for treating hereditary transthyretin (TTR) amyloidosis with polyneuropathy. The potential immunogenicity (IM) response to inotersen was evaluated in chronic nonclinical safety studies and the pivotal phase 2/3 clinical study. The evaluation was designed to assess the characteristics of antidrug antibodies (ADAs) and their effects on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety in animals and humans. No immunogenic response was observed after long-term treatment with inotersen in mice. In monkeys, the incidence rate of IM to inotersen appeared to be dose dependent, with 28.6%-50.0% of animals developing ADAs after 36 weeks of treatment. This was characterized as late onset (median onset of 185 days) with low titers (median titer of 8, or 400 if minimum required dilution of 50 is included). The overall incidence rate of patients who developed ADAs was 30% after 65 weeks of treatment with median onset of 203 days and median peak titer of 300. IM had minimal effect on plasma peak (Cmax) and total exposure (i.e. area under curve, AUC) of inotersen, but showed elevated plasma trough levels in both IM-positive animals and humans. However, ADAs had no effect on tissue exposure, TTR messenger RNA, or plasma TTR levels in the long-term monkey study. Similarly, IM showed no effect on plasma TTR levels in clinical studies. Thus, ADAs antibodies were binding antibodies, but not neutralizing antibodies. Finally, no association was observed between IM and toxicity findings (eg, platelet, complement activation, and histopathology findings) in the inotersen 9-month monkey study. In humans, no difference was observed in hematology, including platelets, kidney function tests, or incidence of adverse events between IM-positive and -negative patients. Overall, IM showed no effect on toxicity or safety of inotersen evaluated in both monkeys and humans. ClinicalTrials.gov Identifier: NCT01737398.

Assessment of patients with hereditary transthyretin amyloidosis - understanding the impact of management and disease progression.

Timely diagnosis of hereditary variant transthyretin (ATTRv) amyloidosis is critical for appropriate treatment and optimal outcomes. Significant differences are seen between patients receiving treatment and those who are not, though disease progression may continue despite treatment in some patients. Healthcare professionals caring for patients with ATTRv amyloidosis therefore need reliable ongoing assessments to understand the continuing course of disease and make appropriate treatment choices on an individual basis. Various signs and symptoms experienced by patients may be evaluated as indicators of disease progression, though there is currently no validated score that can be used for such ongoing assessment. Recognizing this situation, a group of clinicians highly experienced in ATTR amyloidosis developed an approach to understand and define disease progression in diagnosed and treated patients with ATTRv amyloidosis. The suggested approach is based on the recognition of distinct phenotypes which may usefully inform the particular tools, tests and investigations that are most likely to be appropriate for individual patients. It is aimed at implementing appropriate and ongoing assessment of patients being treated for ATTRv amyloidosis, such that the effectiveness of management can be usefully assessed throughout the course of disease and management can be tailored according to the patient's requirements.

Assessment of autonomic innervation of the foot in familial amyloid polyneuropathy.

BACKGROUND AND PURPOSE: Distal involvement of autonomic nerve fibers is critical in familial amyloid polyneuropathy (FAP) due to transthyretin (TTR) mutation. This study compares different methods for assessing autonomic foot innervation in TTR-FAP patients. METHODS: Three groups of seven TTR-FAP patients were included, according to disease severity: clinically asymptomatic, moderate or advanced neuropathy. The autonomic investigation included the eutectic mixture of local anesthetics test and laser Doppler flowmetry for vasomotor aspects and the Sudoscan® (measuring electrochemical skin conductance) and Neuropad® test for sudomotor aspects. Somatic innervation was assessed by performing nerve conduction studies, quantitative sensory testing [including vibration, cold and warm detection threshold (WDT) measurements] and laser evoked potentials. RESULTS: The results of all neurophysiological tests varied according to TTR-FAP severity (P ≤ 0.01, Kruskal-Wallis test), except for the eutectic mixture of local anesthetics test and laser Doppler flowmetry variables. In addition, the sudomotor tests (Sudoscan or Neuropad) or WDT measurement provided early markers of neuropathy in two of the seven asymptomatic carriers. Finally, all neurophysiological results correlated with the Neuropathy Impairment Score (r values between -0.88 and -0.66, P < 0.005, Spearman test), except the cold detection threshold. CONCLUSIONS: The Neuropad test could be used to detect TTR-FAP onset, but confirmation requires electrochemical skin conductance and WDT measurement. The Sudoscan technique, but not the Neuropad test (at least assessed at a fixed time point), could be valuable to follow the progression of the neuropathy. Follow-up investigation should also include large-fiber investigation (e.g. nerve conduction studies and vibration detection threshold). Conversely, reliable tests for assessing vasomotor disturbances in limb extremities of TTR-FAP patients are still awaited.

The Effectiveness and Value of Patisiran and Inotersen for Hereditary Transthyretin Amyloidosis.

DISCLOSURES: Funding for this summary was contributed by the Laura and John Arnold Foundation, Blue Shield of California, and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Cambia Health Solutions, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Prime Therapeutics, Sanofi, Spark Therapeutics, Health Care Service Corporation, Editas, Alnylam, Regeneron, Mallinkrodt, Biogen, HealthPartners, and Novartis. Mickle, Dreitlein, and Pearson are ICER employees. Lasser, Cipriano, and Hoch have nothing to disclose.

TTR Gene Silencers for Hereditary ATTR Amyloidosis: More than ICER Recognized.

DISCLOSURES: No funding support was received for the writing of this commentary. The author ser ves as a consultant for Akcea Therapeutics, Alnylam Phar maceuticals, Corino Therapeutics, Intellia Therapeutics, and Ionis Pharmaceuticals.

The value of electrochemical skin conductance measurement using Sudoscan® in the assessment of patients with familial amyloid polyneuropathy.

OBJECTIVE: To reappraise the value of electrochemical skin conductance (ESC) measurement by Sudoscan® to assess the distal involvement of small autonomic fibers in familial amyloid polyneuropathy (FAP) due to various transthyretin (TTR) mutations. METHODS: ESC was measured at both hands and feet in 126 patients with either Val30Met (n = 65) or non-Val30Met (n = 61) TTR mutation. This series included clinically asymptomatic (n = 21) and paucisymptomatic (n = 30) patients, as well as patients with moderate (n = 37) or advanced (n = 38) TTR-FAP. RESULTS: ESC measures did not differ between patients according to the type of TTR variant and were reduced in 24% of clinically asymptomatic patients, 40% of paucisymptomatic patients, 65% of patients with moderate TTR-FAP, and 92% of patients with advanced TTR-FAP. ESC measures were found to correlate with patients' clinical status, especially assessed by the Neuropathy Impairment Score and Karnofsky Performance Status. CONCLUSION: ESC measures well correlate with the severity of TTR-FAP and could provide early marker of the disease. SIGNIFICANCE: ESC measures appear to be relevant to evaluate distal autonomic involvement in the context of amyloidosis.

Tafamidis meglumina no tratamento da polineuropatia amiloidótica familiar relacionada à proteína transtirretina / Tafamidis meglumine in the treatment of familial amyloid polyneuropathy related to transthyretin protein

CONTEXTO: A polineuropatia amiloidótica familiar relacionada à transtirretina (PAF-TTR) é uma doença genética neurodegenerativa progressiva altamente incapacitante, irreversível e fatal. As manifestações clínicas são variadas, mas a principal disfunção é uma polineuropatia sensório-motora e autonômica progressiva e irreversível. O tratamento envolve medidas para aliviar sintomas e, em casos selecionados, o transplante hepático. No Brasil, estima-se que existam 4.800 pacientes com esta condição. TECNOLOGIA: Tafamidis meglumina (Vyndaqel®). INDICAÇÃO: Tratamento da amiloidose associada à transtirretina em pacientes adultos com polineuropatia sintomática em estágio inicial e não submetidos a transplante hepático. PERGUNTA: O uso de tafamidis é eficaz, seguro e custo-efetivo no tratamento da polineuropatia amiloidótica familiar relacionada à transtirretina em pacientes com estágio inicial da doença? EVIDÊNCIAS CIENTÍFICAS: O demandante apresentou sete artigos sobre o medicamento e uma busca complementar para este relatório identificou mais um. De todos os estudos selecionados, apenas um foi ensaio clínico randomizado, controlado por placebo, duplo-cego, sem limitações metodológicas importantes. Entretanto, houve perda de mais de 20% da amostra, com impactos no poder estatístico. Análise por intenção de tratar não demonstrou benefício em escalas de sintomas neurológicos e qualidade de vida. Análise por protocolo e de desfechos secundários, houve benefício com o uso do tafamidis (proporção de pacientes sem progressão neurológica definida pela NIS-LL de 60,0% para intervenção e 38,1% para placebo, p = 0,041; diferença de média no escore de qualidade de vida TQOL foi de 0,1 pontos no grupo intervenção e de 8,9 no grupo placebo, p = 0,045). Demais artigos não foram considerados. AVALIAÇÃO ECONÔMICA: Custo-utilidade cujo comparador foi ausência de tratamento. O uso de tafamidis resultou em ganhos em qualidade de vida (QALY de 6,48 para 9,01, incremento de 2,54) e em anos de vida (de 10,05 para 13,28, incremento de 3,24), com uma razão de custoutilidade incremental de R$ 974.617/QALY e de R$ 763.609/ano de vida salvo. Modelo apresentado possui crítica em sua validade interna, como ausência de descrição clara dos parâmetros utilizados para população em estudo e dos detalhes da análise de microssimulação; ausência de descrição sobre avaliação de incerteza estocástica (variabilidade); pressupostos utilizados para determinação de eficácia do medicamento e progressão da doença (afetando qualidade de vida e sobrevida) e falta de dados para determinar a incerteza paramétrica do modelo (validade externa limitada). AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: Necessidade de R$ 18,9 milhões no primeiro ano após a incorporação e de R$ 397,5 milhões em cinco anos. Estimativa com validade questionada. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificados 4 medicamentos em desenvolvimento clínico para o tratamento da PAF-TTR (fase 2 ou 3): diflunial (Dolobid®), tolcapona (Tasmar®), Oligonucleotídeo fosfotiorato específico da transtirretina (Inotersen®; ISIS TTR Rx; ISIS-GSK1 Rx; IONIS-TTRRx) e Oligoleucleotídeo de siRNA de cadeia dupla sintético dirigido contra mRNA de transtirretina (Patisiran®; ALN-TTR02). CONSIDERAÇÕES: Baixa confiança na evidência do uso do tafamidis na PAF-TTR, baseada em análise secundária de um único ensaio clínico com desfecho que não é crítico para a tomada de decisão clínica. Eficácia comparativa com outras opções terapêuticas não foi avaliada. Análise econômica com validade questionável. Impacto orçamentário com custo significativo. RECOMENDAÇÃO PRELIMINAR: O Plenário, em sua 57ª reunião ordinária (05/07/2017), recomendou a incorporação no SUS do tafamidis meglumina para tratamento da amiloidose associada à transtirretina em pacientes adultos com polineuropatia sintomática em estágio inicial e não submetidos a transplante hepático. CONSULTA PÚBLICA: Foram recebidas 70 contribuições técnico-científicas e 764 sobre experiência ou opinião. Na 61ª reunião ordinária, após apreciação das contribuições, o plenário da CONITEC considerou contundente a necessidade de retomar a análise do tema incluindo as evidências apresentadas pela contribuição contrária. Na 62ª reunião ordinária, após apreciação das evidências trazidas pela contribuição contrária, o plenário entendeu que não houve nova informação, mantendo recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da CONITEC presentes na 62ª reunião ordinária, no dia 07 de dezembro de 2017, deliberaram, por unanimidade, por recomendar a incorporação no SUS do tafamidis meglumina para tratamento da amiloidose associada à transtirretina em pacientes adultos com polineuropatia amiloidótica familiar sintomática em estágio inicial e não submetidos a transplante hepático, mediante negociação de preço e Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde. Foi assinado o Registro de Deliberação nº 320/2017. A recomendação será encaminhada para decisão do Secretário da SCTIE. DECISÃO: Incorporar o tafamidis meglumina para pacientes adultos com polineuropatia sintomática em estágio inicial e não submetidos a transplante hepático, mediante negociação de preço e Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde, no âmbito do Sistema Único de Saúde ­ SUS. A decisão foi dada pela Portaria SCTIE-MS nº 02 publicada no Diário Oficial da União (DOU) nº 13, de 18 de janeiro de 2018, pág. 56.(AU)