Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy.

BACKGROUND: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. METHODS: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. RESULTS: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. CONCLUSIONS: Patisiran largely stabilised disease in patients with ATTRv amyloidosis.

Impact of patisiran on health status and quality of life in patients with transthyretin cardiac amyloidosis

INTRODUCTION APOLLO-B is a Phase 3 study of patisiran in patients with transthyretin (ATTR) cardiac amyloidosis (NCT03997383), which demonstrated a significant benefit in functional capacity (6-MWT), and health status and quality of life (QoL) (KCCQ-OS) with patisiran vs placebo at Month (M) 12. HYPOTHESIS Patisiran improves health status and QoL in the daily lives of patients with ATTR cardiac amyloidosis vs placebo. METHODS Patients were 18-85 years old with ATTR amyloidosis and a medical history of heart failure (HF) due to ATTR cardiomyopathy, with ≥1 prior hospitalization for HF or current clinical evidence of HF. Patients were randomized (1:1) to intravenous patisiran 0.3 mg/kg or placebo every 3 weeks. These post-hoc analyses evaluated percentage of responders reporting ≥5-point improvement in KCCQ-OS, and change from baseline in 4 KCCQ domains and questions within the domains. RESULTS 359 patients received study drug (patisiran, N=181; placebo, N=178): median age (range), 76 (41, 85) years; male, 89%; wild-type ATTR, 80%; 25% were on tafamidis at baseline. At M12, patisiran showed significant benefit vs placebo in KCCQ-OS (LS mean [SEM] change from baseline: patisiran, 0.30 [1.26]; placebo, -3.41 [1.28]; LS mean [SEM] difference: 3.71 [1.80]; p=0.0397). A ≥ 5-point improvement in KCCQ at M12 was more frequent with patisiran vs placebo (34.1 vs 24.0%: difference [95% CI] 10.1% [0.7, 19.5]). Improvement vs placebo was consistent across domains, with LS mean differences [95% CI] in change from baseline (patisiran - placebo) in Physical Limitations (2.75 [-1.24, 6.74]), Total Symptoms (4.55 [0.75, 8.34]), QoL (4.27 [-0.12, 8.65]), and Social Limitations (2.76 [-2.21, 7.73]). Categorical changes from baseline to M12 demonstrated greater percentages of placebo-treated patients reporting worsening for questions in each domain, including activities requiring greater cardiometabolic demand. In patients with values at baseline and M12, notably greater percentages (>5%) of placebo- vs patisiran-treated patients reported worsening (percent difference; n=placebo/patisiran) for questions related to Walking 1 Block on Level Ground (10%; n=159/162), Frequency and Burden of Dyspnea (9.5% and 7.6%; n=164/170), Frequency of Orthopnea (9.6%; n=163/170), Feeling about Spending the Rest of Their Life with HF the Way It Is Right Now (6.4%; n=164/170), and Intimate Relationships (6.3%; n=88/86). Improvement from baseline was reported by greater percentages (>5%) of patisiran-treated patients (percent difference; n=patisiran/placebo) in Enjoyment of Life Limited Due to HF (12.8%; n=170/164) and Hobbies/Recreational Activities (6.0%; n=141/143). CONCLUSIONS In APOLLO-B, improvements in health status and QoL with patisiran vs placebo were apparent across all 4 KCCQ domains. Greater percentages of patisiran-treated patients had KCCQ-OS improved by ≥ 5 points at M12 and they more often reported improvements in QoL, and ability to enjoy life and perform hobbies/recreational activities. More placebo-treated patients reported worsening in walking on level ground, HF symptoms and QoL.

Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Patient-reported outcome measures for transthyretin cardiac amyloidosis: the ITALY study.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) has a deep impact on the quality of life (QoL), yet no specific patient-reported outcome measures (PROMs) for ATTR-CA exist. METHODS: The ITALY study involved 5 Italian referral centres (Pisa, Pavia, Ferrara, Florence, Messina) enrolling consecutive outpatients with ATTR-CA. RESULTS: Two 30-item questionnaires were created for wild-type (wt) and variant (v) ATTR-CA. Scores ranged from 100 (best condition) to 0 (worst condition). Out of 140 patients enrolled (77% with ATTRwt-CA), 115 repeated the re-evaluation at 6 months. At baseline, only 30% of patients needed help to fill out the questionnaires. Among baseline variables, all KCCQ and SF-36 domains were univariate predictors of ITALY scores in ATTRwt-CA patients, with the KCCQ Symptom Summary score (beta coefficient 0.759), Social Limitations (0.781), and Overall summary score (0.786) being the strongest predictors. The SF-36 Emotional well-being score (0.608), the KCCQ Overall summary score (0.656), and the SF-36 Energy/fatigue score (0.669) were the strongest univariate predictors of ITALY scores in ATTRv-CA. Similar results were found at 6 months. CONCLUSIONS: The ITALY questionnaires are the first specific PROMs for ATTRwt- and ATTRv-CA. Questionnaire completion is feasible. ITALY scores display close relationships with non-ATTR-specific measures of QoL.

Long-Term Efficacy and Safety of Canakinumab in Patients With Tumor Necrosis Factor Receptor-Associated Periodic Syndrome: Results From a Phase III Trial.

OBJECTIVE: We aimed at assessing efficacy, safety, and tolerability of canakinumab in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) during a 72-week long-term, open-label extension of the CLUSTER study. METHODS: Patients received open-label canakinumab 150 or 300 mg, either every 4 weeks (q4w) or every 8 weeks, with up-titration permitted after on-treatment flares (maximum dose: 300 mg q4w). Efficacy assessments included physician global assessment of disease activity, number of flares, and serum C-reactive protein (CRP) and serum amyloid A protein (SAA) levels. Adverse events were also reported. Results are described for the overall population and according to the cumulative dose of canakinumab adjusted for body weight (<36 mg/kg or ≥36 mg/kg). RESULTS: Of 53 patients entering the final phase (epoch 4) of CLUSTER, 51 completed the treatment. At the end of epoch 4, >94% of patients achieved no or minimal disease activity. Most patients had either no (69.8%) or one flare (24.5%), whereas at baseline, the median number of flares was 9.0 per year. Median CRP levels remained at <10 mg/L. Median SAA concentrations were largely unchanged, with medians of 11.5 mg/L and 14.5 mg/L in the <36 mg/kg and ≥36 mg/kg groups, respectively, at the end of the study. No unexpected safety findings were identified. CONCLUSION: Control of disease activity, with low flare incidence, was maintained with long-term canakinumab treatment in patients with TRAPS during the 72-week final epoch of the CLUSTER study, with no new safety findings.

Serum neurofilament light chain: a promising early diagnostic biomarker for hereditary transthyretin amyloidosis?

BACKGROUND AND PURPOSE: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The recent therapeutic advances have underlined the importance of easily accessible, objective biomarkers of both disease onset and progression. Preliminary evidence suggests a potential role in this respect for neurofilament light chain (NfL). In this study, the aim was to determine serum NfL (sNfL) levels in a late-onset ATTRv population and evaluate whether it might represent a reliable biomarker of disease onset (i.e., 'conversion' from the asymptomatic status to symptomatic disease in TTR mutation carriers). METHODS: In all, 111 individuals harbouring a pathogenic TTR variant (61 symptomatic ATTRv patients and 50 presymptomatic carriers) were consecutively enrolled. Fifty healthy volunteers were included as the control group. Ella™ apparatus was used to assess sNfL levels. RESULTS: Serum NfL levels were increased in ATTRv patients compared to both presymptomatic carriers and healthy controls, whilst not differing between carriers and healthy controls. An sNfL cut-off of 37.10 pg/mL could discriminate between asymptomatic and symptomatic individuals with high diagnostic accuracy (area under the curve 0.958; p < 0.001), sensitivity (81.4%) and specificity (100%). CONCLUSIONS: Serum NfL seems to be a promising biomarker of peripheral nerve involvement in ATTRv amyloidosis and might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease. Further longitudinal studies are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy.

Identification and management of gastrointestinal manifestations of hereditary transthyretin amyloidosis: Recommendations from an Italian group of experts.

Gastrointestinal manifestations are common across all hereditary transthyretin amyloidosis (ATTRv) genotypes. However, they are poorly specific, and their recognition as part of ATTRv is difficult, resulting in misdiagnosis with more common conditions. Moreover, delays in diagnosis occur because of fragmented knowledge, a shortage of centers of excellence and specialists dedicated to ATTRv management, and the scarce involvement of gastroenterologists in multidisciplinary teams. A group of Italian gastroenterologists with experience in the management of ATTRv took part in a project aimed at assessing the awareness of ATTRv among the community of Italian gastroenterologists through an online survey and providing education about practical aspects of ATTRv management. Survey results reported low participation, and very few patients with ATTRv were cared for by gastroenterologists. This highlights the need for greater attention to rare diseases in gastroenterology and emphasizes increasing awareness of ATTRv and diagnostic suspicion. Based on the experts' recommendations, a diagnosis of ATTRv should be suspected when at least one of the 'red flags' is detected. Subsequently, it is suggested to promptly ask for genetic testing and exclude a serum and urinary monoclonal protein, even before the detection of amyloid in biopsy samples, particularly in non-endemic areas.

World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM).

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.

Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

Consensus recommendations on holistic care in hereditary ATTR amyloidosis: an international Delphi survey of patient advocates and multidisciplinary healthcare professionals.

BACKGROUND: Hereditary transthyretin-mediated amyloidosis is a rare, progressive and potentially life-limiting multisystem disease, affecting every aspect of a patient's life. OBJECTIVES: This online international Delphi survey aimed to evolve clinical-patient-led practical guidance, to inspire and encourage a holistic approach to care that is managed in specialist settings by multidisciplinary teams and supported by allied healthcare professionals (HCPs) and patient advocacy groups (PAGs). DESIGN: A 14-member joint patient advocate-HCP primary panel was convened including representation from PAGs and key clinical specialties (neurology, cardiology, internal medicine, physiotherapy, clinical psychology, dietetics and specialist nursing). Guidance evolved on the care provision needed to support seven core goals: early diagnosis and treatment; disease monitoring and organisation of care; maintenance of physical and mental health; family-centred care and caregiver support; patient-doctor dialogue; access to social support and social networking. PARTICIPANTS: From June to October 2022, 252 HCPs and 51 PAG representatives from 27 countries were invited to participate in a Delphi survey. Of the 122 respondents who answered at least one survey question, most were HCPs (100, 82%) from specialist centres; the remainder were PAG representatives (22, 18%). MAIN OUTCOME MEASURE: Both level of agreement and feasibility in practice of each recommendation was tested by two anonymised online Delphi voting rounds. RESULTS: Based on an a priori threshold for consensus of ≥75% agreement, the clinical-patient community endorsed all but one recommendation. However, only 17/49 (35%) recommendations were identified by most HCPs as a core part of routine care; the remainder (32/49 (65%)) were identified as part of core care by <50% of HCPs respondents, or as largely achievable by 30%-45% of HCPs. By comparison, PAGs recorded lower implementation levels. CONCLUSIONS: Further consideration is needed on how to evolve multidisciplinary services (supported by allied HCPs and PAGs) to address the complex needs of those affected by this disease.

Peripheral Nervous, Hepatic, and Gastrointestinal Endpoints for AL Amyloidosis Clinical Trials: Report from the Amyloidosis Forum Multi-organ System Working Group.

Systemic immunoglobulin light chain (AL) amyloidosis is a heterogeneous rare disease driven by a destructive monoclonal gammopathy and typified by misfolded immunoglobulin light and/or heavy chains which aggregate and deposit in organs as insoluble amyloid fibrils. Disease heterogeneity is driven by the degree of multi-systemic involvement; cardiac, renal, neurological, and gastrointestinal (GI) systems are affected to varying degrees in different patients. While prognosis is primarily driven by hematologic response to treatment and outcomes associated with cardiac events and overall survival, the involvement of the peripheral nervous, hepatic, and GI systems can also have a significant impact on patients. The Amyloidosis Forum ( https://amyloidosisforum.org ) is a public-private partnership between the nonprofit Amyloidosis Research Consortium ( www.arci.org ) and the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research formed to advance drug development for the treatment of systemic amyloid disorders. A series of virtual workshops focused on the development of novel, patient-relevant endpoint components and analytical strategies for clinical trials in AL amyloidosis. This review summarizes the proceedings and recommendations of the Multi-Systemic Working Group which identified, reviewed, and prioritized endpoints relevant to the impacts of AL amyloidosis on the peripheral nervous, hepatic, and GI systems. The Working Group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the FDA, Medicines and Healthcare products Regulatory Agency (MHRA), and pharmaceutical companies. Prioritized neuropathy/autonomic endpoints included a modified form of the Neuropathy Impairment Score (NIS + 7) and the Composite Autonomic Symptom Score (COMPASS-31), respectively. Alkaline phosphatase was identified as the most relevant indicator of liver involvement and disease progression. Following extensive review of potential GI endpoints, the Working Group identified multiple exploratory endpoints. These recommended components will be further explored through evaluation of clinical trial datasets and possible integration into composite endpoint analysis.

Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy.

INTRODUCTION: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. METHODS: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. RESULTS: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: -21.0; p = 1.84 × 10-10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I-II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10-7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10-7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10-15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10-15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. CONCLUSION: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03759379.

Magnetic resonance neurography and diffusion tensor imaging of the sciatic nerve in hereditary transthyretin amyloidosis polyneuropathy.

The therapeutic advance in hereditary transthyretin amyloidosis (ATTRv amyloidosis) requires quantitative biomarkers of nerve involvement in order to foster early diagnosis and monitor therapy response. We aimed at quantitatively assessing Magnetic Resonance Neurography (MRN) and Diffusion Tensor Imaging (DTI) properties of the sciatic nerve in subjects with ATTRv-amyloidosis-polyneuropathy (ATTRv-PN) and pre-symptomatic carriers (ATTRv-C). Twenty subjects with pathogenic variants of the TTR gene (mean age 62.20 ± 12.04 years), 13 ATTRv-PN, and 7 ATTRv-C were evaluated and compared with 20 healthy subjects (mean age 60.1 ± 8.27 years). MRN and DTI sequences were performed at the right thigh from the gluteal region to the popliteal fossa. Cross-sectional-area (CSA), normalized signal intensity (NSI), and DTI metrics, including fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) of the right sciatic nerve were measured. Increased CSA, NSI, RD, and reduced FA of sciatic nerve differentiated ATTRv-PN from ATTRv-C and healthy subjects at all levels (p < 0.01). NSI differentiated ATTRv-C from controls at all levels (p < 0.05), RD at proximal and mid-thigh (1.04 ± 0.1 vs 0.86 ± 0.11 p < 0.01), FA at mid-thigh (0.51 ± 0.02 vs 0.58 ± 0.04 p < 0.01). According to receiver operating characteristic (ROC) curve analysis, cutoff values differentiating ATTRv-C from controls (and therefore identifying subclinical sciatic involvement) were defined for FA, RD, and NSI. Significant correlations between MRI measures, clinical involvement and neurophysiology were found. In conclusion, the combination of quantitative MRN and DTI of the sciatic nerve can reliably differentiate ATTRv-PN, ATTRv-C, and healthy controls. More important, MRN and DTI were able to non-invasively identify early subclinical microstructural changes in pre-symptomatic carriers, thus representing a potential tool for early diagnosis and disease monitoring.

World heart federation consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.

Diagnostic pathways to wild-type transthyretin amyloid cardiomyopathy: a multicentre network study.

AIM: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival. METHODS AND RESULTS: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival. CONCLUSIONS: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself.

Echocardiographic findings in subjects with an amyloidogenic apolipoprotein A1 pathogenic variant.

BACKGROUND: Very small case series of patients with apolipoprotein A1 (ApoA1) amyloidosis are available. METHODS: We described the clinical and echocardiographic characteristics of individuals with the pathogenic APOA1 variant Leu75Pro (p. Leu99Pro), referred for cardiac screening. RESULTS: We enrolled 189 subjects, 54% men, median age 55 years (interquartile range 42-67), 39% with concomitant renal disease and 31% with liver disease. Median left ventricular ejection fraction was 60% (55-66). Overall, these subjects did not show overt diastolic dysfunction nor left ventricular (LV) hypertrophy. Age correlated with interventricular septal (IVS) thickness (r = 0.484), LV mass index (r = 0.459), E/e' (r = 0.501), and right ventricular free wall thickness (r = 0.594) (all p < 0.001). Some individuals displayed red flags for cardiac amyloidosis (CA), and 14% met non-invasive criteria for CA. Twenty-nine subjects died over 5.8 years (4.1-8.0), with 10 deaths for cardiovascular causes. Individuals meeting echocardiographic criteria for CA had a much higher risk of all-cause death (p = 0.009), cardiovascular death (p = 0.001), cardiovascular death or heart failure (HF) hospitalisation (p < 0.001). Subjects with both renal and liver involvement had a more prominent cardiac involvement, and shortest survival. CONCLUSIONS: Subjects with the APOA1 Leu75Pro variant displayed minor echocardiographic signs of cardiac involvement, but 14% met echocardiographic criteria for CA. Subjects with suspected CA had a worse outcome.

[Rationale and significance of the Italian Network for Cardiac Amyloidosis]. / Razionale e valore fondamentale della Rete Italiana integrata dell'Amiloidosi Cardiaca.

The perspective on amyloidosis has changed deeply over the last 10 years following major advances in diagnosis and treatment options, especially in cardiac amyloidosis. This intrinsically heterogeneous disease exposes to the risk of fragmentation of knowledge and requires the interaction among experts of different specialties and subspecialties. Suspicion of disease, timely recognition and confirmation of final diagnosis, prognostic stratification, clinical management and therapeutic strategies represent essential steps to be taken. Missing or delaying the diagnosis may have dramatic impact on patient outcome, as in the case of chemotherapy in unrecognized light-chain amyloidosis. Therefore, there is an urgent need for the foundation of an Italian Amyloidosis Network to deal with the challenges of this condition and orient clinical management at national and local levels. The present consensus document aims to provide the rationale and scopes of the Italian Amyloidosis Network, which has been conceived as an organizational framework for professionals managing patients with amyloidosis.