Transthyretin Stabilizer Research Articles

New therapies to treat cardiac amyloidosis.

Review advancements in therapies for transthyretin (ATTR-CM) and immunoglobulin light chain (AL-CM) cardiac amyloidosis. In ATTR-CM, tafamidis remains the cornerstone therapy, with Food and Drug Administration (FDA) approval for over 5 years. Acoramidis, another transthyretin stabilizer, has very recently been FDA-approved following positive results in the ATTRibute-CM trial. Vutrisiran, a transthyretin gene silencer, demonstrated efficacy in the HELIOS-B trial and awaits FDA review. Eplontersen's CARDIO-TTRansform trial, the largest ATTR-CM study to date, is expected to report by late 2025. Innovative approaches such as NTLA-2001 (a CRISPR-Cas9 therapy) and fibril depleters like ALXN2220 and coramitug are advancing in clinical trials. In AL-CM, daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) has established itself as the standard of care. Novel antiplasma cell therapies include CAR-T cells and bispecific antibodies (teclistimab) and fibril depleters. Birtamimab improved survival in advanced AL-CM during the VITAL trial and is under investigation in AFFIRM-AL. Anselamimab is in phase III CARES trials, whereas AT-02 undergoes early-phase testing for ATTR-CM and AL-CM. The therapeutic landscape for ATTR-CM and AL-CM is rapidly evolving, driven by novel therapies targeting diverse mechanisms. Ongoing clinical trials promise to further refine the standard of care and improve outcomes for patients with cardiac amyloidosis.

Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial

Background: In the phase 3 randomized controlled study, ATTRibute-CM, acoramidis, a transthyretin (TTR) stabilizer, demonstrated significant efficacy on the primary endpoint. Participants with transthyretin amyloid cardiomyopathy (ATTR-CM) who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. Methods: Participants who previously received acoramidis through Month 30 (M30) in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through M30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through Month 42 (M42) included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), serum TTR, and the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). Safety outcomes were analyzed through M42. Results: Overall, 438 of 632 participants in ATTRibute-CM completed treatment and 389 enrolled in the ongoing OLE (263 continuous acoramidis, 126 placebo to acoramidis). The hazard ratio (HR) (95% CI) for ACM or first CVH was 0.57 (0.46, 0.72) at M42 based on a stratified Cox proportional hazards model ( P -value < 0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with HRs (95% CI) of 0.64 (0.47, 0.88) and 0.53 (0.41, 0.69), respectively, at M42. Treatment effects for NT-proBNP and 6MWD also favored continuous acoramidis. Upon initiation of open-label acoramidis in the placebo-to-acoramidis arm there was a prompt increase in serum TTR. Quality of life assessed by KCCQ-OS was well preserved in continuous acoramidis participants compared with the placebo to acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. Conclusions: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through M42 of the ongoing OLE study was associated with sustained clinical benefits in a contemporary ATTR-CM cohort, with no clinically important safety issues newly identified.

Eplontersen (Wainua)

Canada’s Drug Agency (CDA-AMC) recommends that Wainua be reimbursed by public drug plans for the treatment of polyneuropathy (PN) associated with stage I or stage II hereditary transthyretin amyloidosis (hATTR) in adults, if certain conditions are met. Wainua should only be covered to treat adults with stage I or stage II genetically confirmed hATTR with PN (hATTR-PN) who are symptomatic with early-stage neuropathy, do not have severe heart failure symptoms, and have not had a liver transplant. A patient’s response to treatment with Wainua should be assessed at least every 6 months to determine whether they would benefit from continued treatment. Treatment with Wainua should not be continued in patients who are permanently bedridden and dependent on assistance for basic activities of daily living or who are receiving end-of-life care. Wainua should only be reimbursed if the patient is under the care of a specialist with experience in the diagnosis and management of hATTR-PN, and should not be reimbursed if it is used in combination with interfering ribonucleic acid (RNA) drugs or transthyretin stabilizers. The cost of Wainua should be reduced so that it does not cost more than other drugs for hATTR.

Delays in diagnosis and treatment initiation of ATTR cardiac amyloidosis: a real-world data analysis

Abstract Introduction Cardiac amyloidosis (CA) is a serious condition characterized by the accumulation of abnormal protein deposits in the heart muscle, leading to functional impairments and, ultimately, heart failure. Transthyretin amyloid cardiomyopathy (ATTR-CM) is the most common form encountered in CA diagnosis with previously underestimated prevalence. ATTR-CM poses a diagnostic challenge, with a substantial number of cases diagnosed late and at advanced stages. The availability of specific pharmacological treatment using the transthyretin-stabilizer tafamidis further emphasizes the need for timely diagnosis. Here, we aim to assess delays in diagnosis and initiation of therapy in a real-world collective of patients with ATTR-CM. Methods All individuals diagnosed from 01/2018 to 05/2023 with ATTR-CM at our university hospital, Germany, were systematically assessed for eligibility in this study. Specifically, we enrolled patients who were undergoing transthyretin stabilizer therapy. The investigation aimed to determine the duration, in days, from the initial suspicion of heart disease to the definitive diagnosis of ATTR-CM. It was also investigated whether the diagnosis of ATTR-CM was made more quickly over time as awareness increased. Additionally, the study assessed the time elapsed until patients received pharmacological therapy following the confirmed diagnosis. The study was approved by the local ethics committee (23-11500-BO). Results After screening of 194 consecutive patients, 154 were included in the analysis, while 40 patients were excluded due to insufficient records. The results of this study reveal that a median of 300 (113-962) days elapsed from the initial suspicion of amyloidosis to the final confirmation. Initial indications of CA often presented as nonspecific symptoms such as unclear dyspnea (16.2% n=25), abnormal echocardiography (75.3% n=116), or, in rare cases, incidental findings (8.4% n=13). Following the diagnosis, an additional median of 84 (46-163.5) days passed before the first prescription of a transthyretin stabilizer. To assess an improvement of ATTR-CM diagnosis over time, we stratified the data into tertiles by date of first diagnosis. The results showed a gradually decrease in medium time to diagnosis of 466 (181-1035) days in the earliest tertile (2018-2019) to 389 (141-1508) days in the most recent tertile (2022-2023) (p<0.001). Conclusion This study shows a major healthcare deficit and underscores the medical need for improved screening procedures and diagnostic modalities to expedite the timely diagnosis of CA, as early identification of the condition is crucial for enhancing the quality of life for patients and preventing life-threatening complications.

Tafamidis for the treatment of transthyretin cardiac amyloidosis (ATTR-CM) - Real-world data from a tertiary center

Abstract Introduction Tafamidis 61mg was shown to be the first treatment to reduce cardiovascular hospitalizations and to improve survival in patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM). Real-world data on the efficacy of transthyretin (TTR) stabilizers in patients with Heart Failure (HF) due to ATTR-CM is scarce. Purpose We aimed to assess the use of tafamidis in our center, that features a dedicated Cardiomyopathy Clinic. Methods We conducted an all-comers single-centre prospective study of consecutive patients with symptomatic HF due to ATTR-CM followed up to November 2023. As per site protocol, the diagnosis was established according to the ESC algorithm and all patients were assessed at least twice yearly. Disease management plans include HF treatment tailored to ATTR-CM (CHAD-STOP) and treatment with disease-modifying tafamidis 61mg. The latter is considered in patients who meet the local protocol criteria, including key inclusion criteria - NYHA class I-II - and none of the exclusion criteria - e.g. estimated glomerular filtration rate (GFR) <25mL/min. The primary endpoint was time to cardiovascular hospitalization or all-cause death. Results A total 226 ATTR-CM patients were identified, of whom 181 had a follow-up of at least 6 months and were included in the analysis (mean age 84 ± 7 years; 81% males, 16% hATTR-CM). Overall, there were 84 patients treated with tafamidis. Compared to non-treated patients, those receiving tafamidis were younger (mean age 83 vs. 86 years, p=0.007), more often with a lower NYHA functional class (e.g., NYHA I-II: 92 vs. 62%; p<0.001), scored higher on performance scales (e.g., Karnovsky >70: 67 vs 33%; p<0.001), and had less comorbidities (e.g., GFR: 40 vs. 30mL/min; p<0.001). Over a median follow-up of 16 months, 68 (37.6%) patients met the primary endpoint (49.5% vs. 22.6%, respectively; p<0.001). In multivariate analysis, treatment with tafamidis was an independent predictor of the primary endpoint (HR 0.24; 95%CI 0.13-0.43; p<0.001), adjusted for NYHA functional class (HR for NYHA I-II vs. III-IV: 0.54; 95%CI 0.32-0.92; p=0.023), NT-proBNP (HR 1.83; 95%CI 1.09-3.08; p=0.023) and high-sensitivity Troponin T (HR per 10 units: 1.01; 95%CI 1.01-1.02; p=0.024). These findings were consistent in multivariate analysis with any combination of the prior variables with either creatinine, GFR, albumin, or TTR type (wild-type vs. mutated). These results were primarily driven due to association of tafamidis treatment with increased survival. Conclusion The use of tafamidis in a cohort of patients with symptomatic HF and ATTR-CM was shown to be independently associated with reduced cardiovascular hospitalization or all-cause death. The effect had a similar magnitude of effect to that of the ATTR-ACT trial, suggesting that our local protocol based on the key criteria from this trial may allow for appropriate patient selection.

Detection of ATTR cardiac amyloidosis using a novel artificial intelligence algorithm for wearable-adapted noisy single-lead electrocardiograms

Abstract Background Amyloid cardiomyopathy (ATTR-CM) is often underdiagnosed, with very few diagnosed before the onset of symptoms, leading to delayed use of disease-modifying therapies that could have substantial prognostic implications early in the disease course. In the US, the disease has a substantially higher prevalence among Black adults, who are further challenged by lower access to healthcare services and lower preventative care, further reducing the ability for clinician-led diagnosis. We sought to develop an approach for identifying ATTR-CM on noisy single-lead ECGs obtainable on portable and wearable ECG devices, allowing broad use in community screening. Purpose To develop a portable/wearable device-adapted AI-ECG algorithm capable of detecting ATTR-CM on noisy single-lead ECGs. Methods We identified patients with ATTR-CM from 2015 through June 2023 across 5 hospitals of a large U.S.-based hospital system using positive bone scintigraphy scans or pharmacotherapy with an approved transthyretin stabilizer. In the development cohort, we used lead I of 12 lead ECGs, commonly captured by portable and wearable ECG devices, to train a novel noise-adapted model explicitly designed to infer information against simulated real-world noises. For this, ECG signals were augmented using random Gaussian real-world noise within four frequency ranges at multiple signal-to-noise ratios. We tested the model in an independent set of cases and matched controls drawn from July through December 2023. Results The development cohort consisted of 1,011 ECGs from 234 patients (median age 79 years [IQR:70-85], 17% women), with 10:1 age- and sex-matched 10,110 controls with 10,110 ECGs (age 79 [IQR:70-85] years 17.7% female). In the independent test set of 139 ECGs from 47 patients (age 80 [75-86] years, 32% women) and matched controls (1390 ECGs and patients) from July through December 2023, the AUROC (area under the receiver operating characteristic curve) of the AI-ECG model for ATTR-CM was 0.90 [95%CI: 0.88-0.92] (A). The AUPRC was 0.44 [0.36-0.53]. The sensitivity and specificity of the model were 0.85 and 0.80. The positive predictive value ranged from 0.12 at a 3% prevalence level to 0.59 at a 25% prevalence (B). Conclusions A novel portable and wearable-devices adapted model demonstrates promising performance for detecting ATTR-CM on single-lead ECGs, representing a more accessible method for screening in community-dwelling adults.

Characterizing the progression of subclinical cardiac amyloidosis through artificial intelligence applied to electrocardiographic images and echocardiograms

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) follows an indolent course and may remain undiagnosed for many years before resulting in clinical disease. Purpose To assess the utility of scalable artificial intelligence (AI) methods applied to electrocardiographic (ECG) images and echocardiograms in detecting longitudinal changes that precede the clinical diagnosis of ATTR-CM. Methods Across 5 hospitals of a large U.S.-based hospital system, we identified a total of 234 patients (age 79 [IQR:70-85] years, n=56 (23.9%) women) with ATTR-CM, defined by the presence of a positive bone scintigraphy scan (or pharmacotherapy with an approved transthyretin stabilizer) between 2015 and 2023. Using 10:1 age- and sex-matched controls, we independently trained convolutional neural network algorithms to discriminate ATTR-CM from controls using i) ECG images (AUROC 0.915) or ii) echocardiographic studies by incorporating all available views (AUROC 0.93). In a leave-out testing set of n=82 individuals with serial ECGs and n=49 individuals with serial echocardiograms we characterized longitudinal patterns in the evolution of the AI ECG and echo-based scores, and estimated the percentage of individuals that would have screened positive across distinct time intervals. Results In the leave-out testing set 52.4% and 34.7% of all individuals who went on to receive a diagnosis of ATTR-CM would have screened positive by AI deployed to ECGs and echocardiograms, respectively, 1 to 3 years before their confirmatory testing, with the percentage increasing to 75.6% and 69.4% in the 12 months before their eventual diagnosis (A). Across both modalities, there was a longitudinal increase in AI predictions when comparing the median of all studies performed more than a year before diagnosis versus the median of any studies performed within 12 months of diagnosis (AI-Echo: 0.20 [IQR: 0.04-0.35] to 0.49 [0.24-0.59] & AI-ECG: 0.07 [0.02-0.20] to 0.32 [0.11-0.49], p<0.001 for both) (B), consistent with evolution in the ECG and echocardiographic signature of ATTR-CM before its clinical diagnosis. Conclusions We demonstrate that AI applied directly to ECG images and echocardiography may enable scalable monitoring of subclinical ATTR-CM progression.

Artificial intelligence applied to electrocardiographic images for scalable screening of cardiac amyloidosis

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) remains largely under-recognized, under-diagnosed, and under-treated. We hypothesized that the myocardial remodeling seen in ATTR-CM may be detectable through artificial intelligence (AI) applied to 12-lead electrocardiographic (ECG) images. Purpose To develop an AI-ECG algorithm that can detect ATTR-CM from images of 12-lead electrocardiograms. Methods Across 5 hospitals of a large U.S.-based hospital system, we identified patients with ATTR-CM, defined by the presence of a positive bone scintigraphy scan or pharmacotherapy with an approved transthyretin stabilizer between 2015 and the first half of 2023. The development cohort consisted of 1,011 ECGs from 234 patients (age 79 [IQR:70-85], n=176 (17.4%) women), who were age- and sex-matched in a 10:1 ratio to 10,110 ECGs from 10,110 controls (age 79 [IQR:70-85] years, n=1,800 [17.7%] female). A convolutional neural network (CNN) pre-trained using a bio-contrastive pretext on ECGs before 2015 was fine-tuned for ATTR-CM using 5-fold cross-validation and subsequently tested in an independent set of cases (139 ECGs in 47 patients; age 80 [75-86] years, n=44 (31.7% women)) and matched controls (1390 ECGs and patients) from the second half of 2023. Results The AUROC (area under the receiver operating characteristic curve) of the AI-ECG model for discriminating ATTR-CM in the cross-validation set was 0.90 [95%CI: 0.89-0.91], and in the leave-out, temporally distinct dataset was 0.915 [95%CI: 0.89-0.94] (A), with a sensitivity of 0.85 [95%CI: 0.79-0.91] and specificity 0.80 [95%CI 0.78-0.82]. Representative saliency maps are shown in panel B. In simulations, the positive predictive value ranged from 0.12 [95%CI: 0.10-0.13] at a 3% prevalence level to 0.59 [95%CI: 0.56-0.62] at 25% prevalence. Conclusions We demonstrate that AI applied directly to ECG images represents a promising approach for the screening of ATTR-CM.

Clinical outcomes for 2788 patients with transthyretin amyloidosis: Tafamidis meglumine early access program in France

BackgroundEarly access experience in France with tafamidis meglumine, a selective transthyretin stabilizer for transthyretin-related amyloidosis cardiomyopathy (ATTR-CM), following transthyretin-related amyloidosis (ATTR) polyneuropathy approval and positive ATTR-ACT study results. AimTo describe the characteristics and clinical outcomes for patients in the French ATTR-CM tafamidis meglumine early access programme (28 Nov 2018 to 01 Jun 2021). MethodsPatients with confirmed ATTR-CM received tafamidis meglumine 20mg/day or 80mg/day. Demographic and clinical data were collected prospectively until patients discontinued treatment or died, or the programme ended. ResultsOverall, 222 physicians from 126 centres enrolled 2788 patients. The median age was 82years, 81.6% were male and New York Heart Association severity was class I for 12.8%, class II for 60.1% and class III for 27.0%. Overall, 1943 (74.6%) had genetic testing, and the results were available at tafamidis start for 1208 (62.2%) patients: 995 (82.4%) had wild-type ATTR and 213 (17.6%) had hereditary ATTR. Most patients started treatment≤12months after diagnosis (88.3%): 2268 (81.3%) at 20mg/day, with 401 (17.7%) increasing to 80mg/day. Median follow-up duration was 11.8months. New York Heart Association class improved or remained stable for 1299 (77.6%), whereas 376 (22.4%) worsened between inclusion and last follow-up. Among patients initiated at 80mg, 297 (81.1%) improved or remained stable and 69 (18.9%) worsened. New York Heart Association class progression did not vary with age. The 18-month survival rates were 89.8% (95% confidence interval: 87.0–92.0) among patients aged<80years, and 86.5% (95% confidence interval: 83.9–88.7) among those aged≥80years. ConclusionsEarly tafamidis meglumine access was given to 2788 patients with ATTR-CM. New York Heart Association class progression and survival were consistent with previously published data.

A Snapshot of the Most Recent Transthyretin Stabilizers.

In recent years, several strategies have been developed for the treatment of transthyretin-related amyloidosis, whose complex clinical manifestations involve cardiomyopathy and polyneuropathy. In view of this, transthyretin stabilizers represent a major cornerstone in treatment thanks to the introduction of tafamidis into therapy and the entry of acoramidis into clinical trials. However, the clinical treatment of transthyretin-related amyloidosis still presents several challenges, urging the development of new and improved therapeutics. Bearing this in mind, in this paper, the most promising among the recently published transthyretin stabilizers were reviewed. Their activity was described to provide some insights into their clinical potential, and crystallographic data were provided to explain their modes of action. Finally, structure-activity relationship studies were performed to give some guidance to future researchers aiming to synthesize new transthyretin stabilizers. Interestingly, some new details emerged with respect to the previously known general rules that guided the design of new compounds.

Quantitative 99mTc-pyrophosphate myocardial uptake: Changes on transthyretin stabilization therapy

BackgroundQuantitative technetium-99m-pyrophosphate cardiac single-photon emission computed tomography (99mTc-PYP SPECT/CT) is an emerging method for estimating myocardial burden of transthyretin cardiac amyloidosis (ATTR-CA), but its efficacy in monitoring longitudinal changes remains uncertain. We aimed to investigate longitudinal changes in cardiac ATTR amyloid burden following transthyretin stabilization therapy using visual and quantitative 99mTc-PYP SPECT/CT and to relate these with changes in cardiac biomarkers and function. MethodsThis prospective longitudinal cohort study investigated changes in 99mTc-PYP SPECT/CT in 23 participants with ATTR-CA on transthyretin stabilization therapy (median: 2.6 years). Quantitative analysis included left ventricular (LV) standardized uptake values (SUVs) (SUVmax, SUVmean), cardiac amyloid activity (CAA; SUVmean∗LV activity volume), and percent injected dose (%ID) (mean activity concentration∗LV activity volume/injected activity), calculated using a threshold of >1.5 times left atrial blood pool activity concentration on SPECT/CT. Longitudinal changes of paired continuous and ordinal variables were analyzed using Wilcoxon signed-rank test. ResultsFollowing therapy, visual grade decreased significantly (P = 0.003). Several quantitative 99mTc-PYP metrics also decreased significantly: SUVmax (median −0.75, P = 0.011), CAA (median: −406.6, P < 0.001), and %ID (median: −0.45, P < 0.001). Serum transthyretin levels improved (median: +6.5 mg/dL, P = 0.008). Echocardiographic parameters (global longitudinal strain, LV mass index, and LV wall thickness), N-terminal pro-B-type natriuretic peptide, and estimated glomerular filtration rate remained stable. ConclusionsFavorable changes in 99mTc-PYP myocardial uptake were observed in participants on transthyretin stabilization therapy, whereas echocardiographic parameters and biomarkers remained stable. These results likely signify myocardial ATTR amyloid stabilization rather than amyloid burden regression. Further investigation is needed to understand the implications of these findings.

History of the study of amyloidosis: from the Rokitansky's theory to the present day

In the history of amyloidosis studying the concept of liquids dyscrasia has been predominated and finally it is resulted in accepting a serum protein-precursor as a leading amyloidogenic factor in the disease pathogenesis. Consequently basic diagnostic and treatment strategy was aimed to find and eliminate this protein from the blood and this approach evidenced high effectiveness in most frequent AA and AL-amyloidosis characterized with anomaly high levels of precursors in the blood. At the same time there are less frequent and slower progressing inheritant forms of systemic amyloidosis including transthyretin induced, which are less depending on amyloidogenecity of amyloid precursor and because of that, in example, the effectiveness of transthyretin stabilizers or blockers of its synthesis is limited comparing with the precursor elimination in AA or AL. Developed in the middle of XX century a theory of local synthesis by macrophages is more preferable to describe the pathogenesis of these forms. And modern proteome analysis using give rise to confirm the key meaning of macrophage in the amyloidogenesis and proves necessity to know deeply mechanisms of macrophagial autophagia - basic tool of maintaining intracellular protein homeostasis. That is why it is difficult to hope on high effectiveness of chemical amyloid solvents in vivo, which being under macrophages regulation never could realize its chemical activities.

Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis.

Amyloid neuropathy is caused by deposition of insoluble β-pleated amyloid sheets in the peripheral nervous system. It is most common in: (1) light-chain amyloidosis, a clonal non-proliferative plasma cell disorder in which fragments of immunoglobulin, light or heavy chain, deposit in tissues, and (2) hereditary transthyretin (ATTRv) amyloidosis, a disorder caused by autosomal dominant mutations in the TTR gene resulting in mutated protein that has a higher tendency to misfold. Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood-nerve barrier disruption. Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure. Small unmyelinated nerves are involved early and prominently in early-onset Val30Met ATTRv, whereas other ATTRv and light-chain amyloidosis often present with large- and small-fiber involvement. Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation. Amyloid deposition can be demonstrated by tissue biopsy of the affected organ or surrogate site, as well as bone-avid radiotracer cardiac imaging. Treatment of light-chain amyloidosis has been revolutionized by monoclonal antibodies and stem cell transplantation with improved 5-year survival up to 77%. Novel gene therapy and transthyretin stabilizers have revolutionized treatment of ATTRv, improving the course of neuropathy (less change in the modified Neuropathy Impairment Score + 7 from baseline) and quality of life. With great progress in amyloidosis therapies, early diagnosis and presymptomatic testing for ATTRv family members has become paramount. ANN NEUROL 2024;96:423-440.

Treatment characteristics of patients with hereditary transthyretin amyloidosis: a cohort study

BackgroundThere are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers. While many patients may be on both classes of medications, there is no data available on the safety and efficacy of combination therapy.ObjectivesTo describe ATTRv patient and TTR-targeted therapy characteristics in a US cohort, and compare outcomes with combination therapy versus monotherapy.MethodsWe performed a retrospective cohort study with electronic health record data of patients with ATTRv seen at a single institution between January 2018 and December 2022. We collected data on symptomatology, gene mutation, disease severity, ATTRv treatment, hospitalizations, and mortality.ResultsOne hundred sixty-two patients with ATTRv were identified. The average age at diagnosis was 65 years. 86 patients (53%) had the V122I variant. 119 patients were symptomatic, of whom 103 were started on ATTRv-specific treatment. 41 patients (40%) had cardiomyopathy only, and 53 (51%) had a mixed phenotype of cardiomyopathy and neuropathy. 38 patients (37%) received therapy with both a gene silencer and protein stabilizer. 9 patients (15%) in the monotherapy group had two or more cardiac hospitalizations after starting treatment, compared to 3 patients (9%) on combination therapy (p=0.26). The adjusted hazard ratio of all-cause mortality for the patients on combination therapy compared to monotherapy was 0.37 (0.08-1.8, p=0.21).ConclusionsWhile the efficacy is unproven, over one-third of patients with ATTRv are on both a stabilizer and a silencer. There were no safety issues for combination therapy. There was a trend towards improved hospitalizations and survival in patients in the combination group but this was not statistically significant. Larger studies with longer follow-up are necessary to determine benefit of combination therapy.

Sodium-glucose cotransporter 2 inhibitors for transthyretin amyloid cardiomyopathy: Analyses of short-term efficacy and safety.

Despite their potential, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been well-studied in transthyretin amyloid cardiomyopathy (ATTR-CM) as randomized trials have excluded patients with this morbid disease. We performed a retrospective study assessing the short-term efficacy and safety of SGLT2i in ATTR-CM. We screened consecutive patients seen at a tertiary care centre and identified 87 ATTR-CM patients treated with SGLT2i and 95 untreated control patients. Endpoints included changes in weight, loop diuretic dose, and cardiac/renal biomarkers. The median age of the overall population was 79 (interquartile range [IQR] 11) years. Nearly 90% of patients were male, and 93% were on a transthyretin stabilizer. Control patients demonstrated generally less severe disease at baseline compared to SGLT2i-treated patients, with lower median Columbia risk score (p < 0.001). Median follow-up time was 5.6 (IQR 5.2) and 8.4 (IQR 2.1) months in the SGLT2i and control cohorts, respectively. Compared with controls, SGLT2i treatment was associated with significantly greater reductions from baseline in weight, loop diuretic dose, and uric acid during follow-up (p < 0.001). While no significant between-group differences were observed on cardiac biomarkers, estimated glomerular filtration rate was significantly reduced versus controls 1 month after SGLT2i initiation (p = 0.002), but no significant differences were observed at later timepoints. Results were similar in a propensity score-matched analysis (n = 42 per cohort). A total of 10 (11.5%) patients discontinued SGLT2i, most commonly due to genitourinary symptoms. Sodium-glucose cotransporter 2 inhibitors were well tolerated by most patients with ATTR-CM and appeared to improve volume status and combat diuretic resistance. Randomized studies are needed to confirm these findings.

Vutrisiran (Amvuttra)

&#x0D; CADTH recommends that Amvuttra be reimbursed by public drug plans for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin-mediated (hATTR) amyloidosis if certain conditions are met.&#x0D; Amvuttra should only be covered to treat adults with stage 1 or stage 2 genetically confirmed hATTR amyloidosis with polyneuropathy (hATTR-PN) who are symptomatic with early-stage neuropathy, do not have severe heart failure symptoms, and have not had a liver transplant. A patient’s response to treatment with Amvuttra should be assessed at least every 6 months to determine whether they would benefit from continued treatment. Treatment with Amvuttra should not be continued in patients who are permanently bedridden and dependent on assistance for basic activities of daily living or who are receiving end-of-life care.&#x0D; Amvuttra should only be reimbursed if the patient is under the care of a specialist with experience in the diagnosis and management of hATTR-PN and should not be reimbursed if it is used in combination with interfering ribonucleic acid drugs or transthyretin stabilizers. The cost of Amvuttra should be reduced so that it does not cost more than other drugs for hATTR amyloidosis.&#x0D;

Interleukin-6 plasma levels predict mortality and heart failure events in cardiac transthyretin amyloidosis

Abstract Background Low-grade systemic inflammation is a key component in the pathophysiology of heart failure (HF). In particular, the pleiotropic effects of interleukin-6 (IL-6) signaling are of interest as circulating IL-6 levels are associated with mortality in HF patients. Purpose The purpose of this study was to investigate whether IL-6 plasma levels predict mortality and HF events in patients with cardiac transthyretin amyloidosis (ATTR-CM). Methods This was an analysis of a prospective single-center cohort study comprising 98 ATTR-CM patients. The endpoint was defined as a composite of all-cause mortality and worsening HF events. HF events included HF related hospitalizations and urgent outpatient clinic visits with concomitant intravenous diuretic treatment. Follow-up data were collected using central medical records. Kaplan-Meier estimates and Cox regression analyses were calculated to assess the association between IL-6 and the composite endpoint. Moreover, receiver operator characteristics (ROC) analysis was performed to evaluate the predictive accuracy of IL-6 for the composite endpoint. Results Median age was 79 years (76-81), 86 patients (88%) were male, and 46 patients (47%) received the transthyretin (TTR) stabilizer tafamidis at baseline. Median NT-proBNP levels were 2813 pg/ml (1365-4856), mean estimated glomerular filtration rate (eGFR) was 57.9±17.6 ml/min/1.73m², and median urine protein to creatinine ratio (UPCR) was 122.0 mg/g (89.8-204.5). Median IL-6 plasma levels were 4.9 pg/ml (3.0-9.4). During a median observation period of 21.2 months (11.4-32.4), 27 patiens (28%) reached the composite endpoint. IL-6 levels were associated with the composite endpoint (hazard ratio = 1.028, 95% confidence interval = 1.004 to 1.051; p = 0.012). The association was independent of age, TTR stabilizing medication, log-transformed and eGFR-adjusted NT-proBNP levels, as well as UPCR. The area under the ROC curve for IL-6 was 0.70 (95% confidence interval = 0.59 to 0.81; p = 0.003). The optimal cutoff value was 5.3 pg/ml, as determined by Youden’s index, with a sensitivity of 70% and specificity of 66%. Kaplan-Meier estimates demonstrated a mean survival time of 1030 days (95% confidence interval = 911 to 1150) for the study population. A statistically significant difference between the survival rates of ATTR-CM patients with IL-6 levels ≥5.3 pg/ml and those with IL-6 levels below the threshold was indicated by the log-rank test (p = 0.002). Conclusion Circulating levels of IL-6 independently predicted adverse outcomes in patients with ATTR-CM. IL-6 plasma levels may be useful for identifying a high-risk ATTR-CM subpopulation.Tablewith baseline characteristicsFigurewith Kaplan-Meier estimates

Abstract 12278: A Case of Hereditary Transthyretin Amyloidosis Caused by a Rare Mutation

Introduction: Transthyretin amyloidosis (ATTR) is an underdiagnosed multisystem disease caused by dissociation of the tetrameric structure, misfolding, and deposition of the protein transthyretin. More than 100 known mutations that decrease the stability of transthyretin have been implicated in hereditary ATTR (ATTRv). Organ tropism and disease progression can vary significantly depending on the specific mutation, though cardiomyopathy and neuropathy are the most common phenotypes (Figure 1b). Reproducibly tracking the pattern of end organ dysfunction in ATTRv caused by novel mutations may help elucidate the mechanism of mutation-specific organ tropism and predict the potential disease course for patients with the same mutation. Case: The index patient is an 86-year-old male with a history of atrial fibrillation, tachy-brady syndrome requiring a pacemaker, orthostatic hypotension, peripheral neuropathy, and left ventricular hypertrophy (interventricular septum 1.4 cm prior to diagnosis) on echocardiogram. The constellation of symptoms raised the clinical suspicion for amyloidosis which was confirmed on endomyocardial biopsy. Given his age, he was presumed to have wild type ATTR by the local team. Upon referral to our center, genetic testing was performed which revealed the missense mutation c.229G&gt;A which results in the amino acid substitution p.Gly77Arg, and has previously only been reported in one patient in Sweden. We initiated family screening and identified multiple family members with the mutation with varying phenotypes including no symptoms, cardiomyopathy, and neuropathy (figure 1a). Discussion: We identified a family with a rare c.229G&gt;A mutation, and report on a mixed cardiomyopathy and neuropathy phenotype. Our report highlights the importance of screening for pathologic genetic variants in all patients with a diagnosis of ATTR given the treatment and prognostic implications for patients and their family members.

Saturation of fatty acids in phosphatidic acid uniquely alters transthyretin stability changing morphology and toxicity of amyloid fibrils

Transthyretin (TTR) is a small, β-sheet-rich tetrameric protein that transports thyroid hormone thyroxine and retinol. Phospholipids, including phosphatidic acid (PA), can uniquely alter the stability of amyloidogenic proteins. However, the role of PA in TTR aggregation remains unclear. In this study, we investigated the effect of saturation of fatty acids (FAs) in PA on the rate of TTR aggregation. We also reveal the extent to which PAs with different length and saturation of FAs altered the morphology and secondary structure of TTR aggregates. Our results showed that TTR aggregation in the equimolar presence of PAs with different length and saturation of FAs yielded structurally and morphologically different fibrils compared to those formed in the lipid-free environment. We also found that PAs drastically lowered the toxicity of TTR aggregates formed in the presence of this phospholipid. These results shed light on the role of PA in the stability of TTR and transthyretin amyloidosis.

A case of disappearing amyloid on technetium pyrophosphate scan

Technetium-99mm pyrophosphate (Tc-PYP) scintigraphy is a highly accurate non-invasive method for the diagnosis of transthyretin (ATTR) cardiac amyloidosis. Prognosis for this disease is improved following treatment with the transthyretin (TTR) stabilizer tafamidis. Although tafamidis slows disease progression, its effects on myocardial amyloid and Tc-PYP uptake remain unclear. We present a patient with ATTR cardiac amyloidosis who had a strongly positive initial Tc-PYP scan, with a dramatic decrease in Tc-PYP uptake on repeat scan after 3 years of tafamidis treatment. However, myocardial biopsy showed persistent diffuse amyloid deposits. This case highlights the need for further studies regarding the utility of serial Tc-PYP scans in monitoring the progress of ATTR cardiomyopathy.