RARE DISEASE
Wild type ATTR amyloidosis
Wild type ATTR amyloidosis
Wild type ATTR amyloidosis
Synonyms: ATTRwt amyloidosis, ATTRwt-related amyloidosis, Senile systemic amyloidosis, Wild type ATTR-related amyloidosis
Synonyms: ATTRwt amyloidosis, ATTRwt-related amyloidosis, Senile systemic amyloidosis, Wild type ATTR-related amyloidosis
Synonyms: ATTRwt amyloidosis, ATTRwt-related amyloidosis, Senile systemic amyloidosis, Wild type ATTR-related amyloidosis
Drug discovery
1
drug
With orphan designation
Overview
Wild-type ATTR amyloidosis (ATTRwt) is a systemic disorder caused by age-related destabilization of transthyretin protein, leading to amyloid deposits predominantly in the heart. It manifests as restrictive cardiomyopathy with diastolic dysfunction, arrhythmias, and heart failure, often preceded by carpal tunnel syndrome or lumbar stenosis. Diagnosis typically occurs after age 60, with men comprising >90% of cases [1][5][7]. Non-cardiac involvement includes tendon ruptures and neuropathy [6][16].
Categories: rare cardiac diseases, rare systemic and rheumatological diseases
Research Papers
543 drug discovery papers related to Wild type ATTR amyloidosis, with 6 first-in-class and 8 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
543 drug discovery papers related to Wild type ATTR amyloidosis, with 6 first-in-class and 8 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-27 | Consistent Efficacy of Vutrisiran Across Sexes in Transthyretin Cardiac Amyloidosis: Evidence from the HELIOS-B Trial.
Sex differences in transthyretin cardiac amyloidosis (ATTR-CM) are increasingly recognised; however, women are underrepresented in trials and sex-specific treatment effects remain incompletely understood. We evaluated sex differences in baseline phenotype, outcomes and vutrisiran response in ATTR-CM. HELIOS-B was a phase 3, randomised, double-blind, placebo-controlled trial enrolling patients with wild-type or variant ATTR-CM, randomised 1:1 to receive subcutaneous vutrisiran (25 mg every 12 weeks) or placebo. This prespecified analysis assessed baseline characteristics, efficacy, and safety according to sex. Among 654 participants, 49 (7.5%) were women. Variant ATTR-CM was more prevalent in women (42.9% vs 9.1%, p < 0.001). At baseline, women had smaller absolute left ventricular dimensions and wall thicknesses (p < 0.05), but when indexed to body surface area, wall thicknesses were higher. Women demonstrated better systolic function, but worse 6-minute walk distances and quality-of-life scores. Vutrisiran reduced the primary composite endpoint of all-cause mortality and recurrent cardiovascular events in both sexes (women, HR 0.59, 95% CI 0.26-1.30; men, HR 0.71, 95% CI 0.54-0.94; p-interaction = 0.66). Confidence intervals were wide in women, reflecting limited precision from small subgroup size. Mortality reduction was observed in both sexes (HR 0.56, 95% CI 0.14-2.34 in women, HR 0.65, 95% CI 0.46-0.90 in men, p-interaction = 0.91 for all-cause mortality at 42 months). Decline in 6-minute walk distance and quality-of-life scores was attenuated in both sexes, with no statistically detectable sex-specific interaction, and safety outcomes were comparable. Women with ATTR-CM demonstrated a distinct baseline phenotype in HELIOS-B. Despite this, vutrisiran showed no statistically detectable heterogeneity of treatment effect by sex within the limits of statistical power, supporting therapeutic benefit across the phenotypic spectrum of ATTR-CM.
2026-06-17 | Differential Transthyretin Stabilization in Patients With Wild Type and Variant Transthyretin Amyloidosis.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease caused by transthyretin (TTR) tetramer destabilization, leading to amyloid deposition from either age-related wild type TTR or pathogenic TTR variants. TTR variants are less stable than wild type TTR, leading to lower serum TTR (sTTR) and worse clinical outcomes. TTR stabilizers, tafamidis and acoramidis, are approved for treatment of patients with ATTR-CM. The aim of this study was to evaluate the differences in stabilizing effect and magnitude of sTTR increases for acoramidis and tafamidis using data from the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) trial. Stabilizing potency was analyzed using sTTR as an in vivo readout and by applying 2 orthogonal pharmacodynamic assays: Western blot and fluorescent probe exclusion. In vitro analyses used blood samples from patients with variant ATTR-CM at clinically relevant concentrations of acoramidis (10 μM) and tafamidis (16-26 μM). In ATTRibute-CM, treatment with acoramidis (n = 234) resulted in a greater rise in sTTR from baseline to month 30 vs placebo plus tafamidis (n = 34). Acoramidis achieved greater TTR stabilization than placebo plus tafamidis at month 30 by Western blot (90.2% [n = 83] vs 60.6% [n = 6]) and fluorescent probe exclusion (99.7% [n = 71] vs 68.0% [n = 4]), although this was limited by a small sample size. Subsequent in vitro analysis corroborated acoramidis was a more effective TTR stabilizer than tafamidis across all 51 individual participant samples tested, representing 17 unique variants. Acoramidis is a near-complete stabilizer of wild type and variant TTR. Although in vitro comparisons between acoramidis and tafamidis suggest greater stabilization by acoramidis, randomized prospective trial data comparing these TTR stabilizers are lacking, and further investigation is warranted. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).
2026-06-01 | Spectrum of cardiac amyloidosis in clinical practice: insights from a single centre
Abstract Background Cardiac amyloidosis (CA) is a frequently underdiagnosed cause of heart failure. Early identification of affected patients and close interdisciplinary collaboration are essential for accurate diagnosis, appropriate subtyping, and timely initiation of disease-specific therapy. Methods From January 2023 to December 2025, 78 consecutive patients with suspected cardiac amyloidosis were referred to a specialized outpatient clinic. Referrals originated predominantly from cardiology (53.8%) and neurology departments (29.4%), followed by internal medicine (3.8%), hematology (5.1%), and radiology (1.3%). All patients underwent a comprehensive diagnostic evaluation including echocardiography, cardiac magnetic resonance imaging, bone scintigraphy, laboratory assessment, genetic testing, and endomyocardial biopsy when clinically indicated. Results Cardiac amyloidosis was confirmed in 44 of 78 patients (56.4%). Wild-type transthyretin amyloidosis (ATTRwt) was the most prevalent subtype (n=26), followed by light-chain amyloidosis (AL, n=12) and hereditary transthyretin amyloidosis (ATTRh, n=6). The median age was 73 years (IQR 66,2–80,5), and 70% of patients were male. All ATTRh patients presented with concomitant polyneuropathy. Compared with ATTRwt, AL patients were younger (median 67.5 vs. 77 years; p=0.007) and more frequently exhibited renal impairment (60% vs. 71%; p=0.01). Biomarker analysis revealed significantly higher NT-proBNP and troponin T levels in AL amyloidosis (p=0.05 and p=0.02, respectively). Echocardiography demonstrated preserved left ventricular ejection fraction across subtypes (median EF: AL 50%, ATTRwt 55%, ATTRh 60%) and increased interventricular septal thickness (median IVSd: 18 mm in AL and ATTRwt, 16 mm in ATTRh). Cardiac magnetic resonance imaging was most frequently utilized in AL patients (80%), whereas bone scintigraphy confirmed the diagnosis in all ATTRwt and ATTRh cases. Endomyocardial biopsy established the diagnosis in 8 patients (5 AL, 3 ATTRwt). Standard heart failure therapy included diuretics (84%), mineralocorticoid receptor antagonists (up to 70%), and SGLT2 inhibitors, particularly in ATTRwt patients (62%). Disease-specific treatment comprised tafamidis in 88% of ATTRwt patients and patisiran in 33% of ATTRh patients. Overall mortality during the study period was 10%. Conclusion This single-centre experience demonstrates the growing recognition of cardiac amyloidosis and emphasizes the necessity of a multidisciplinary diagnostic strategy. ATTRwt amyloidosis was the predominant subtype, characterized by distinct clinical, echocardiographic, and therapeutic features. Accurate and timely subtyping is crucial for guiding tailored therapy and improving patient outcomes.
2026-06-27 | Consistent Efficacy of Vutrisiran Across Sexes in Transthyretin Cardiac Amyloidosis: Evidence from the HELIOS-B Trial.
Sex differences in transthyretin cardiac amyloidosis (ATTR-CM) are increasingly recognised; however, women are underrepresented in trials and sex-specific treatment effects remain incompletely understood. We evaluated sex differences in baseline phenotype, outcomes and vutrisiran response in ATTR-CM. HELIOS-B was a phase 3, randomised, double-blind, placebo-controlled trial enrolling patients with wild-type or variant ATTR-CM, randomised 1:1 to receive subcutaneous vutrisiran (25 mg every 12 weeks) or placebo. This prespecified analysis assessed baseline characteristics, efficacy, and safety according to sex. Among 654 participants, 49 (7.5%) were women. Variant ATTR-CM was more prevalent in women (42.9% vs 9.1%, p < 0.001). At baseline, women had smaller absolute left ventricular dimensions and wall thicknesses (p < 0.05), but when indexed to body surface area, wall thicknesses were higher. Women demonstrated better systolic function, but worse 6-minute walk distances and quality-of-life scores. Vutrisiran reduced the primary composite endpoint of all-cause mortality and recurrent cardiovascular events in both sexes (women, HR 0.59, 95% CI 0.26-1.30; men, HR 0.71, 95% CI 0.54-0.94; p-interaction = 0.66). Confidence intervals were wide in women, reflecting limited precision from small subgroup size. Mortality reduction was observed in both sexes (HR 0.56, 95% CI 0.14-2.34 in women, HR 0.65, 95% CI 0.46-0.90 in men, p-interaction = 0.91 for all-cause mortality at 42 months). Decline in 6-minute walk distance and quality-of-life scores was attenuated in both sexes, with no statistically detectable sex-specific interaction, and safety outcomes were comparable. Women with ATTR-CM demonstrated a distinct baseline phenotype in HELIOS-B. Despite this, vutrisiran showed no statistically detectable heterogeneity of treatment effect by sex within the limits of statistical power, supporting therapeutic benefit across the phenotypic spectrum of ATTR-CM.
2026-06-17 | Differential Transthyretin Stabilization in Patients With Wild Type and Variant Transthyretin Amyloidosis.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease caused by transthyretin (TTR) tetramer destabilization, leading to amyloid deposition from either age-related wild type TTR or pathogenic TTR variants. TTR variants are less stable than wild type TTR, leading to lower serum TTR (sTTR) and worse clinical outcomes. TTR stabilizers, tafamidis and acoramidis, are approved for treatment of patients with ATTR-CM. The aim of this study was to evaluate the differences in stabilizing effect and magnitude of sTTR increases for acoramidis and tafamidis using data from the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) trial. Stabilizing potency was analyzed using sTTR as an in vivo readout and by applying 2 orthogonal pharmacodynamic assays: Western blot and fluorescent probe exclusion. In vitro analyses used blood samples from patients with variant ATTR-CM at clinically relevant concentrations of acoramidis (10 μM) and tafamidis (16-26 μM). In ATTRibute-CM, treatment with acoramidis (n = 234) resulted in a greater rise in sTTR from baseline to month 30 vs placebo plus tafamidis (n = 34). Acoramidis achieved greater TTR stabilization than placebo plus tafamidis at month 30 by Western blot (90.2% [n = 83] vs 60.6% [n = 6]) and fluorescent probe exclusion (99.7% [n = 71] vs 68.0% [n = 4]), although this was limited by a small sample size. Subsequent in vitro analysis corroborated acoramidis was a more effective TTR stabilizer than tafamidis across all 51 individual participant samples tested, representing 17 unique variants. Acoramidis is a near-complete stabilizer of wild type and variant TTR. Although in vitro comparisons between acoramidis and tafamidis suggest greater stabilization by acoramidis, randomized prospective trial data comparing these TTR stabilizers are lacking, and further investigation is warranted. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).
2026-06-01 | Spectrum of cardiac amyloidosis in clinical practice: insights from a single centre
Abstract Background Cardiac amyloidosis (CA) is a frequently underdiagnosed cause of heart failure. Early identification of affected patients and close interdisciplinary collaboration are essential for accurate diagnosis, appropriate subtyping, and timely initiation of disease-specific therapy. Methods From January 2023 to December 2025, 78 consecutive patients with suspected cardiac amyloidosis were referred to a specialized outpatient clinic. Referrals originated predominantly from cardiology (53.8%) and neurology departments (29.4%), followed by internal medicine (3.8%), hematology (5.1%), and radiology (1.3%). All patients underwent a comprehensive diagnostic evaluation including echocardiography, cardiac magnetic resonance imaging, bone scintigraphy, laboratory assessment, genetic testing, and endomyocardial biopsy when clinically indicated. Results Cardiac amyloidosis was confirmed in 44 of 78 patients (56.4%). Wild-type transthyretin amyloidosis (ATTRwt) was the most prevalent subtype (n=26), followed by light-chain amyloidosis (AL, n=12) and hereditary transthyretin amyloidosis (ATTRh, n=6). The median age was 73 years (IQR 66,2–80,5), and 70% of patients were male. All ATTRh patients presented with concomitant polyneuropathy. Compared with ATTRwt, AL patients were younger (median 67.5 vs. 77 years; p=0.007) and more frequently exhibited renal impairment (60% vs. 71%; p=0.01). Biomarker analysis revealed significantly higher NT-proBNP and troponin T levels in AL amyloidosis (p=0.05 and p=0.02, respectively). Echocardiography demonstrated preserved left ventricular ejection fraction across subtypes (median EF: AL 50%, ATTRwt 55%, ATTRh 60%) and increased interventricular septal thickness (median IVSd: 18 mm in AL and ATTRwt, 16 mm in ATTRh). Cardiac magnetic resonance imaging was most frequently utilized in AL patients (80%), whereas bone scintigraphy confirmed the diagnosis in all ATTRwt and ATTRh cases. Endomyocardial biopsy established the diagnosis in 8 patients (5 AL, 3 ATTRwt). Standard heart failure therapy included diuretics (84%), mineralocorticoid receptor antagonists (up to 70%), and SGLT2 inhibitors, particularly in ATTRwt patients (62%). Disease-specific treatment comprised tafamidis in 88% of ATTRwt patients and patisiran in 33% of ATTRh patients. Overall mortality during the study period was 10%. Conclusion This single-centre experience demonstrates the growing recognition of cardiac amyloidosis and emphasizes the necessity of a multidisciplinary diagnostic strategy. ATTRwt amyloidosis was the predominant subtype, characterized by distinct clinical, echocardiographic, and therapeutic features. Accurate and timely subtyping is crucial for guiding tailored therapy and improving patient outcomes.
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Drug Discovery Landscape
1 orphan drug designation for Wild type ATTR amyloidosis, including 1 approved therapy.
1 orphan drug designation for Wild type ATTR amyloidosis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
tafamidis meglumine [VYNDAQEL; VYNDAMAX] | small molecules | FDA | 2012-02-17 | 2019-05-03 | FoldRx Pharmaceuticals, Inc., a subsidiary of Pfizer Inc. |
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