tafamidis TTR reduction and Eplontersen TTR reduction 2025-09-24 13:21:00

tafamidis TTR reduction ans Eplontersen TTR reduction summary of the trials results

Сравнительный анализ снижения уровня TTR в клинических исследованиях: Тафамидис и Эплонтерсен

Введение

Транстиретиновый амилоидоз (ATTR) — прогрессирующее, потенциально фатальное заболевание, при котором накопление амилоидных фибрилл транстиретина (TTR) приводит к поражению сердца (ATTR-CM) и/или периферических нервов (ATTRv-PN). В последние годы появились две основные стратегии терапии: стабилизация молекулы TTR (тафамидис) и ингибирование продукции TTR (эплонтерсен и другие "TTR knock-down" препараты). В настоящем обзоре сопоставляются результаты крупных клинических исследований по снижению уровня TTR для обеих стратегий.

1. Эплонтерсен: ингибитор продукции TTR

1.1 Механизм действия и дизайн исследований

Эплонтерсен — это конъюгированный антисмысловой олигонуклеотид (ASO), предназначенный для ингибирования синтеза TTR в печени, что приводит к снижению циркулирующего TTR и уменьшению амилоидных отложений. Основные клинические данные получены из глобального открытого рандомизированного исследования NEURO-TTRansform, включившего пациентов с наследственным ATTR-полинейропатией (ATTRv-PN), сравнивающего эплонтерсен с внешней (исторической) плацебо-группой (AstraZeneca, 2023).

1.2 Снижение TTR: основные результаты

66 недель: Эплонтерсен обеспечил LS-среднее снижение концентрации сывороточного TTR на 82% от исходного уровня, тогда как в группе плацебо — только на 11% (различие статистически значимо, p<0,0001) (AstraZeneca, 2023).
85 недель: Эффект по снижению TTR сохранялся, что подтверждает устойчивое ингибирование продукции TTR на протяжении длительного времени (AstraZeneca, 2023).

1.3 Клинические исходы и безопасность

Прогрессирование невропатии (mNIS+7): у пациентов, получавших эплонтерсен, среднее изменение составило +0,28 балла (почти полная стабилизация), тогда как у плацебо +25,06 балла (значительное ухудшение); разница — 24,8 балла в пользу эплонтерсена (p<0,0001).
Качество жизни (Norfolk QoL-DN): улучшение на 5,5 баллов против ухудшения на 14,2 баллов в группе плацебо (разница 19,7 баллов; p<0,0001).
Безопасность: профиль нежелательных явлений сопоставим с плацебо; серьезные нежелательные явления и прекращение терапии по причине безопасности — крайне редки (AstraZeneca, 2023).

1.4 Сравнение с другими "TTR knock-down" препаратами

В систематическом обзоре и мета-анализе не выявлено значимых различий между эплонтерсеном, инотерсеном и другими препаратами данного класса по снижению смертности и влиянию на функциональные показатели у пациентов с ATTR-CM (Fabbri et al., 2024).

2. Тафамидис: стабилизатор тетрамера TTR

2.1 Механизм действия и исследования

Тафамидис стабилизирует тетрамерную структуру TTR, предотвращая его диссоциацию и дальнейшее образование амилоидных фибрилл. Основные данные основаны на международном, многоцентровом рандомизированном исследовании ATTR-ACT у пациентов с ATTR-CM (Maurer et al., 2018; Damy et al., 2021).

2.2 Снижение уровня TTR

Стабилизация TTR (Month 1): 87,8% пациентов на 80 мг и 82,7% на 20 мг достигли стабилизации TTR против 3,5% в группе плацебо (p < 0,0001).
Абсолютный уровень TTR: В течение 30 месяцев средние концентрации TTR в крови были выше у пациентов на 80 мг по сравнению с 20 мг и плацебо, что свидетельствует о стабилизации, а не о снижении уровня TTR (Damy et al., 2021).

Важное отличие: Тафамидис НЕ снижает общий уровень TTR, а сохраняет его в стабильной форме, препятствуя образованию амилоида.

2.3 Клинические исходы и безопасность

Смертность (ATTR-ACT, 30 месяцев):
Тафамидис 80 мг: 30,7% умерших (n=54/176)
Тафамидис 20 мг: 27,3% (n=24/88)
Плацебо: 42,9% (n=76/177)
Относительное снижение риска смерти (RRR): 0,70 (95% CI: 0,57–0,85), p=0,0005 для 80 мг
Госпитализации по поводу ССЗ: Тафамидис 80 мг — 0,49 госпитализации на пациента в год против 0,70 в плацебо.
Функциональные и биомаркеры: Тафамидис замедлял снижение дистанции 6MWT, уровня NT-proBNP и ухудшение качества жизни (KCCQ-OS).
Безопасность: Частота нежелательных явлений была сопоставима с плацебо, без значимых сигналов по безопасности (Damy et al., 2021).

3. Сравнительный анализ и мета-анализы

3.1 Сравнение классов: стабилизаторы TTR vs. ингибиторы продукции TTR

В крупном мета-анализе 9 РКИ (2713 пациентов) показано, что обе тактики — как стабилизация, так и ингибирование синтеза TTR — ассоциированы с 30%-ным снижением общей смертности по сравнению с плацебо (RR 0,70; 95% CI 0,60–0,83; p<0,01) (Fabbri et al., 2024). Не выявлено достоверных различий между подклассами (стабилизаторы vs. knock-down препараты) (p=0,98).

3.2 Эффективность по вторичным показателям

Улучшение продольной деформации ЛЖ (SMD –0,22; 95% CI –0,34; –0,10; p<0,01)
Снижение массы ЛЖ (MD –9,11 г; 95% CI –16,4; –1,82 г; p=0,01)
Безопасность: отсутствие различий по частоте серьезных нежелательных явлений между группами терапии и плацебо (Fabbri et al., 2024).

4. Ключевые различия между эплонтерсеном и тафамидисом

| Параметр | Эплонтерсен | Тафамидис |
|---|---|---|
| Механизм | Снижает продукцию TTR (до 82-85%↓ TTR) | Стабилизирует тетрамер TTR (нет снижения общего TTR) |
| Клинический эффект | Улучшает/стабилизирует невропатию и качество жизни, замедляет прогрессирование | Замедляет СС- и общую смертность, госпитализации, снижает NT-proBNP, замедляет ухудшение функции |
| Безопасность | Сопоставима с плацебо | Сопоставима с плацебо |
| Популяция | ATTRv-PN (пока нет данных по ATTR-CM) | ATTR-CM (есть доказательства и для ATTRv-PN) |
| Степень снижения TTR | До 82% | Нет снижения (стабилизация) |
| Доказательства по снижению TTR | Явное и существенное | Нет, только стабилизация тетрамера |

5. Заключение

Эплонтерсен обеспечивает выраженное снижение уровня сывороточного TTR (до 82%), приводя к клинически значимым улучшениям у пациентов с ATTRv-PN и потенциально — с ATTR-CM (ожидаются результаты CARDIO-TTRansform).
Тафамидис не снижает уровень TTR, а стабилизирует его структуру, что также приводит к существенному снижению смертности и госпитализаций при ATTR-CM.
По текущим данным, оба класса препаратов имеют схожую эффективность по снижению смертности и улучшению клинических исходов; различия заключаются в механизмах действия и прямом влиянии на уровень TTR.
Безопасность обеих стратегий подтверждена в крупных РКИ.

Вывод: Оба подхода — ингибирование продукции TTR и стабилизация тетрамера — являются эффективными и безопасными стратегиями для лечения ATTR, но эплонтерсен обеспечивает более выраженное абсолютное снижение уровня TTR, тогда как тафамидис — его стабилизацию (Fabbri et al., 2024), (Damy et al., 2021), (AstraZeneca, 2023).

Основные источники:

REFERENCES

Eplontersen demonstrated sustained benefit in Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks - last accessed: 2025-09-24

Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses - last accessed: 2025-09-24

NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks - last accessed: 2025-09-24

Vyndaqel (tafamidis) vs Wainua (eplontersen) | Everyone.org - last accessed: 2025-09-24

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC - last accessed: 2025-09-24

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC - last accessed: 2025-09-24

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text - last accessed: 2025-09-24

Sources used

QUERY: tafamidis AND transthyretin AND reduction AND trial

Real-World Efficacy of Tafamidis in Patients With Transthyretin Amyloidosis and Heart Failure.
Current problems in cardiology. 2023/2/12; Impact Factor: 4.14, Quartile: Q1
DOI: 10.1016/j.cpcardiol.2023.101667
PMID: 36828040
Abstract
Tafamidis was associated with a reduction in cardiovascular hospitalizations and all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the ATTR-ACT trial. However, real-world data on the efficacy of tafamidis are limited. We conducted a retrospective, observational cohort study using the TriNetX research network. Patients with wild-type TTR amyloidosis and heart failure (HF) were divided into 2 groups based on treatment with tafamidis. Propensity score matching (PSM) was performed, and rates of heart failure exacerbations (HFE) and all-cause mortality at 12 months were compared. After PSM, 421 patients were in each group (tafamidis vs nontafamidis). During the 12-month follow-up period, patients treated with tafamidis experienced significantly less HFE and all-cause mortality. A higher probability of event-free survival for HFE and all-cause mortality was noted with tafamidis. This real-world analysis supports that tafamidis use is associated with reduced HFE and all-cause mortality in patients with wild-type TTR amyloidosis and HF. Longer-term follow-up is needed to better understand the utility of tafamidis, given the increasing recognition of ATTR-CM and the high cost of tafamidis.

QUERY: eplontersen AND transthyretin AND reduction AND trial

Switching from inotersen to eplontersen in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: analysis from NEURO-TTRansform.
Journal of neurology. 2024/6/27; Impact Factor: 5.32, Quartile: Q1
DOI: 10.1007/s00415-024-12616-6
PMID: 39138650
Abstract
The phase 3 NEURO-TTRansform trial showed eplontersen treatment for 65 weeks reduced transthyretin (TTR), halted progression of neuropathy impairment, and improved quality of life (QoL) in adult patients with hereditary TTR-mediated amyloidosis with polyneuropathy (ATTRv-PN), vs. historical placebo.
NEURO-TTRansform enrolled patients with ATTRv-PN. A subset of patients were randomized to receive subcutaneous inotersen 300 mg weekly (Weeks 1-34) and subsequently switched to subcutaneous eplontersen 45 mg every 4 weeks (Weeks 37-81). Change in serum TTR and treatment-emergent adverse events (TEAEs) were evaluated through Week 85. Effects on neuropathy impairment, QoL, and nutritional status were also evaluated.
Of 24 patients randomized to inotersen, 20 (83%) switched to eplontersen at Week 37 and four discontinued due to AEs/investigator decision. Absolute change in serum TTR was greater after switching from inotersen (-74.3%; Week 35) to eplontersen (-80.6%; Week 85). From the end of inotersen treatment, neuropathy impairment and QoL were stable (i.e., did not progress) while on eplontersen, and there was no deterioration in nutritional status. TEAEs were fewer with eplontersen (Weeks 37-85; 19/20 [95%] patients) compared with inotersen (up to Week 35; 24/24 [100%] patients). Mean platelet counts decreased during inotersen treatment (mean nadir reduction ‒40.7%) and returned to baseline during eplontersen treatment (mean nadir reduction, ‒3.2%).
Switching from inotersen to eplontersen further reduced serum TTR, halted disease progression, stabilized QoL, restored platelet count, and improved tolerability, without deterioration in nutritional status. This supports a positive benefit-risk profile for patients with ATTRv-PN who switch from inotersen to eplontersen.

QUERY: tafamidis OR eplontersen AND transthyretin amyloidosis AND TTR reduction AND clinical trial

RNA Targeting and Gene Editing Strategies for Transthyretin Amyloidosis.
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2023/1/10; Impact Factor: 6.88, Quartile: Q1
DOI: 10.1007/s40259-023-00577-7
PMID: 36795354
Abstract
Transthyretin (TTR) is a tetrameric protein synthesized primarily by the liver. TTR can misfold into pathogenic ATTR amyloid fibrils that deposit in the nerves and heart, causing a progressive and debilitating polyneuropathy (PN) and life-threatening cardiomyopathy (CM). Therapeutic strategies, which are aimed at reducing ongoing ATTR amyloid fibrillogenesis, include stabilization of the circulating TTR tetramer or reduction of TTR synthesis. Small interfering RNA (siRNA) or antisense oligonucleotide (ASO) drugs are highly effective at disrupting the complementary mRNA and inhibiting TTR synthesis. Since their development, patisiran (siRNA), vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN, and early data suggest these drugs may have efficacy in treating ATTR-CM. An ongoing phase 3 clinical trial will evaluate the efficacy of eplontersen (ASO) in the treatment of both ATTR-PN and ATTR-CM, and a recent phase 1 trial demonstrated the safety of novel in vivo CRISPR-Cas9 gene-editing therapy in patients with ATTR amyloidosis. Recent results from trials of gene silencer and gene-editing therapies suggest these novel therapeutic agents have the potential to substantially alter the landscape of treatment for ATTR amyloidosis. Their success has already changed the perception of ATTR amyloidosis from a universally progressive and fatal disease to one that is treatable through availability of highly specific and effective disease-modifying therapies. However, important questions remain including long-term safety of these drugs, potential for off-target gene editing, and how best to monitor the cardiac response to treatment.Kindly check and confirm the processed running title.This is correct.

Web Sources

Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses

Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses Skip to content skip to navigation Search Menu Search Search Search Close About Us AstraZeneca impact in the US AstraZeneca in the US Corporate Transparency Responsible Business What science can do What science can do Campaign films Thank you, science Our impact, our people Community Impact AstraZeneca Foundation Employee Volunteerism and Giving Request support Sustainability Patients & Caregivers Affordability AstraZeneca Direct Medicines Patient Resources Product counterfeiting Healthcare Providers Medicines Medical Information Product counterfeiting Careers Careers Media Media center Press Releases Personified That's Understandable AZ&You Blog Articles Statements Contact Us Inside the US Outside the US More Hide AstraZeneca Websites Global site Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses PUBLISHED 28 September 2023 First publication from NEURO-TTRansform trial in the treatment of patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) Consistent and sustained benefit on all co-primary and secondary endpoints across patients with a diverse range of disease characteristics Positive results from the NEURO-TTRansform Phase III trial for eplontersen in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) were published in The Journal of the American Medical Association (JAMA) today further demonstrating the benefit of eplontersen across the spectrum of the disease. 1 Results from the week 66 primary analysis demonstrated improvement across all co-primary and secondary outcomes, indicating the broad range of clinically relevant benefits from treatment with eplontersen, a ligand-conjugated antisense oligonucleotide (ASO) that inhibits hepatic transthyretin (TTR) protein production. 1 An end-of-treatment analysis also showed eplontersen continued to demonstrate sustained improvements through 85 weeks. 2 Sami Khella, M.D., Chief, Department of Neurology at Penn Presbyterian Medical Center, Professor of Clinical Neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine and a Principal Investigator on the NEURO-TTRansform trial, said: “

Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses

Q392Pb~W9vhOVXdEWIW8AqEl35g-H~Dxmyl1gh85R8iRv6JsX-2YVLKt70y91~BEFC4N7rwhKAKmjdtkQLGpWUyb2N1P3SduE57w2vjHbniRl1aEYS3WbMVaNqZCf3a0kvllqokl9YDh7sVlWUAfG3Bt1e9q-c6HI3RTQuy8mGlO4zhPEKJ4SJmIXiqibxSoskqMFHnWGz1RgbWcSpJldHgnHDg5fBTI-uFJkCinw2wwXElrwpMAF57kTpEGKERe7e1-41MQabtFe7PBcb~t3qQ~LoLCCD3MEBpe7DOjzRwjT9K69VFwagtArYn~6KoA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA . AstraZeneca [Internet]. Press release. NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks [last accessed 5 Sep 2023]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2023/neuro-ttransform-phase-iii-results-presented-at-aan-showed-eplontersen-demonstrated-consistent-and-sustained-improvement.html . Ionis Pharmaceuticals [Internet]. Press release. Eplontersen continued to demonstrate improvement in ATTRv-PN through 85 weeks [last accessed 5 Sep 2023]. Available from: https://ir.ionispharma.com/news-releases/news-release-details/eplontersen-continued-show-improvement-attrv-pn-through-85-weeks. Cortese A, et al. Diagnostic challenges

Eplontersen demonstrated sustained benefit in Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks

trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks PUBLISHED 27 March 2023 27 March 2023 07:00 BST Positive high-level results from the NEURO-TTRansform Phase III trial in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) showed eplontersen met its co-primary endpoints through 66 weeks. The results were consistent with the positive 35-week findings announced in June 2022 . 1 At 66 weeks, patients treated with eplontersen continued to demonstrate a statistically significant and clinically meaningful change from baseline versus an external placebo group on the co-primary endpoints of modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression, 2 and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN). The trial also met its third co-primary endpoint demonstrating a statistically significant reduction in serum TTR concentration versus an external placebo group. TTR reductions were consistent with those reported at week 35. Eplontersen continued to demonstrate a safety and tolerability profile consistent with that observed at 35 weeks. Sami Khella, M.D., Chief, Department of Neurology, Penn Presbyterian Medical Center and Professor of Clinical Neurology, University of Pennsylvania School of Medicine, said: “The positive results from the 66-week analysis of the Phase III NEURO-TTRansform trial show that eplontersen provided consistent and sustained transthyretin protein reduction and that a substantial number of patients improved in measures of both neuropathy progression and quality of life. This builds on the favourable 35-week results, which first demonstrated eplontersen’s potential to significantly improve outcomes in this underserved population.” Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “These results further underscore eplontersen’s potential to be a best-in-class treatment across all forms of transthyretin-mediated amyloidosis, including polyneuropathy and cardiomyopathy which can lead to heart failure. With limited treatment options currently available, there is an urgent unmet medical need for new therapies

NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks

at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks PUBLISHED 24 April 2023 Eplontersen halted neuropathy disease progression and improved neuropathy impairment and quality of life Detailed results from the NEURO-TTRansform Phase III trial in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) showed AstraZeneca and Ionis’ eplontersen met all co-primary endpoints and secondary endpoints at 66 weeks versus an external placebo group. 1 The positive results being presented today in an Emerging Science Session at the American Academy of Neurology (AAN) 2023 Annual Meeting in Boston, Massachusetts demonstrate that eplontersen’s efficacy, safety and administration profile may provide an important new option in this fatal disease with significant unmet need. 1 At 66 weeks, patients treated with eplontersen demonstrated consistent and sustained benefit on the three co-primary endpoints of serum transthyretin (TTR) concentration, neuropathy impairment and quality of life (QoL). Eplontersen achieved a least squares (LS) mean reduction of 82% in TTR serum concentration from baseline, compared to an 11% reduction from baseline in the external placebo group (p<0.0001). 1 Eplontersen halted disease progression as measured by modified Neuropathy Impairment Score +7 (mNIS+7), resulting in a 0.28 point LS mean increase compared to a 25.06 point increase for the external placebo group from baseline (24.8 point LS mean improvement; p<0.0001). Overall, 47% of treated patients showed improvements in neuropathy at 66 weeks compared to baseline versus 17% in the external placebo group. Among study completers, 53% of treated patients showed improvements in neuropathy at 66 weeks compared to baseline versus 19% in the external placebo group. Eplontersen also improved QoL demonstrating a 5.5 point LS mean decrease (improvement) on the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN), compared to a 14.2 point increase (worsening) in the external placebo group (19.7 point LS mean improvement; p<0.0001). Overall, 58% of treated patients

NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks

NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks Skip to content Skip to navigation Skip to footer Search Menu Search Search Search Close What science can do What science can do Stories of impact Publications Close R&D R&D Our approach Our approach to R&D STEM at AstraZeneca Precision medicine Transformative science Data science & AI Clinical innovation Our technologies Next generation therapeutics R&D strategic centres Featured website AstraZeneca Clinical Trials Featured website Open Innovation Close Our therapy areas Our therapy areas Oncology BioPharmaceuticals Cardiovascular, Renal and Metabolism Respiratory & Immunology Vaccines and Immune Therapies Rare Disease Pipeline All medicines Close Our company Our company Our history Our people Our people Oncology BioPharmaceuticals Rare Disease Research & Development Enabling functions Operations International Our leadership Cambridge Gothenburg Gaithersburg Close Careers Careers Great place to work Inclusion and diversity Learning and development Employee resource groups Close Investors Investor Relations (Global) Investor Relations (Sweden) Resources Governance Shareholder information Dividend policy Key facts FAQs Debt Investors ADR Programme Investor Relations contacts Feature Results and presentations Close Media Media Press Releases Articles Image library Archive Media contacts Investor Day 2024 Close Sustainability Sustainability Climate change Climate change overview Renewables Product sustainability AZ Forest Nature Nature overview Water stewardship Pharmaceuticals in the environment Waste and circularity Health equity Health equity overview Science Healthcare delivery Community investment Health systems resilience Health systems resilience overview Partnership for Health System Sustainability and Resilience (PHSSR) Ethics and governance Ethics and Compliance Governance Sustainability governance Our people Great place to work Inclusion and diversity Learning and development Workforce safety and health Our Values Partnerships and alliances Resources Sustainability resources Our sustainability impact Feature Our sustainability impact Feature Sustainable science Close Partnering Partnering Our business development teams Our areas of partnering interest Why partner with AstraZeneca? Information for Suppliers Supplier Sustainability Hub Sustainable procurement A Catalyst Network Close AstraZeneca Websites Global site NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks PUBLISHED 24 April 2023 Eplontersen halted neuropathy disease progression and improved neuropathy impairment and

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

to 5 years [ 3 ]. In recent years, novel TTR-targeting therapies have been developed. These therapies either reduce the production of TTR (RNA inhibitors and antisense oligonucleotides) or stabilize the circulating TTR molecule (TTR stabilizers). The TTR tetramer stabilizer tafamidis is currently the only approved agent for treating ATTR-CM [ 4 ]. Recent trials have demonstrated the efficacy of emerging therapies, including Vutrisiran, Patisiran, Eplontersen, Inotersen, and Acoramidis, in managing ATTR [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Therefore, we propose to conduct a systematic review and meta-analysis to compare the efficacy of ATTR-specific therapies with placebo and evaluate the comparative effectiveness of different therapeutic classes in patients with ATTR-CM. Methods This meta-analysis and systematic review was performed and reported according to the Cochrane Collaboration Handbook for Systematic Reviews of Intervention and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 13 , 14 ]. The prospective meta-analysis protocol has been uploaded to the International Prospective Register of Systematic Reviews (CRD42024592297). Eligibility criteria There were no restrictions regarding publication date, status, or language. Studies were considered eligible for inclusion if they (1) were randomized controlled trials (RCTs); and (2) compared the following therapies for ATTR with placebo: Tafamidis, Acoramidis, Patisiran, Vutrisiran, Inotersen, and Eplontersen; 3) enrolled patients with ATTR-CM; and 4) presented data regarding any of the prespecified efficacy and safety endpoints. We excluded studies that (1) did not report any of the outcomes of interest, (2) had overlapping patient populations, and (3) abstracts presented in congresses. Search strategy and data extraction We systematically searched Medline via Pubmed, EMBASE, and Cochrane from the database inception to September 2024. The study selection process included reviewing titles and abstracts initially, followed by a thorough examination of the full texts of potentially suitable studies. The full search strategy is reported in the Supplemental Methods S3 . Eight authors (J.F.; G.B.; R.P.; P.S.; C.F.; W.N

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC

use of eplontersen for treatment of polyneuropathy in patients with hATTR on December 21, 2023 [ 48 ]. A Study to Evaluate the Efficacy and Safety of Eplontersen in Patients With Transthyretin-Mediated Amyloid Cardiomyopathy (CARDIO-TTRransform; NCT04136171 ) is a counterpart trial that is investigating eplontersen for cardiomyopathy in hATTR patients. It is a phase 3 clinical trial which enrolled more than 1,400 patients making it one of the largest studies in this patient population to date and projected to share data in 2025. NTLA-2001 NTLA-2001 is an in vivo gene-editing therapy designed to reduce TTR in serum using the technology based on clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system [ 20 ]. It includes mRNA for Cas9 protein and a single guide RNA targeting the TTR protein encapsulated in a lipid nanoparticle coat. Preclinical in vitro and in vivo studies using mice and monkeys showed durable knockout of TTR after a single dose [ 20 , 21 ]. A Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis with Polyneuropathy and Patients With Transthyretin Amyloidosis-Related Cardiomyopathy with a Phase 1 clinical trial with two parts: Part 1 (open-label, single ascending dose) and Part 2 (open-label, single dose expansion) ( NCT04601051 ). In published results from Part 1, Gilmore et . al . evaluated the safety and effect of single escalating doses of NTLA-2001 in 6 patients with hATTR-PN with three patients in each of the initial groups (0.1 mg/kg and 0.3 mg/kg) as part of the ongoing trial [ 20 ]. They demonstrated a decrease in serum TTR protein concentrations due to target knockout of TTR with minimal side effects. The follow-up investigation of the 72 patients enrolled in the Phase 1 trial showed that there are 15 out of 36 patients with hATTR-PN and 12 out of 36 patients with hATTR-CM in Part 1: single-ascending dose escalation [ 49

NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks

pathy (Norfolk QoL-DN), compared to a 14.2 point increase (worsening) in the external placebo group (19.7 point LS mean improvement; p<0.0001). Overall, 58% of treated patients showed improvements in QoL at 66 weeks compared to baseline versus 20% in the external placebo group. Among study completers, 65% of treated patients showed improvements in QoL at 66 weeks compared to baseline versus 23% in the external placebo group. Eplontersen demonstrated statistically significant benefits on both mNIS+7 and Norfolk QoL-DN at 35 weeks versus the external placebo group, which were further improved at 66 weeks. 1 Eplontersen also achieved statistically significant improvements in all secondary endpoints versus the external placebo group and continued to demonstrate a favourable safety and tolerability profile. The rate of treatment emergent adverse events in the eplontersen group was comparable or similar to the external placebo group across all major categories. There were no adverse events of special interest that led to study drug discontinuation. 1 Sami Khella, M.D., Chief, Department of Neurology at Penn Presbyterian Medical Center, Professor of Clinical Neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine and a Principal Investigator on the NEURO-TTRansform trial, said: “In the past, patients with hereditary transthyretin amyloid polyneuropathy usually deteriorated given the limited available treatments. This new study shows eplontersen can halt progression of neuropathy and improve quality of life at 66 weeks when compared to placebo. Today’s important results demonstrate that eplontersen has a consistent and sustained treatment effect and reinforces its potential as an important medicine for the thousands of patients living with this debilitating and fatal disease.” Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “Without treatment, hereditary transthyretin-mediated amyloid polyneuropathy is a relentlessly progressive disease. These results show that eplontersen sustains reduced transthyretin levels and improves neuropathy progression and quality of life consistently across a substantial number of patients. We are confident in eplontersen’s potential to be a much needed and differentiated treatment option for patients living with all types

Eplontersen demonstrated sustained benefit in Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks

pathy-related QoL. 10 Eplontersen Eplontersen is a ligand-conjugated antisense (LICA) investigational medicine designed to reduce the production of transthyretin, or TTR protein, to treat all types of ATTR, a systemic, progressive and fatal disease. 6,9 AstraZeneca in CVRM Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and improving outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases, and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide. AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca . Contacts For details on how to contact the Investor Relations Team, please click here . For Media contacts, click here . References 1. AstraZeneca [Internet]. Press release. Eplontersen met co-primary and secondary endpoints in interim analysis of the NEURO-TTRansform Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) [last accessed 16 March 2023]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2022/eplontersen-phase-iii-trial-met-co-primary-endpoints.html .

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC

months of the study, patients treated with tafamidis 80 mg had higher mean TTR concentrations than those treated with 20 mg or placebo, with tafamidis 20 mg also higher than placebo (online supplementary Figure S1 B ). Efficacy in ATTR‐ACT In ATTR‐ACT, both tafamidis 80 and 20 mg significantly reduced all‐cause mortality and CV‐related hospitalizations compared with placebo ( P = 0.0030 and P = 0.0048, respectively) ( Table 1 ). Table 1. Primary analysis with the Finkelstein–Schoenfeld method, all‐cause mortality and frequency of cardiovascular‐related hospitalizations Tafamidis 80 mg ( n = 176) Tafamidis 20 mg ( n = 88) Placebo ( n = 177) Primary analysis P ‐value from F‐S method 0.0030 0.0048 Patients a alive, n (%) 122 (69.3) 64 (72.7) 101 (57.1) Average CV‐related hospitalizations during 30 months (PPPY) among those alive at Month 30 0.339 0.218 0.455 All‐cause mortality, n (%) 54 (30.7) 24 (27.3) 76 (42.9) Deaths 46 (26.1) 23 (26.1) 72 (40.7) Heart transplants 6 (3.4) 1 (1.1) 4 (2.3) Implantation of a CMAD 2 (1.1) 0 0 Patients with CV‐related hospitalizations, n (%) 96 (54.5) 42 (47.7) 107 (60.5) Frequency of CV‐related hospitalizations per year 0.49 0.46 0.70 Tafamidis vs. placebo treatment difference, RRR (95% CI) 0.70 (0.57–0.85) 0.66 (0.51–0.86) – P ‐value 0.0005 0.0017 – CV‐related events, n (%) 45 (25.6) 19 (21.6) 63 (35.6) CV‐related deaths 37 (21.0) 18 (20.5) 59 (33.3) Heart transplants 6 (3.4) 1 (1.1) 4 (

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC

in I) were evaluated at each time point post‐baseline using a mixed model repeated measures ANCOVA (MMRM) with an unstructured covariance matrix (or as appropriate), centre, and patients within centre as random effects. The fixed effects were treatment, visit, TTR genotype (ATTRv vs. ATTRwt), and visit by treatment interaction; and baseline score was used as a covariate. For all MMRM analyses, there was no imputation of missing values. The proportion of patients achieving TTR stabilization at Month 1 was compared using the Cochran–Mantel–Haenszel test. All‐cause mortality in ATTR‐ACT alone and combined with the LTE was assessed as above, based on the pre‐specified Cox proportional hazards model with treatment, NYHA baseline classification, and genotype in the model, and also separately adjusted for additional covariates by adding age, NT‐proBNP (log transformed), and 6MWT distance as covariates to the pre‐specified model (both individually and all three combined). Time of initiation of tafamidis was used as time zero in all survival analyses. Results Patient characteristics and transthyretin stabilization in ATTR‐ACT Of the 548 patients screened for ATTR‐ACT, 441 were randomized to receive tafamidis 80 or 20 mg or placebo (176, 88, and 177, respectively), and 113, 60, and 85 patients, respectively, completed the study. Survival status was collected for all 441 patients at Month 30. Demographic and clinical characteristics are shown in online supplementary Table S1 . Transthyretin stabilization at Month 1 was achieved in a significantly greater proportion of patients treated with tafamidis 80 and 20 mg [144/164 (87.8%) and 67/81 (82.7%) patients, respectively] than with placebo [6/170 (3.5%) patients, P < 0.0001 for both]. Treatment with tafamidis 80 mg also resulted in a greater degree of TTR tetramer stabilization than 20 mg (online supplementary Figure S1 A ). Over the 30 months of the study, patients treated with tafamidis 80 mg had higher mean TTR concentrations than those treated with 20 mg or placebo, with tafamidis 20 mg also higher than placebo (online supplementary Figure

NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks

an estimated 300,000 - 500,000 patients with ATTR-CM 7 and about 40,000 patients with ATTRv-PN. 5,7 NEURO-TTRansform NEURO-TTRansform is a global, open-label, randomised trial evaluating the efficacy and safety of eplontersen in patients with ATTRv-PN. 8 The trial has enrolled adult patients with ATTRv-PN Stage 1 or Stage 2 and will be compared to the external placebo group from the TEGSEDI ® (inotersen) NEURO-TTR registrational trial that Ionis completed in 2017. 8 The final analysis comparing eplontersen to external placebo was completed at week 66 and all patients will be followed on treatment until week 85, when they will have the option to transition into an open-label extension study. 8 The 66-week analysis evaluated percent change from baseline in serum TTR concentration, changes in the mNIS+7 and Norfolk-QOL-DN in the eplontersen group versus an external placebo group. 8 The mNIS+7 uses highly standardised, quantitative and referenced assessments to quantify muscle weakness, muscle stretch reflexes, sensory loss and autonomic impairment. 9 The Norfolk QoL-DN is a patient-reported questionnaire capturing neuropathy-related QoL. 8 Eplontersen Eplontersen is a ligand-conjugated antisense (LICA) investigational medicine designed to reduce the production of transthyretin, or TTR protein, to treat all types of ATTR, a systemic, progressive and fatal disease. 7,10 AstraZeneca in CVRM Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and improving outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases, and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide

Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses

of Neurology at Penn Presbyterian Medical Center, Professor of Clinical Neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine and a Principal Investigator on the NEURO-TTRansform trial, said: “The totality of positive, consistent eplontersen data position this therapy, which can be self-administered, to be an important and empowering potential new medicine for treating hereditary transthyretin-mediated amyloid polyneuropathy. Without treatment, hereditary transthyretin-mediated amyloid polyneuropathy is a debilitating and devasting disease that can ultimately result in death. The JAMA publication reinforces the growing body of evidence showing that eplontersen significantly reduces serum transthyretin concentration, may halt progression of neuropathy impairment, and improves overall patient quality of life, providing hope to this community.” Sharon Barr, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “Eplontersen demonstrated improvements in a wide array of disease-related endpoints across transthyretin-mediated amyloid polyneuropathy in patients with a diverse range of disease characteristics. Publication of these positive results provides further evidence of eplontersen’s ability to achieve consistent and sustained benefit in this patient population and its potential to be an important treatment option across all types of transthyretin-mediated amyloidosis.” In the NEURO-TTRansform Phase III trial, patients treated with eplontersen demonstrated consistent and sustained benefit on the three co-primary endpoints of serum transthyretin (TTR) concentration, neuropathy impairment measured by modified Neuropathy Impairment Score +7 (mNIS+7) and quality of life (QoL) on the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN). 1 Eplontersen achieved a least squares (LS) mean reduction of 82% in TTR serum concentration from baseline at 65 weeks, compared to an 11% reduction from baseline in the external placebo group (p<0.001). 1 Eplontersen demonstrated statistically significant benefits on both mNIS+7 and Norfolk QoL-DN at 35 weeks versus the external placebo group, which were further improved at 66

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

ense oligonucleotides). Results Nine RCTs were included, involving 2,713 patients, of whom 1,160 (59.34%) were assigned to the TTR-specific therapies group. In the pooled analysis, TTR-specific therapies were associated with a significant reduction in all-cause mortality (RR 0.70; 95% CI 0.60, 0.83; p < 0.01; I² = 0%), with both TTR stabilizers and knock-down therapies showing equally effective reductions ( p = 0.97). Additionally, TTR-specific therapies improved LV longitudinal strain (SMD − 0.22; 95% CI -0.34, -0.10; p < 0.01; I² = 17%) and reduced LV mass (SMD − 9.11 g; 95% CI -16.4 g, -1.82 g; p = 0.01; I² = 0%). Conclusion This meta-analysis highlights the potential of TTR-targeting therapies as an effective option for managing ATTR-CM, with significant improvements in survival. No efficacy differences were found between TTR stabilizers and knock-down therapies. Peer Review reports Introduction Transthyretin (TTR) amyloidosis (ATTR) is a disease characterized by the deposition of misfolded TTR monomers in vital organs. This condition arises either from destabilizing mutations in hereditary ATTR (hATTR) or from an age-associated mechanism in wild-type ATTR (wtATTR), frequently involving the heart and presenting as TTR amyloid cardiomyopathy (ATTR-CM) [ 1 ]. Recent research indicates that as many as 10–15% of older adults with heart failure (HF) with preserved ejection fraction may have undiagnosed wtATTR. The natural history of the disease, encompassing factors such as age of onset, primary phenotype, and clinical course, varies according to the specific mutation and familial traits [ 2 ]. Untreated patients with ATTR-CM typically experience progressive HF, with an approximate survival time of 3 to 5 years [ 3 ]. In recent years, novel TTR-targeting therapies have been developed. These therapies either reduce the production of TTR (RNA inhibitors and antisense oligonucleotides) or stabilize the circulating TTR molecule (

Vyndaqel (tafamidis) vs Wainua (eplontersen) | Everyone.org

ing and subsequent buildup as amyloid fibrils. Clinical trials have demonstrated the efficacy of Vyndaqel in patients with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy. The use of tafamidis has been shown to significantly reduce the progression of neurologic impairment and to improve quality of life for patients suffering from this condition. In addition to its effects on neuropathy, Vyndaqel has also been evaluated for its efficacy in treating cardiomyopathy associated with ATTR. Studies have indicated that tafamidis can lead to a reduction in hospitalizations related to cardiovascular issues and can decrease mortality in patients with ATTR cardiomyopathy. By stabilizing the transthyretin tetramer, tafamidis helps to slow the deterioration of heart function, providing a therapeutic option for patients with this life-threatening manifestation of amyloidosis. Wainua (Eplontersen) and Its Role in Amyloidosis Treatment Wainua (eplontersen), formerly known as IONIS-TTR-LRx, is an investigational antisense oligonucleotide designed to reduce the production of transthyretin (TTR) protein by the liver. It is being studied for the treatment of ATTR amyloidosis, including both the hereditary form and the wild-type form that usually affects the heart. Eplontersen works by binding to the TTR mRNA, promoting its degradation, and thereby decreasing the production of TTR protein and the subsequent formation of amyloid fibrils. Although still under investigation, preliminary data from clinical trials suggest that eplontersen can significantly lower TTR protein levels in patients with ATTR amyloidosis. The reduction in TTR levels is expected to translate into clinical benefits, such as slowing the progression of neuropathy and cardiomyopathy. Ongoing studies are aimed at further evaluating the long-term efficacy and safety of eplontersen in patients with ATTR amyloidosis, with the goal of providing a new treatment option that targets the underlying cause of the disease. Regulatory Agency Approvals Vyndaqel European Medical Agency (EMA), European Union Food and Drug Administration (FDA), USA Health Canada Pharmaceuticals and Medical Devices Agency (PMDA), Japan Therapeutic Goods Administration (TGA), Australia Wainua Food and

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

agram. PRISMA flow diagram of study screening and selection Full size image Table 1 Baseline characteristics of included studies Full size table Risk of Bias assessment and small study effect Six included trials [ 4 , 5 , 8 , 9 , 11 , 12 ] were evaluated as having a low risk of bias in all domains. Two trials were assessed as having some concerns [ 6 , 10 ], and one was evaluated as having a high risk of bias [ 7 ]. The individual RCT appraisal is reported in Supplemental Fig. S1 A and S1 B. Moreover, our funnel plot (Supplemental Fig. S2 ) shows a symmetrical distribution of studies with convergence toward the pooled treatment effect size as weights increased, suggesting no evidence of a small study effect. Our GRADE assessments are presented in Supplemental Table S3 . The certainty of evidence was high for all-cause mortality, SAE, cardiac AE, and LV longitudinal strain. For other outcomes, the certainty ranged from moderate to low. Pooled analysis In those receiving TTR-specific therapies, there was a significant reduction in all-cause mortality (RR 0.70; 95% CI 0.60, 0.83; p < 0.01; I² = 0%; Fig. 2 ). The LV longitudinal strain endpoint demonstrated a statistically significant reduction in the TTR-specific therapy group (SMD − 0.22; 95% CI -0.34, -0.10; p < 0.01; I² = 17%; Fig. 3 A). TTR-specific therapies consistently reduced LV mass compared to placebo (MD -9.11 g; 95% CI -16.4 g, -1.82 g; p = 0.01; I² = 0%; Fig. 3 B). Fig. 2 Forest Plot for All Cause Mortality. TTR-specific therapies showed a significant reduction in all-cause mortality compared to placebo. Abbreviations: CI: Confidence Interval; RR: Risk Ratio; TTR: Transthyretin Full size image Fig. 3 A . Forest Plot for LV Longitudinal Strain. TTR-specific therapies significantly reduced LV longitudinal strain compared to placebo. Abbreviations: CI: Confidence Interval; SMD: Standardized Mean Difference; LV: Left Ventricle; TTR: Transthyretin. B . Forest Plots for LV Mass

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

rates with TTR-specific therapies in patients with ATTR-CM compared to placebo. Specifically, TTR-specific therapies reduced mortality by 30% (RR 0.70; 95% CI 0.60, 0.83; Fig. 2 ), underscoring their clinical efficacy in managing this condition. Our findings align with major RCTs included in the analysis, such as the ATTR-ACT trial, which evaluated tafamidis in ATTR-CM patients (RR 0.69 [0.53; 0.89]), and the HELIOS-B trial, which assessed vutrisiran in ATTR-CM patients (RR 0.71 [0.53; 0.95]). (RR 0.71 [0.53; 0.95]). Moreover, the ATTRibute-CM, APOLLO A, APOLLO B and NEURO TTR TRANSFORM RCTs did not yield statistically significant results individually. Additionally, some studies relied on historical placebo groups, which may introduce variability and affect comparability, such as HELIOS A, which referenced the placebo group from the APOLLO A trial, and NEURO TTR TRANSFORM, which used the placebo group from the NEURO TTR study. Although the historical placebo groups had similar endpoints and eligibility criteria, this may introduce bias in interpreting the results. However, our meta-analysis revealed 0% heterogeneity. These consistent results, confirmed by subgroup analysis (Fig. 5 ), trials explicitly designed for ATTR-CM (Supplemental Figs. S3 – S5 ) populations, and funnel plot analysis (Supplemental Fig. S2 ), further validate the efficacy of both TTR stabilizers and knock-down therapies in reducing mortality among patients with ATTR-CM. Moreover, our findings align with observational phase 4 studies, such as Garcia-Pavia et al. [ 25 ], which reported survival rates at 30 and 42 months of 84.4% and 76.8%, respectively, in tafamidis-treated patients, compared to 70.0% and 59.3% in untreated patients. In cardiac imaging, the term strain describes myocardial shortening and thickening, the fundamental features of myocardial fiber function [ 26 , 27 ]. Our meta-analysis also demonstrated a significant improvement in LV longitudinal strain in patients on TTR therapy. In ATTR-CM, peak longitudinal strain from the ap

Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses

marrow. 4,7 The presence of TTR fibrils interferes with the normal functions of these tissues. 5 As the TTR protein fibrils accumulate, more tissue damage occurs and the disease worsens, resulting in poor QoL and eventually death. 5 Worldwide, there are an estimated 300,000 - 500,000 patients with ATTR-CM 7 and about 40,000 patients with ATTRv-PN. 5,7 NEURO-TTRansform NEURO-TTRansform is a global, open-label, randomized trial evaluating the efficacy and safety of eplontersen in patients with ATTRv-PN. 8 The trial has enrolled adult patients with ATTRv-PN Stage 1 or Stage 2 and will be compared to the external placebo group from the TEGSEDI ® (inotersen) NEURO-TTR registrational trial that Ionis completed in 2017. 8 The final analysis comparing eplontersen to external placebo was completed at week 66 and all patients will be followed on treatment until week 85, when they will have the option to transition into an open-label extension study. 8 The 66-week analysis evaluated percent change from baseline in serum TTR concentration, changes in the mNIS+7 and Norfolk-QOL-DN in the eplontersen group versus an external placebo group. 8 The mNIS+7 uses highly standardized, quantitative and referenced assessments to quantify muscle weakness, muscle stretch reflexes, sensory loss and autonomic impairment. 9 The Norfolk QoL-DN is a patient-reported questionnaire capturing neuropathy-related QoL. 8 Eplontersen Eplontersen is a ligand-conjugated antisense (LICA) investigational medicine designed to reduce the production of transthyretin, or TTR protein, to treat all types of ATTR, a systemic, progressive and fatal disease. 7,10 AstraZeneca in CVRM Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and improving outcomes by slowing disease

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

and thickening, the fundamental features of myocardial fiber function [ 26 , 27 ]. Our meta-analysis also demonstrated a significant improvement in LV longitudinal strain in patients on TTR therapy. In ATTR-CM, peak longitudinal strain from the apical 4-chamber view is independently associated with mortality, regardless of genotype or disease severity [ 26 , 28 ]. Both mortality and LV longitudinal strain were improved in the TTR therapy group compared to placebo. In HELIOS-B, vutrisiran attenuated the decline in peak longitudinal strain compared to placebo (LS mean difference − 1.23; 95% CI: -1.73 to -0.73), aligning with the observed reduction in mortality. This suggests that TTR therapies may help to halt the progression of myocardial dysfunction. Our analysis shows a significant reduction in LV mass with TTR-specific therapies compared to placebo (SMD − 9.11; 95% CI: -16.40 to -1.82]; I² = 0%), highlighting consistency across trials. This finding is clinically meaningful, as concentric LV hypertrophy with increased LV mass index is characteristic of ATTR-CM [ 29 ]. Like Dobner et al. [ 30 ], cohort studies observed similar LV mass reduction with tafamidis. However, the mechanisms—whether due to decreased amyloid deposition, clearance, or reverse remodeling—are yet to be fully understood. TTR-specific therapies also trended toward reducing CV mortality, with the strongest support from the ATTR-ACT study. Though reductions in all-cause and HF hospitalizations were observed, these outcomes lacked statistical significance. Given that fewer studies have been reported on these endpoints, further research with larger samples and longer follow-ups is essential to confirm these potential benefits and clarify the impact of TTR-targeting therapies on reducing these endpoints. TTR-specific therapies consistently improved KCCQ-OS scores and 6MWT performance compared to placebo (Supplemental Tables S5 and S7 ) and showed reduced NT-proBNP levels (Supplemental Table S4 ), indicating slower ATTR-CM progression and enhanced functional capacity [ 31 ]. Safety analyses found no evidence of increased risk for overall AE, serious AE, cardiac AEs, or cardiac SAE associated with TTR-specific therapies, supporting a favorable safety profile. Continued monitoring of broader populations will be essential, as long-term effects remain

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

) TTR-specific therapies significantly reduced all-cause mortality; (2) no subgroup difference in all-cause mortality endpoint was observed between knock-down therapies and TTR stabilizers; (3) TTR-specific therapies significantly reduced LV mass and LV longitudinal strain; (4) no significant difference in CV mortality, all-cause hospitalization, or HF hospitalization between TTR-specific therapies and placebo; and (5) no significant differences in the incidence of AE between patients receiving TTR-specific therapies and in the placebo group. In our sensitivity analysis of only ATTR-CM designed trials, (6) TTR-specific therapies significantly reduced all-cause mortality; (7) no subgroup difference in all-cause mortality endpoint was observed between knock-down therapies and TTR stabilizers; (8) TTR-specific therapies slightly but significantly reduced CV mortality. Therapeutic options for ATTR have advanced significantly. Historically, liver transplantation was considered the only method to address hATTR. It halts the production of mutant TTR but has limited efficacy due to the continued deposition of wtATTR in tissues. In contrast, recent FDA-approved therapies target the protein directly [ 23 ]. Currently, there are two major classes of TTR-targeting therapies for ATTR: TTR stabilizers, which bind to transthyretin, stabilizing the protein’s tetrameric structure and affecting rate-limiting steps in ATTR amyloidogenesis, and TTR knock-down therapies, such as RNA inhibitors and antisense oligonucleotides, target the gene encoding transthyretin, thereby reducing circulating levels of the implicated protein [ 24 ]. Approved through organ-specific trials, these therapies address polyneuropathy and cardiomyopathy, with some studies overlapping both. In our proposed systematic review and meta-analysis, we specifically evaluate TTR-targeting therapies for patients with cardiomyopathy, independent of other organ involvement. This approach enables us to compare different therapies for ATTR-CM, expand therapeutic options, and confirm the efficacy of these treatments. The main result of our meta-analysis highlights the significant reduction in mortality rates with TTR-specific therapies in patients with ATTR-CM compared to placebo. Specifically, TTR-specific therapies reduced mortality by 30% (RR 0.70; 95% CI 0.60, 0.83; Fig. 2

Eplontersen demonstrated sustained benefit in Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks

Eplontersen demonstrated sustained benefit in Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks Skip to content Skip to navigation Skip to footer Search Menu Search Search Search Close What science can do What science can do Stories of impact Publications Close R&D R&D Our approach Our approach to R&D STEM at AstraZeneca Precision medicine Transformative science Data science & AI Clinical innovation Our technologies Next generation therapeutics R&D strategic centres Featured website AstraZeneca Clinical Trials Featured website Open Innovation Close Our therapy areas Our therapy areas Oncology BioPharmaceuticals Cardiovascular, Renal and Metabolism Respiratory & Immunology Vaccines and Immune Therapies Rare Disease Pipeline All medicines Close Our company Our company Our history Our people Our people Oncology BioPharmaceuticals Rare Disease Research & Development Enabling functions Operations International Our leadership Cambridge Gothenburg Gaithersburg Close Careers Careers Great place to work Inclusion and diversity Learning and development Employee resource groups Close Investors Investor Relations (Global) Investor Relations (Sweden) Resources Governance Shareholder information Dividend policy Key facts FAQs Debt Investors ADR Programme Investor Relations contacts Feature Results and presentations Close Media Media Press Releases Articles Image library Archive Media contacts Investor Day 2024 Close Sustainability Sustainability Climate change Climate change overview Renewables Product sustainability AZ Forest Nature Nature overview Water stewardship Pharmaceuticals in the environment Waste and circularity Health equity Health equity overview Science Healthcare delivery Community investment Health systems resilience Health systems resilience overview Partnership for Health System Sustainability and Resilience (PHSSR) Ethics and governance Ethics and Compliance Governance Sustainability governance Our people Great place to work Inclusion and diversity Learning and development Workforce safety and health Our Values Partnerships and alliances Resources Sustainability resources Our sustainability impact Feature Our sustainability impact Feature Sustainable science Close Partnering Partnering Our business development teams Our areas of partnering interest Why partner with AstraZeneca? Information for Suppliers Supplier Sustainability Hub Sustainable procurement A Catalyst Network Close AstraZeneca Websites Global site Eplontersen demonstrated sustained benefit in Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks PUBLISHED 27 March 2023 27 March 2023 07:00 BST Positive high-level results from

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC

or wtATTR-CM [ 46 ]. It demonstrated decreased LV mass by 8.4% (measured on CMR), and increased 6MWT distance both at year 2 and year 3. However, inotersen was not comprehensively studied further or currently approved for ATTR-CM. Eplontersen Eplontersen, formerly known as ION-682,884, IONIS-TTR-LRx, and AKCEA-TTR-LRx, is another antisense oligonucleotide that binds to TTR-mRNA to promote degradation of the subsequent TTR-mRNA product to reduce the serum TTR protein and its deposition in tissue [ 47 ]. A Study to Evaluate the Efficacy and Safety of Eplontersen in Patients With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy (NEURO-TTRansform; NCT04136184 ) was an open-label, single-group, phase 3 trial conducted at 40 sites in 15 countries of 168 adults with Stage 1 or 2 polyneuropathy in patients with hATTR who were treated with subcutaneous eplontersen 45 mg every 4 weeks (144 patients) or 300 mg weekly (24 patients) treated from December 2019 to April 2023 compared to the placebo arm (66 patients) from March 2013 to November 2017 [ 47 ]. The same primary endpoints used in the NEURO-TTR trial for inotersen were used in this trial: serum transthyretin concentration, change in mNIS + 7 score and change in QOL-DN score were used in this trial. There was an −70.4% reduction in serum transthyretin concentration in the eplontersen arm compared to the placebo arm. In total, there were 6 versus 2 discontinuation events in the eplontersen group compared to placebo; there were 2 deaths in the eplontersen group which was consistent with known disease-related sequelae (cardiac arrhythmia, intracranial hemorrhage). The FDA approved the use of eplontersen for treatment of polyneuropathy in patients with hATTR on December 21, 2023 [ 48 ]. A Study to Evaluate the Efficacy and Safety of Eplontersen in Patients With Tr

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC

measured biventricular function and reduced left ventricular (LV) mass compared to the placebo group [ 30 ]. Irrespective of tafamidis treatment, extracellular volume and T1-mapping did not significantly change from baseline in both the tafamidis and placebo groups. Another post hoc analysis demonstrated that tafamidis slowed the decline in LV systolic and diastolic function as measured by echocardiography [ 13 ]. A long-term extension (LTE) study for the patients in the ATTR-ACT trial was conducted in which patients in both the tafamidis and placebo group would be given tafamidis [ 31 ]. All-cause mortality was higher in patients with LVEF < 50%, but those treated continuously with tafamidis had a 47% reduction in mortality risk compared to those who received delayed treatment, irrespective of ejection fraction. Acoramidis Acoramidis, formerly known as AG10, is a stabilizer molecule that acts to inhibit dissociation of tetrameric TTR and ex vivo has been shown to have more than 90% stabilization of the TTR molecule [ 32 ]. In vitro studies show superior selectivity and efficacy towards stabilization of TTR compared to tafamidis and diflunisal [ 32 ]. In the patients who completed the phase 2 study and enrolled in the open-label extension ( n = 25), acoramidis was well-tolerated with adverse events that were consistent with disease severity, concurrent illness, and/or age [ 33 ]. They demonstrated stable N-terminal, pro-B-type natriuretic peptide (NT-proBNP) and sustained increases in serum TTR. The Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM; NCT03860935 ) was a phase 3 trial which was designed to evaluate the safety and efficacy of acoramidis in patients with either wtATTR-CM ( n = 571) or hATTR-CM ( n = 61) [ 14 ]. Patients were treated with either acoramidis 800 mg twice a day or placebo. The study evaluated 4 outcomes including reduction in all-cause mortality, hospitalization for cardiovascular causes, change in baseline of NT-proBNP and change in baseline

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC

capone after 15 weeks of follow up [ 36 ]. Further studies are needed to establish the efficacy and utility of tolcapone as a TTR stabilizer. TTR Silencers Transthyretin silencers reduce intrahepatic TTR production by preventing the transcription of its messenger RNA (mRNA). They have three different mechanisms: (1) small interfering RNA agents, which include patisiran, revusiran, and vutrisiran; (2) anti-sense oligonucleotides, which include inotersen and eplontersen; (3) gene editing (Table 2 ). Table 2. TTR silencing therapies for transthyretin amyloid cardiomyopathy (ATTR-CM) Drug Clinical trial (year) Design Population % Black patients V142I patients Outcomes Small Interfering RNA agents Patisiran (formerly known as ALN-TTR02) APOLLO-B [ 16 ] Phase 3, multicenter randomized, double-blind, placebo-controlled clinical trial for 18 months to receive patisiran or placebo N = 360 (hATTR-CM, n = 72) 8.6% ( n = 31) 40.3% ( n = 29) Lower decline in 6MWT distance, increased KCCQ-OS score, more infusion-related reactions, arthralgia, muscle spasms associated with patients in patisiran group Revusiran (formerly known as ALN-TTRsc) ENDEAVOUR [ 38 ] Phase 3, randomized, 2:1 ratio, double-blind, placebo controlled multicenter clinical trial for 18 months N = 206 (hATTR-CM) 51% ( n = 104) 57% ( n = 117) Trial terminated early due to increased mortality compared to placebo Vutrisiran* (formerly known as ALN-TTRsc02) HELIOS-B [ 18 ] Phase 3, randomized, double-blind, placebo controlled multicenter clinical trial received SC vutrisiran 25 mg every 3 months for 36 months N = 655 (hATTR-CM, n = 76) 7.2% ( n = 47) 64% ( n = 49) Lower all-cause mortality

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC

afamidis dose (80 and 20 mg) compared with placebo. The key secondary endpoints were change from baseline to Month 30 in the distance walked during the 6MWT 19 and the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ‐OS) score, based on a subset of the 23‐item, patient‐completed KCCQ that assesses HRQoL. 20 Additional secondary analyses included CV‐related mortality and TTR stabilization at Month 1. Exploratory endpoints included change from baseline to Month 30 in NT‐proBNP and troponin I concentrations, and TTR stabilization and TTR concentration throughout the study. The TTR stabilization assay was performed using plasma samples (LabCorp, Los Angeles, CA, USA). 10 , 11 , 12 All‐cause mortality with tafamidis 80 mg compared with 20 mg was assessed over a longer duration of treatment by combining data from ATTR‐ACT (median follow‐up 30 months) with the LTE (median follow‐up 51 months). In addition to ATTR‐ACT data alone, analyses were conducted for ATTR‐ACT combined with LTE patients, which included the additional exposure to tafamidis free acid 61 mg after patients transitioned to the new 61 mg formulation (as of 1 August 2019). Patients continued to be compared based on their initial dose randomization (tafamidis 80 vs. 20 mg). Statistical analyses Unless stated otherwise, all analyses were carried out on the modified intent‐to‐treat population of the randomized controlled study, which included all randomized patients with at least one post‐baseline efficacy evaluation and who received at least one dose of study drug. Details on the statistical analyses have previously been published. 14 , 15 Here, the two doses of tafamidis were compared with placebo using the Finkelstein–Schoenfeld method, 18 as applied in the primary analysis. The Cox proportional hazards model was used to analyse all‐cause mortality. Poisson regression analysis was used to analyse frequency of CV‐related hospitalization. Secondary and exploratory endpoints (NT‐proBNP and troponin I) were evaluated at each time point post‐baseline using a mixed model repeated measures ANCOVA (MMRM) with an unstructured covariance matrix (or as appropriate), centre, and patients within centre as random effects. The

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC

concentration with tafamidis 80 mg, compared with 20 mg, suggesting that more TTR was conserved in its tetramer structure and less dissociated TTR was consumed in the amyloidogenic cascade. Cardiac biomarkers such as NT‐proBNP and troponin have previously been used alongside other biomarkers to assess disease progression in patients with ATTR‐CM. 12 , 23 , 24 , 27 Higher baseline levels of NT‐proBNP (>3000 pg/mL) and reduced eGFR (<45 mL/min) were significantly associated with increased mortality in patients with ATTR‐CM. 24 Higher baseline NT‐proBNP and troponin T levels were also significantly associated with increased mortality in patients with ATTRwt. 23 In ATTR‐ACT, there was a significant reduction in the increase in NT‐proBNP and troponin I over time with tafamidis 80 mg compared with placebo, and the reduction in the increase in NT‐proBNP with tafamidis 80 mg was significantly greater than that with 20 mg. Furthermore, the percentage of patients with stable or reduced NT‐proBNP levels at Month 30 was higher with tafamidis 80 mg than 20 mg. NT‐proBNP was reduced in almost half (45.5%) of tafamidis 80 mg patients [compared with one‐quarter (23.3%) with 20 mg]. Limitations As not all secondary and exploratory outcome measures were collected in the LTE, it was not possible to assess the longer‐term effect of tafamidis treatment on cardiac biomarkers or measures of functional capacity and HRQoL. Conclusions Tafamidis, at both 80 and 20 mg, effectively reduced mortality and CV‐related hospitalizations, and the decline in functional capacity and HRQoL in patients with ATTR‐CM. While ATTR‐ACT was not designed to assess the relative efficacy of each tafamidis dose, the lack of dose‐related safety concerns, together with TTR stabilization and NT‐proBNP data, supported the use of tafamidis 80 mg as the preferred dose. This was confirmed by longer‐term (median 51 months) treatment data in which there was a significant, 30% relative reduction in the risk of death

Eplontersen demonstrated sustained benefit in Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks

news/drug-reduces-deaths-underdiagnosed-form-heart-failure . 8. Rintell D, et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis. 2021;16:70. 9. Ionis Pharmaceuticals [Internet]. Annual Report, 2022 [last accessed 16 March 2023]. Available from: https://ir.ionispharma.com/static-files/db9dff5d-8683-485a-a517-15e264fe7532 . 10. Coelho T, et al. Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx(ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy. Neurol Ther . 2021 Jun;10(1):375-389. tags Corporate and financial AstraZeneca Websites This website is intended for people seeking information on AstraZeneca's worldwide business. Our country sites can be located in the AZ Network. Veeva ID: Z4-68564 Date of next review: August 2026 Resources All resources Open Innovation Externally sponsored scientific research Medical Information for HCPs US prescription assistance programmes Global clinical trials information Medicines Report a possible side effect Quick links Media Investor Relations Partnering Careers Sustainability Modern Slavery Statement AZethics – Report A Concern Supplier information Social Media Community Guidelines Social Media Linkedn Instagram Facebook Twitter YouTube Glassdoor utility links Legal notice and Terms of Use Privacy notice Site map Contact us Cookie preferences © AstraZeneca 2025 You are now leaving AstraZeneca.com You have selected a link that will take you to a site maintained by a third party who is solely responsible for its contents. AstraZeneca provides this link as a service to website visitors. AstraZeneca is not responsible for the privacy policy of any third party websites. We encourage you to read the privacy policy of every website you visit. Click ‘cancel’ to return to AstraZeneca’s site or ‘continue’ to proceed. Cancel

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC

. Conclusion Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular‐related hospitalizations in patients with ATTR‐CM. The longer‐term survival data and the lack of dose‐related safety concerns support tafamidis 80 mg as the optimal dose. Clinical Trial Registration: ClinicalTrials.gov NCT01994889 ; NCT02791230 . Keywords: Transthyretin amyloid cardiomyopathy, Clinical trial, Biomarkers, Mortality Design of ATTR‐ACT and the LTE and reduction in all‐cause mortality with tafamidis 80 mg/61 mg compared with tafamidis 20 mg Introduction Transthyretin amyloid cardiomyopathy (ATTR‐CM) is caused by the accumulation of wild‐type (ATTRwt) or variant (ATTRv) transthyretin (TTR) amyloid fibrils in the myocardium, leading to cardiomyopathy and symptoms of heart failure (HF). 1 ATTRwt typically has a late symptom onset (>60 years of age) with the majority of patients being male, while symptom onset in patients with ATTRv may occur at younger ages. 1 , 2 Specific TTR mutations, such as Val122Ile, Thr60Ala, Leu111Met, Ile68Leu, 3 , 4 , 5 , 6 are commonly associated with ATTR‐CM, but cardiomyopathy can occur with other mutations. For example, Val30Met is generally associated with polyneuropathy, but many patients also experience cardiac findings, including cardiomyopathy. 2 , 7 , 8 , 9 In this disease, dissociation of the tetrameric TTR into monomers is followed by a rapid misfolding and misassembling of the monomers into aggregates, with tetramer dissociation being the rate‐limiting step in TTR amyloid formation. 10 Tafamidis inhibits TTR dissociation into monomers by binding to the thyroxine‐binding sites, which stabilizes the tetramers, thereby preventing fibril formation, 11 , 12 , 13 and has been shown to slow the progression of peripheral neurologic impairment in transthyretin amyloid polyneuropathy (ATTR‐PN). 10 The Tafamidis in Transthyret

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

S5 ) therapies significantly reduced all-cause mortality. There was no evidence of a difference in efficacy between these subgroups ( p = 0.98; Supplemental Fig. S5 ). Adverse events There were no significant increases in SAE (RR 0.91; 95% CI 0.86, 0.97; p < 0.01; I² = 0%; Supplemental Fig. S6 ), cardiac AE (RR 0.90; 95% CI 0.81, 0.99; p = 0.037; I² = 39%; Supplemental Fig. S7 ), or cardiac SAE (RR 0.98; 95% CI 0.82, 1.18; p = 0.861; I² = 0%; Supplemental Fig. S8 ) between the TTR-specific therapies group and the placebo group. Similarly, there was no significant difference in overall AE (RR 1.0; 95% CI 0.98, 1.01; p = 0.66; I² = 41%; Supplemental Fig. S9 ) between the two groups. Trial sequential analysis Our TSA results for the primary endpoint of All-cause mortality achieved the required information size, indicating a low risk of type 1 error (Supplemental Fig. S10 ). Post-hoc network meta-analysis for the primary endpoints In our post-hoc network meta-analysis, we observed no differences between the specific therapies for ATTR-CM in our indirect estimations for all-cause mortality and CV mortality endpoints. Patisiran (P-Score = 0.75; Supplemental Table S9 ) and Tafamidis (P-Score = 0.84; Supplemental Table S9 ), were ranked the best treatment for all-cause mortality and CV mortality endpoints. Detailed results for the post-hoc network meta-analysis can be found in Supplemental Results. Discussion In this updated systematic review and meta-analysis of 9 RCTs encompassing 2,713 patients, we compared TTR-specific therapies with placebo in the population with ATTR-CM. Our main findings were as follows: (1) TTR-specific therapies significantly reduced all-cause mortality; (2) no subgroup difference in all-cause mortality endpoint was observed between knock-down therapies and TTR stabilizers; (3) TTR-specific therapies significantly reduced LV

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC

11 , 12 , 13 and has been shown to slow the progression of peripheral neurologic impairment in transthyretin amyloid polyneuropathy (ATTR‐PN). 10 The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) demonstrated that tafamidis (compared with placebo) improves survival, reduces cardiovascular (CV)‐related hospitalizations, and improves measures of function and health‐related quality of life (HRQoL) in patients with ATTR‐CM. 14 In ATTR‐ACT, patients were randomized in a 2:1:2 ratio to tafamidis 80 mg, tafamidis 20 mg, or placebo, and the primary analysis compared the pooled tafamidis (80 and 20 mg) treated group with the placebo group. 14 ATTR‐ACT was not designed to assess the relative efficacy of each dose of tafamidis. The 80 mg dose was included as it results in near maximal TTR stabilization 10 and, together with the 20 mg dose, enabled the assessment of adequately separated doses. 15 Higher doses of tafamidis were previously assessed in a randomized placebo‐controlled study in healthy subjects ( n = 42), in which a single supra‐therapeutic dose of tafamidis (400 mg), with a maximum steady‐state tafamidis concentration approximately 7.5 times higher than with a clinical dose of 20 mg, was generally well tolerated. 16 Here we present the results of additional analyses of data from ATTR‐ACT and the long‐term extension study (LTE), separately comparing the safety and efficacy of the 80 and 20 mg doses of tafamidis with placebo, in addition to changes in biomarkers and survival data directly comparing the tafamidis 80 and 20 mg doses. Methods Study design and patients The design of this phase 3, multicentre, international, three‐arm, parallel‐design, placebo‐controlled, double‐blind, randomized study (ATTR‐ACT) has been published previously ( NCT01994889 ). 14 , 15 Briefly, patients were eligible to enrol if they met the following criteria: (i) age ≥18 and ≤90 years with ATTR‐CM defined by the presence of either ATTRv or ATTRwt amyloid deposits

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC

. 2024 Aug 30. Findings from this recent study suggest that a TTR silencer lowers all-cause mortality and frequency of CV events, increasing the possibility of another agent approved for treatment of transthyretin cardiomyopathy. Gillmore JD, Judge DP, Cappelli F, Fontana M, Garcia-Pavia, P et al. Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2024. Findings from this recent study demonstrate a second TTR stabilizer agent that may be approved for treatment of transthyretin cardiomyopathy in the next few years. Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med. 2021; 385(6): 493–502. Findings from this study demonstrate the efficacy of a single infusion of a gene-editing therapy that can significantly decrease serum TTR protein concentrations. The therapy is currently being studied in a Phase 3 clinical trial. Author Contributions AGMP and KBS contributed to the ideation, literature review and writing of all drafts of the paper. The other authors contributed to literature review and the first draft of the paper and initial revision of the manuscript. All authors contributed to the article and approved the submitted version. Funding Dr. Patel is supported by the National Institutes of Health (NIH) (grant 5T32 HL149645-05). Data Availability No datasets were generated or analysed during the current study. Compliance with Ethical Standards Conflict of Interests KBS is on a medical advisory board for Bridgebio and Ionis; he is the PI for clinical trials funded by Bridgebio, Ionis, AstraZeneca/Alexion, and Intellia. The other authors declare that the research was conducted in the absence of commercial or financial relationships that may be construed as a potential conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. Footnotes Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Adam RD. Progress and challenges in the treatment of cardiac am

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC

2791230 ), in which patients could be treated with tafamidis for up to an additional 60 months. 15 In the LTE, patients continued to receive the tafamidis dose to which they had been randomized in ATTR‐ACT. Patients who had received placebo in ATTR‐ACT were re‐randomized to receive either 80 or 20 mg tafamidis in the LTE [in a 2:1 ratio; stratified by TTR genotype (ATTRv and ATTRwt)]. In ATTR‐ACT and the LTE, a dose reduction could be requested if patients experienced adverse events that may be associated with poor tolerability. The only actual reduction possible was for patients randomized to 80 mg. As of 20 July 2018, the LTE protocol was amended to transition all patients to tafamidis free acid 61 mg; a new, single capsule formulation bioequivalent to the tafamidis meglumine 80 mg used in ATTR‐ACT 17 ( graphical abstract ). The transition to tafamidis free acid 61 mg followed the protocol amendment date, not a specified duration of treatment. As such, patients were treated with tafamidis 80 or 20 mg during the LTE for different durations prior to the protocol amendment. The median duration of exposure to tafamidis prior to the transition to tafamidis free acid 61 mg was 39 months in total (in ATTR‐ACT and the LTE). Both studies were approved by the independent review boards or ethics committee at each participating site, and were conducted in accordance with the provisions of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent. Efficacy outcomes The primary analysis in ATTR‐ACT was a hierarchical combination of all‐cause mortality (in which transplantation, either heart or combined heart and liver, or implantation of cardiac mechanical assist device were counted as death) and frequency of CV‐related hospitalizations for pooled tafamidis compared with placebo using the Finkelstein–Schoenfeld method. 14 , 15 , 18 Here, this analysis was conducted separately for each tafamidis dose (80 and 20 mg) compared with placebo. The key secondary endpoints were change from baseline to Month 30 in the distance walked during the 6MWT 19 and the Kansas City Cardiomyopathy Questionnaire Overall Summary

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

found no evidence of increased risk for overall AE, serious AE, cardiac AEs, or cardiac SAE associated with TTR-specific therapies, supporting a favorable safety profile. Continued monitoring of broader populations will be essential, as long-term effects remain to be fully understood. An important aspect of our meta-analysis is that it addresses a contemporary cohort of patients with ATTR-CM, most of whom receive multidisciplinary care. It shows that both knock-down therapies and TTR stabilizers offer similar mortality reduction benefits, with consistent effect sizes across patient subgroups. Furthermore, our findings align with long-term extension studies, highlighting the sustained impact of these therapies with longer follow-ups, and emphasizing the benefits of early diagnosis and early initiation of treatment [ 32 , 33 ]. However, the advantage of combining these two classes of medication or identifying optimal therapeutic strategies for severe cases, such as advanced HF, remains unclear and requires further investigation. Another significant issue is the lack of cost-effectiveness of available medications. The annual acquisition cost of disease-modifying therapies ranges from over $100,000 to nearly $600,000, several times higher than even liberal cost-effectiveness thresholds [ 34 , 35 ]. Our meta-analysis has several important strengths, addressing key gaps in the existing literature. First, our TSA confirmed that the required information size was met, providing sufficient power to support the benefits of TTR-specific therapies in reducing mortality in patients with ATTR-CM. Second, our subgroup analysis also helps close a key gap in the literature by showing comparable efficacy between TTR knock-down therapies and TTR stabilizers, supporting the potential expansion of therapeutic options beyond tafamidis, currently the only FDA-approved ATTR-CM therapy. The specific treatment of cardiac amyloidosis has significant practical implications, as it represents a novel approach that effectively reduces amyloid deposition, improves cardiac function, modifies the natural course of the disease, and enhances patient outcomes. It is also important to acknowledge that more recent studies may benefit from earlier patient diagnoses. This leads to the inclusion of individuals with less severe disease compared to earlier cohorts. Current research indicates a shift towards a greater prevalence of wild-type forms, a reduced proportion of hereditary forms, lower NT-proBNP levels, and improved functional capacity in patients. These trends suggest that early diagnosis and treatment are increasingly influencing the current clinical landscape of the disease. These are important confounders that should be addressed

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

reduced proportion of hereditary forms, lower NT-proBNP levels, and improved functional capacity in patients. These trends suggest that early diagnosis and treatment are increasingly influencing the current clinical landscape of the disease. These are important confounders that should be addressed in further studies. This study has some limitations that warrant consideration. First, cross-trial comparisons are challenging due to differences in the enrolled cohorts. Additionally, some studies used historical placebo groups, which may introduce bias when interpreting the results. However, our sensitivity analyses validated our findings in most instances, thus confirming the results of the overall pooled analysis (Supplemental Figs. S2 – S5 ). Second, we did not assess the effects in patients using a combination of two or more TTR-specific therapies. Third, a direct comparison between stabilizers and knock-down therapies was not possible. None of the included studies directly compared these two treatment classes, precluding the identification of subgroups that might benefit more from one over the other. Finally, due to study heterogeneity and the limited number of studies evaluating these endpoints, we could not assess the impact of TTR-specific therapies on NT-proBNP levels, quality of life, or the 6MWT. Future well-designed studies are needed to directly compare the efficacy of TTR targeting therapies, both as monotherapies and in combination, and to evaluate potential subpopulations that may benefit from one therapy over another. Conclusion Overall, this updated systematic review and meta-analysis provide strong evidence supporting the use of TTR-specific therapies to manage ATTR-CM. These therapies significantly improve all-cause mortality and have demonstrated a favorable safety profile in patients with ATTR-CM. No significant differences were found regarding efficacy between TTR stabilizers and TTR knock-down therapies. As the treatment landscape for ATTR-CM continues to evolve, TTR-specific therapies offer a novel and potentially disease-modifying option for patients with this challenging condition. Data availability All data generated or analysed during this study are included in this published article [and its supplementary information files]. Abbreviations 6MWT: 6-minute walk test AE: Adverse events ATTR: Transthyretin amyloidosis ATTR-CM: Transthyretin amyloid cardiomyopathy CI: Confidence interval CV: Cardiovascular FDA: US Food and Drug Administration HF: Heart failure hATTR: Hereditary transthy

NEURO-TTRansform Phase III results presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks

sthyretin levels and improves neuropathy progression and quality of life consistently across a substantial number of patients. We are confident in eplontersen’s potential to be a much needed and differentiated treatment option for patients living with all types of this devastating disease, which can also lead to heart failure.” ATTRv-PN is a debilitating disease that leads to peripheral nerve damage with motor disability within five years of diagnosis and, without treatment, is generally fatal within a decade. 2 As part of a global development and commercialisation agreement, AstraZeneca and Ionis are seeking regulatory approval for eplontersen for the treatment of ATTRv-PN in the US and plan to seek regulatory approval in Europe and other parts of the world. 3 Last month, the US Food and Drug Administration accepted a New Drug Application for eplontersen for the treatment of ATTRv-PN. 3 Eplontersen was granted Orphan Drug Designation in the US. 3 Eplontersen is currently being evaluated in the CARDIO-TTRansform Phase III trial for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), 4 a systemic, progressive and fatal condition that typically leads to progressive heart failure and often death within three to five years from disease onset. 5,6 Notes TTR Amyloidosis ATTR cardiomyopathy and polyneuropathy are progressive systemic diseases caused by aging or genetic mutations, resulting in misfolded TTR protein and accumulation as amyloid fibrils in the cardiac myocardium and peripheral nerves, respectively. 4,5 In patients with ATTR, both hereditary and wild type (non-hereditary), TTR protein builds up as fibrils in tissues, such as the peripheral nerves and heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow. 4,7 The presence of TTR fibrils interferes with the normal functions of these tissues. 5 As the TTR protein fibrils accumulate, more tissue damage occurs and the disease worsens, resulting in poor QoL and eventually death. 5 Worldwide, there are an estimated 300,000 - 500,000 patients with ATTR-CM 7 and about 40,000 patients with ATTRv-PN. 5,7 NEURO-TTRansform NEURO-TTRansform is a

Eplontersen Phase III results published in JAMA showing consistent and sustained benefit at 35, 66 and 85-week analyses

.com/news-releases/news-release-details/eplontersen-continued-show-improvement-attrv-pn-through-85-weeks. Cortese A, et al. Diagnostic challenges in hereditary transthyretin amyloidosis with polyneuropathy: avoiding misdiagnosis of a treatable hereditary neuropathy. J Neurol Neurosurg Psychiatry . 2017;88(5):457-458. Ionis Pharmaceuticals [Internet]. Press release. Ionis expands eplontersen agreement with AstraZeneca to include exclusive rights in Latin America [last accessed 5 Sep 2023]. Available from: https://ir.ionispharma.com/news-releases/news-release-details/ionis-expands-eplontersen-agreement-astrazeneca-include . Viney N, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Failure. 2020; 8:652-661. Rintell D, et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis. 2021;16:70. Columbia University Irving Medical Center [Internet]. Drug Reduces Death from Underdiagnosed Form of Heart Failure [last accessed 5 Sep 2023]. Available from: https://www.cuimc.columbia.edu/news/drug-reduces-deaths-underdiagnosed-form-heart-failure . Ionis Pharmaceuticals [Internet]. Annual Report, 2022 [last accessed 5 Sep 2023]. Available from: https://ir.ionispharma.com/static-files/db9dff5d-8683-485a-a517-15e264fe7532 . Coelho T, et al. Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx(ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyne

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC

j.jaccao.2024.02.007. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 29. Garcia-Pavia P. Tafamidis efficacy among octogenarian patients in the phase 3 ATTR-ACT and ongoing long-term extension study. JACC Heart Fail. 2024;12(1):150–60. 10.1016/j.jchf.2023.08.032. [ DOI ] [ PubMed ] [ Google Scholar ] 30. Dobner S. Impact of tafamidis on myocardial function and CMR tissue characteristics in transthyretin amyloid cardiomyopathy. ESC Heart Failure. 2024;11:2759–68. 10.1002/ehf2.14815 [ DOI ] [ PMC free article ] [ PubMed ] 31. Drachman B, Damy T, Hanna M, Wang R, Angeli FS, Garcia-Pavia P. Long-term tafamidis efficacy in patients with transthyretin amyloid cardiomyopathy by baseline left ventricular ejection fraction. Eur J Heart Fail. 2024;26(9):2038–46. 10.1002/ejhf.3330. [ DOI ] [ PubMed ] [ Google Scholar ] 32. Penchala SC, et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci. 2013;110(24):9992–7. 10.1073/pnas.1300761110. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 33. Masri A. Long-term safety and tolerability of Acoramidis (AG10) in symptomatic transthyretin amyloid cardiomyopathy: 4-year update from an ongoing, phase 2, open-label extension study. J Card Fail. 2024;30(1):221. 10.1016/j.cardfail.2023.10.251. [ Google Scholar ] 34. Stowe R. Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson’s disease. Mov Disord. 2011;26(4):587–98

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC

(ATTR-ACT; NCT01994889 ) was the first clinical trial that showed tafamidis was associated with a lower all-cause mortality in patients with ATTR amyloidosis [ 12 ]. This study randomized patients in a 2:1: ratio to receive 80 mg tafamidis, 20 mg tafamidis, or placebo for 30 months. Both wtATTR-CM and hATTR-CM patients were included in the trial. The study also demonstrated a lower rate of cardiovascular hospitalizations, as well as lower rate of decline in a 6 min walking test and in quality of life. The effect of tafamidis was also dose-dependent, showing greater mean TTR concentrations in the 80 mg tafamidis group compared to the 20 mg group [ 25 ]. There was also a long-term extension study which had a mean follow up of 58.5 months. This analysis demonstrated continued benefits of tafamidis treatment, including better survival independent of New York Heart Association (NYHA) class and genotype compared to the placebo [ 26 ]. Of note, NYHA class IV patients were excluded from this trial. The NYHA class I or II subgroups showed a 44% decrease, and the NYHA class III group had a 35% decrease in risk of all-cause mortality. This trial used tafamidis meglumine, and subsequently another single center, phase I trial established equivalence in bioavailability of tafamidis 61 mg free-acid capsules (Vyndamax) when compared to 80 mg tafamidis meglumine (Vyndaqel) [ 27 ]. A post hoc analysis showed that tafamidis treatment was associated with a significantly smaller decline in kidney function and a higher likelihood of improvement in CKD and eGFR [ 28 ]. Another post hoc analysis exploring treatment efficacy in octogenarian patients also demonstrated efficacy with tafamidis treatment in elderly populations [ 29 ]. Tafamidis treatment also yielded significant changes notable on cardiac imaging as well. A prospective analysis on the effects of tafamidis treatment in 12 months showed preserved cardiac magnetic resonance (CMR)-measured biventricular function and reduced left ventricular (LV) mass compared to the placebo group [ 30 ]. Irrespective of tafamidis treatment, extracellular volume and T1-mapping did not significantly change from baseline in

The efficacy and safety of specific therapies for cardiac Transthyretin-mediated amyloidosis: a systematic review and meta-analysis of randomized trials | BMC Cardiovascular Disorders | Full Text

C . Forest Plot for HF Hospitalization. TTR-specific therapies did not lead to a statistically significant difference in HF hospitalization compared to placebo. Abbreviations: CI: Confidence Interval; RR: Risk Ratio; HF: Heart Failure; TTR: Transthyretin Full size image Subgroup analysis Our subgroup analysis shows that both TTR Stabilizers (RR: 0.71; 95% CI 0.58, 0.86; p < 0.01; I² = 0%; Fig. 5 ) and knock-down therapies (RR: 0.70; 95%CI 0.53, 0.92; p = 0.01; I² = 0%; Fig. 5 ) therapies significantly reduced all-cause mortality. There was no evidence of difference in efficacy between these subgroups ( p = 0.93; Fig. 5 ). Fig. 5 Forest Plot for Subgroup analysis of All Cause Mortality. TTR knock-down therapies and TTR stabilizers showed an equally effective reduction in all-cause mortality compared to placebo. Abbreviations: CI: Confidence Interval; RR: Risk Ratio; TTR: Transthyretin Full size image Pooled analysis of trials specifically designed for ATTR-CM In those receiving TTR-specific therapies, there was a significant reduction in all-cause mortality (RR 0.71; 95% CI 0.60, 0.83; p < 0.001; I² = 0%; Supplemental Fig. S3 ) and CV mortality (RR 0.71; 95% CI 0.51, 0.99; p = 0.041; I² = 0%; Supplemental Fig. S4 ). Our subgroup analysis shows that both TTR Stabilizers (RR: 0.71; 95% CI 0.58, 0.86; p < 0.001; I² = 0%; Supplemental Fig. S5 ) and knock-down therapies (RR: 0.70; 95% CI 0.53, 0.93; p = 0.015; I² = 0%; Supplemental Fig. S5 ) therapies significantly reduced all-cause mortality. There was no evidence of a difference in efficacy between these subgroups ( p = 0.98; Supplemental Fig. S5 ). Adverse events There were no significant increases in SAE

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and long‐term extension study - PMC

s) was similar across all three groups, with the majority of TEAEs being mild or moderate in severity. Dose reductions were infrequent, with two patients in the tafamidis 80 mg group and four in the placebo group requesting a dose reduction. Treatment‐related TEAEs were reported by 79 (44.9%), 34 (38.6%), and 90 (50.8%) patients in the tafamidis 80 mg, 20 mg, and placebo groups, respectively, with diarrhoea being the most common treatment‐related TEAE with tafamidis 80 mg [14 (8.0%) patients], compared with two (2.3%) patients with 20 mg and 18 (10.2%) patients with placebo. In the tafamidis 20 mg group, urinary tract infection was the most common treatment‐related TEAE [5 (5.7%) patients] compared with four (2.3%) patients with 80 mg and eight (4.5%) patients with placebo. A greater proportion of deaths was observed with placebo [49 (27.8%), 23 (26.1%), and 72 (40.7%) patients for tafamidis 80 mg, 20 mg, and placebo, respectively]; the majority of all deaths were considered to be a result of the disease [28 (57.1%), 17 (73.9%), and 49 (68.1%) for tafamidis 80 mg, 20 mg, and placebo, respectively] and none were considered related to treatment with tafamidis. Safety and tolerability in ATTR‐ACT combined with the long‐term extension study Safety in the LTE (up to an additional 12 months of treatment with tafamidis, median follow‐up of 36 months across both studies) combined with ATTR‐ACT was similar to the 30‐month ATTR‐ACT alone; safety was comparable for both tafamidis 80 and 20 mg after a prolonged treatment period. In the combined analysis, there were 227 and 115 patients evaluable for TEAEs with tafamidis 80 and 20 mg, respectively. The incidence of serious TEAEs was comparable between tafamidis 80 and 20 mg (69.6% and 72.2%, respectively), as was the incidence of severe TEAEs

Eplontersen demonstrated sustained benefit in Phase III trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) through 66 weeks

yloidosis ATTR cardiomyopathy and polyneuropathy are progressive systemic diseases caused by aging or genetic mutations, resulting in misfolded TTR protein and accumulation as amyloid fibrils in the cardiac myocardium and peripheral nerves, respectively. 5,6,8 In patients with ATTR, both hereditary and wild type (non-hereditary), TTR protein builds up as fibrils in tissues, such as the peripheral nerves and heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow. 5,9 The presence of TTR fibrils interferes with the normal functions of these tissues. 8 As the TTR protein fibrils accumulate, more tissue damage occurs and the disease worsens, resulting in poor QoL and eventually death. 8 Worldwide, there are an estimated 300,000 - 500,000 patients with ATTR-CM 9 and about 40,000 patients with ATTRv-PN. 8,9 NEURO-TTRansform NEURO-TTRansform is a global, open-label, randomised trial evaluating the efficacy and safety of eplontersen in patients with ATTRv-PN. 6,10 The trial has enrolled adult patients with ATTRv-PN Stage 1 or Stage 2 and will be compared to the external placebo group from the TEGSEDI ® (inotersen) NEURO-TTR registrational trial that Ionis completed in 2017. 6,10 The final analysis comparing eplontersen to external placebo was completed at week 66 and all patients will be followed on treatment until week 85, when they will have the option to transition into an open-label extension study. 10 The 66-week analysis evaluated percent change from baseline in serum TTR concentration, changes in the mNIS+7 and Norfolk-QOL-DN in the eplontersen group versus an external placebo group. 10 The mNIS+7 uses highly standardised, quantitative and referenced assessments to quantify muscle weakness, muscle stretch reflexes, sensory loss and autonomic impairment. 2 The Norfolk QoL-DN is a patient-reported questionnaire capturing neuropathy-related QoL. 10 Eplontersen Eplontersen is a ligand-conjugated antisense (LICA) investigational medicine designed to reduce the production of transthyretin, or T

Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies - PMC

mg every 3 months for 36 months N = 655 (hATTR-CM, n = 76) 7.2% ( n = 47) 64% ( n = 49) Lower all-cause mortality and recurrent CV events, 0.72; change from baseline to month 30 in 6-MWT distance, KCCQ-OS favoring vutrisiran Antisense Oligonucleotides Inotersen NEURO-TTR [ 41 ] Phase 3, randomized, 2:1 ratio, double-blind, placebo controlled clinical trial to receive weekly SC inotersen (300 mg) or placebo over 15 months N = 172 (hATTR-PN; 63%, n = 108, subset with cardiomyopathy) 2.3% ( n = 4) Not reported (52%, n = 89) Val30Met – associated with more polyneuropathy symptoms) Change from baseline in mNIS + 7, QOL-DN, favoring inotersen (cardiac subgroup) [ 44 ] Single-center, open-label, protocol over 3 years N = 33 ( n = 10 hATTR-CM) Not reported Not reported Decrease in mean LV mass by 8.4% / 11.4% on MRI and increased 6MWT distance by 20.2 / 16.2 m in years 2 and 3, respectively Eplontersen (formerly known as ION-682884, IONIS-TTR-LRx, AKCEA-TTR-LRx) CARDIO-TTRansform (2025, ongoing) Phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial to receive subcutaneous injections of eplontersen or placebo every 4 weeks Target enrollment of 1400 patients with hATTR-CM or wtATTR-CM, thus far N = 1438 patients enrolled Not reported Not reported Pending Gene Editing (CRISPR-Cas9) NTLA-2001* MAGNITUDE (2028, ongoing) Phase 3 multicenter randomized, 2:1 ratio double-blind, placebo-controlled study to receive a single 55 mg infusion of NTLA-2001 or placebo Target enrollment of 765 patients with hATTR-CM or wt