Eplontersen 2025-09-24 13:12:12

Evidence synthesis and indirect comparison on tafamidis vs Eplontersen. Summarize study quality, consistency, and clinical implications.

Indirect comparative efficacy and safety, durability of response and other potential benefits of Eplontersen vs tafamidis

Сравнительный синтез доказательств и непрямое сравнение: тафамидис против эплонтерсена

Введение

Тафамидис и эплонтерсен представляют собой современные лекарственные средства, применяемые при амилоидозе, вызванном транстиретином (ATTR), в частности при наследственной форме (hATTR) с полинейропатией (hATTR-PN) и/или кардиомиопатией (ATTR-CM). Оба препарата имеют разные механизмы действия: тафамидис стабилизирует тетрамер транстиретина, предотвращая его диссоциацию и формирование амилоидных фибрилл, тогда как эплонтерсен является антисмысловой олигонуклеотидной терапией, снижающей синтез TTR. Прямых сравнительных исследований между этими средствами не проводилось, а непрямые сравнения (indirect treatment comparison, ITC) имеют свои ограничения. Ниже приведён глубокий анализ качества исследований, согласованности данных и клинических последствий с акцентом на непрямое сравнение эффективности, безопасности и дополнительных преимуществ эплонтерсена по сравнению с тафамидисом.

Качество и структура исследований

Эплонтерсен

Ключевые данные по эплонтерсену получены в ходе исследования NEURO-TTRansform — 85-недельного, многоцентрового, рандомизированного, открытого исследования III фазы с участием 168 пациентов с hATTR-PN. Пациенты были рандомизированы в соотношении 6:1 (эплонтерсен:инотерсен), с последующим переходом части пациентов с инотерсена на эплонтерсен. Использовалась также внешняя контрольная группа (плацебо) из исследования NEURO-TTR (Clinical Review - Eplontersen, 2023).

Критическая оценка:
- Открытый дизайн и использование внешнего контроля увеличивают риск смещения.
- Размер выборки ограничен редкостью заболевания, но был достаточен для оценки основных конечных точек.
- Основные исходы (уровень TTR, mNIS+7, Norfolk QoL-DN) не широко применяются в рутинной практике, что снижает экстраполируемость результатов.
- Серьёзное снижение эффективного размера выборки (ESS) при проведении MAIC и STC из-за необходимости согласования исходных характеристик пациентов между исследованиями.

Тафамидис

Данные по тафамидису базируются преимущественно на исследовании ATTR-ACT (фаза III, двойное слепое, плацебо-контролируемое, 441 пациент), а также на долгосрочных расширениях (LTE) и ряде пост-хок анализов (Tafamidis therapy in transthyretin amyloid cardiomyopathy, 2024).

Критическая оценка:
- Основные исходы: общая смертность, госпитализации по сердечно-сосудистым причинам, 6-минутный тест ходьбы, шкала качества жизни KCCQ.
- Длительность наблюдения: до 58,5 месяцев (LTE).
- Ограничения включают небольшое представительство отдельных подтипов ATTR, отсутствие разграничения доз (20 мг vs 80 мг), недопредставленность пожилых и тяжёлых пациентов, а также ограниченное количество реальных (real-world) исследований и вариабельность дозировок.

Непрямое сравнение эффективности и безопасности

Методология непрямого сравнения

Из-за отсутствия прямых сравнительных исследований между эплонтерсеном и тафамидисом, были проведены непрямые сравнения (MAIC, STC) между эплонтерсеном и другими препаратами (инотерсен, патисеран, вутрисеран), но не с самим тафамидисом. Все ITC основаны на систематическом литературном обзоре, с последующей фильтрацией и согласованием характеристик пациентов (Clinical Review - Eplontersen, 2023).

Ключевые моменты:
- MAIC и STC позволили сбалансировать исходные характеристики, однако существенное снижение ESS и гетерогенность исходов/популяций между исследованиями ограничивают интерпретацию результатов.
- Для оценки эффективности использовались mNIS+7, Norfolk QoL-DN, уровень TTR.

Эффективность

Эплонтерсен (NEURO-TTRansform)

Снижение уровня TTR: значимое снижение (>50%) по сравнению с плацебо, что считается клинически значимым, но не является валидированным суррогатным маркером клинических исходов.
Стабилизация состояния: mNIS+7 и Norfolk QoL-DN у пациентов на эплонтерсене оставались стабильными, тогда как у пациентов на плацебо наблюдалось ухудшение (Clinical Review - Eplontersen, 2023).
Качество жизни: улучшение по шкале Norfolk QoL-DN.

Тафамидис (ATTR-ACT, LTE, мета-анализы)

Снижение общей смертности: HR 0,70 (95% CI: 0,51–0,96) по сравнению с плацебо за 30 месяцев (Maurer et al., 2018).
Снижение госпитализаций: RR 0,68 (95% CI: 0,56–0,81).
Стабилизация функциональных исходов: замедление снижения 6MWT и KCCQ-CSS (p < 0,001).
Мета-анализ (2765 пациентов): RR по комбинированной конечной точке (смерть, пересадка сердца и др.) 0,44 (95% CI: 0,31–0,65; p < 0,01) (Tafamidis therapy, 2024).

Результаты непрямых сравнений для эплонтерсена

mNIS+7: статистически значимых различий между эплонтерсеном и вутрисераном/патисераном не обнаружено; патисеран лишь незначительно превосходил эплонтерсен.
Norfolk QoL-DN и уровень TTR: эплонтерсен преимущественно показывал лучшие результаты по сравнению с другими препаратами, но с очень широкими 95% ДИ, часто включающими как отсутствие эффекта, так и возможное преимущество любого из препаратов.
Общее заключение: из-за ограничений методологии и малой точности оценок нельзя с уверенностью утверждать о превосходстве эплонтерсена над существующими альтернативами (Clinical Review - Eplontersen, 2023).

Безопасность

Эплонтерсен

Частота нежелательных явлений (НЯ): сопоставима с другими препаратами; в группе плацебо чаще встречались падения, утомляемость, невралгия, астения, боль.
Особые риски: гиповитаминоз А и тромбоцитопения — реже, чем при инотерсене; гиповитаминоз А управляемый в клинической практике.
Прекращение терапии из-за НЯ: 4% на эплонтерсене, 3% на плацебо (Eplontersen for Hereditary Transthyretin Amyloidosis, 2023).

Тафамидис

Частота НЯ: 44,9% (80 мг), 38,6% (20 мг) и 50,8% (плацебо).
Серьёзные НЯ: чаще в группе плацебо (40,7% смертей), в основном обусловленных тяжестью болезни.
Дозоснижение из-за НЯ: 0,8% для тафамидиса, 2,3% для плацебо.
Профиль переносимости: сопоставим с плацебо, специфического лабораторного мониторинга не требует (Tafamidis therapy, 2024).

Согласованность данных

Для эплонтерсена основной массив данных получен из одного крупного исследования, результаты которого поддерживаются непрямыми сравнениями, однако точность и обобщаемость оценок ограничены из-за существенной гетерогенности популяций и малых ESS.
Для тафамидиса имеются данные как рандомизированных, так и долговременных исследований, а также мета-анализов и real-world evidence, однако последние ограничены по объёму и гетерогенности популяций.
Ни для одного из препаратов не продемонстрировано явного преимущества в head-to-head сравнении; все сравнения между эплонтерсеном и тафамидисом косвенные, с низкой степенью достоверности.

Клинические последствия и потенциальные преимущества эплонтерсена

Преимущества эплонтерсена: реже вводится (1 раз в 4 недели), потенциально выше снижения TTR, сопоставимая или лучшая переносимость по сравнению с инотерсеном, возможность применения у пациентов с быстрым прогрессированием невропатии.
Клинический выбор: на данный момент основан на профиле нежелательных явлений, удобстве для пациента и индивидуальных особенностях течения болезни.
Перспективы: долгосрочные данные по эплонтерсену пока отсутствуют, продолжается расширенное исследование (Long-Term Extension). Остаётся необходимость в прямых сравнительных исследованиях, особенно для ATTR-CM.

Заключение

В отсутствие прямых сравнительных исследований между эплонтерсеном и тафамидисом, непрямые сравнения (MAIC, STC) дают ограниченную и низконадёжную информацию. Эплонтерсен и тафамидис оба демонстрируют значимую клиническую пользу в снижении прогрессии hATTR, стабилизации состояния и улучшении качества жизни. Преимущество эплонтерсена по частоте введения и профилю безопасности (по сравнению с инотерсеном) может быть существенным для отдельных пациентов, однако доказательств превосходства по эффективности над тафамидисом нет. Окончательный выбор терапии должен учитывать индивидуальные характеристики пациента, профиль нежелательных явлений и предпочтения пациента. Необходимы дальнейшие исследования, включая head-to-head сравнения, расширение real-world данных и оценку долгосрочной эффективности и безопасности для обеих стратегий лечения.

Источники:
- Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf
- Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC
- Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy - PubMed

REFERENCES

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

Indirect treatment comparison (ITC) of the efficacy of vutrisiran and tafamidis for hereditary transthyretin-mediated amyloidosis with polyneuropathy - PubMed - 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 - PMC - last accessed: 2025-09-24

ClinicalTrials.gov - last accessed: 2025-09-24

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf - last accessed: 2025-09-24

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy - PubMed - last accessed: 2025-09-24

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC - last accessed: 2025-09-24

Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy - PubMed - last accessed: 2025-09-24

Sources used

QUERY: ((tafamidis OR eplontersen) AND ("randomized controlled trial" OR "clinical trial") AND (efficacy OR safety OR "clinical outcomes" OR "durability of response"))+AND+(efficacy+OR+safety+OR+"clinical+outcomes"+OR+"durability+of+response")))

Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.
The New England journal of medicine. 2025/1/3; Impact Factor: 33.93, Quartile: Q1
DOI: 10.1056/NEJMoa2409134
PMID: 39213194
Abstract
Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.
In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically.
A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio in the overall population, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). Among the patients in the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least one primary end-point event. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group.
Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

Web Sources

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

, the target of the certainty of evidence assessment was based on the point estimate and its location relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of any effect for serum TTR, mNIS + 7 composite score, and Norfolk QoL-DN total score. Table 2 presents the GRADE summary of findings for eplontersen versus placebo for outcomes in the pivotal NEURO-TTRansform trial. Table 2 Summary of Findings for Eplontersen Versus Placebo (NEURO-TTR Study) for Patients With hATTR-PN in the NEURO-TTRansform Trial. Long-Term Extension Studies One open-label extension study of patients with hATTR-PN who are continuing to receive eplontersen after week 85 in the NEURO-TTRansform trial is currently ongoing. No data were available at the time of this review. Indirect Comparisons Description of Studies Given the lack of head-to-head studies comparing the efficacy and/or safety of eplontersen to other treatments available in Canada (i.e., vutrisiran, patisiran, and inotersen) for hATTR-PN, the sponsor submitted an indirect treatment comparison (ITC) to evaluate the comparative efficacy of eplontersen versus other medical therapies used for the treatment of patients with hATTR-PN. 14 The sponsor conducted unanchored matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STCs) comparing eplontersen from the NEURO-TTRansform study to inotersen from the NEURO-TTR trial, patisiran from the APOLLO and HELIOS-A trials, and vutrisiran from the HELIOS-A trial for the outcomes of change from baseline in mNIS + 7, change from baseline in Norfolk QoL-DN, and percentage change from baseline in serum TTR. 14 Efficacy Results For change from baseline in mNIS + 7, there were no statistically significant differences detected between eplontersen and vutrisiran in the HELIOS-A trial, patisiran in the HELIOS-A trial, or inoters

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

afamidis or diflunisal, disease stage, cardiac involvement, and baseline measurement of the outcome of interest. Disease stage was not included in the reference model for the comparison of eplontersen and inotersen because FAP stage was not reported in the NEURO-TTR study. A smaller subset of the prognostic factors and treatment-effect modifiers was included in the alternative models and is described later in the report. 14 For the comparison of eplontersen to vutrisiran ( Table 21 ), following adjustment in the reference model, the ESSs for eplontersen were 77 patients for the mNIS + 7 composite score outcome, 95 patients for the Norfolk QoL-DN outcome, and 96 patients for the serum TTR concentration outcome. The ESSs were slightly greater for all outcomes in the alternative models ██ █ ██ █████████ ███ █████████ ███ ██ ████████ ███ ███ ████████ ██ ██████ █████████ ██████ ███████ ███████ ███ █████ ███ ██████████████ █████████████, based on the adjustment factors included. The reported baseline characteristics were well-balanced following adjustment in the reference model. Following adjustment in the alternative model, differences remained for some variables not included in the adjustment; notable differences remained in V30M mutation and cardiac involvement for the outcomes of mNIS + 7 composite score and Norfolk QoL-DN. For the alternative model of serum TTR concentration, there were differences in age, race, and prior treatment, given that these were the covariates not included in the alternative model. 14 ███ ███ ██████████ ██ ███████████ ██ █████████ Table 22 ███ Table 23 ██ █████████ ██████████ ██ ███ █████████ ██████ ██████ █████████ ████ ███ ██████ ███ ████████ ███████ ███ ███ ███ ███████████ ███ ██ ███ ██ ████████ ███ ███ ██████ █████████ █████ ████████ ███ ██ ███ ██ ████████ ███ ███ ███████ ██████ ████████ ███ ███ ██████████ ██ ███████████ ██ █████████ ████ ███ ████████ ██████ ███ ███ █

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

comparisons were conducted comparing eplontersen with the concurrent inotersen arm for randomized patients as the sponsor considered the large sample size that would have been required to be infeasible for this rare indication. As such, this comparison was only used for safety considerations. The baseline characteristics were generally well-balanced, with the exception of some baseline scores (i.e., the mNIS + 7 and Neuropathy Impairment Score [NIS] composite scores and PND scores), which were generally higher in the eplontersen group, suggesting a population with more severe neuropathy impairment compared to those in the inotersen-eplontersen group. In comparison to the external placebo group from the NEURO-TTR study, the NEURO-TTRansform study included younger patients, had a greater proportion of Asian and Black patients, included more patients with FAP and/or Coutinho stage 1 disease (but fewer with stage 2), had a longer period of time from diagnosis to enrolment, included fewer patients with CM, and included more patients who had previous experience with tafamidis or diflunisal. The impact of these differences on the results remains unknown, but results of the subgroup analyses for these variables were generally consistent with those of the primary results. The NEURO-TTRansform study met its coprimary and key secondary end points at the interim analysis; therefore, further statistical testing was not conducted on these end points at the final analysis. Results at the final analysis were consistent with those at the interim analysis across all study end points, despite the switch from analysis of covariance (ANCOVA) at the interim analysis to a mixed model for repeated measures (MMRM) at the final analysis for the end points of change from baseline in mNIS + 7 and change from baseline in Norfolk QoL-DN. Given the use of the external placebo control, the MMRM for each end point was adjusted by propensity score weights for each patient. It was unclear how the covariates for adjustment were selected or whether all relevant prognostic factors and effect modifiers were considered. Additionally, it was not possible to account for differences in known unmeasured or unknown confounders. As such, there is a risk of bias due to residual baseline confounding of unknown magnitude and direction. The NEURO-TTRansform trial was an international trial conducted in 15 countries, including

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of any effect for serum TTR, mNIS + 7 composite score, and Norfolk QoL-DN total score. Results of GRADE Assessments Table 2 presents the GRADE summary of findings for eplontersen compared to placebo from the NEURO-TTRansform study in the treatment of adult patients with hATTR-PN. Long-Term Extension Studies The contents of this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the CDA-AMC review team. One open-label extension study of patients with hATTR-PN from the NEURO-TTRansform study who continued to receive eplontersen after week 85 is currently ongoing. No data were available at the time of this review. Indirect Evidence The contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CDA-AMC review team. Objectives for the Summary of Indirect Evidence Given the lack of head-to-head studies comparing the efficacy and/or safety of eplontersen to other treatments for hATTR-PN available in Canada (i.e., vutrisiran, patisiran, and inotersen), the sponsor submitted ITCs to evaluate the comparative efficacy of eplontersen versus other medical therapies used for the treatment of patients with hATTR-PN. 14 Description of Indirect Comparisons The sponsor-submitted ITCs began with an SLR to identify relevant published studies for the treatment of patients with hATTR-PN. A feasibility assessment was performed to determine the most appropriate ITC methods for the included studies based on cross-trial differences in study design, baseline patient characteristics, treatment regimens evaluated, outcome definitions and availability, and time points of outcome assessment. The results of the feasibility assessment concluded that comparisons of epl

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

databases and standard screening and extraction methods. Risk-of-bias assessments of the included studies were conducted per the University of York Centre for Reviews and Dissemination criteria; however, the results of this quality assessment were not provided. Thus, the potential impact of study-level biases on the results of the MAICs and STCs could not be comprehensively judged. In total, 4 trials evaluating eplontersen, vutrisiran, patisiran, and inotersen were identified for inclusion during the sponsor’s feasibility assessment. Given the heterogeneity observed, the lack of a common comparator across the included trials, and the unique design of 2 studies that included randomized reference arms (the NEURO-TTRansform study [inotersen arm] and HELIOS-A study [patisiran arm]), the sponsor concluded that MAIC and STC methods were most appropriate for comparing eplontersen and relevant comparators. Other sources of heterogeneity in the included studies were the baseline characteristics of age, proportion of patients who identify as white, proportion of patients with V30M mutation, proportion of patients with hATTR with CM, proportion of patients previously treated with tafamidis or diflunisal, proportion of patients with stage 1 and stage 2 disease, as well as differences in various outcome scores. In the base-case (reference) models, comparisons of eplontersen to other treatments resulted in sample-size decreases of █████ ██ █████ across outcomes and treatments. These decreases were generally smaller in the alternative models, given that fewer variables were included in the adjustment. Given the reduction in effective sample size (ESS), there was likely considerable heterogeneity between studies among the variables included in the weighting process. Despite the substantial reduction in ESS for nearly all comparisons following the matching and adjustment, the populations in all MAIC and STC analyses were relatively balanced. Substantial reductions in ESS have implications for generalizability and the precision of effect estimates. A comprehensive list of prognostic factors and treatment-effect modifiers was included and — based on discussions with the clinical experts consulted for this review —considered relevant. However, it was noted that the exclusion of region as a factor may bias the results because there may be regional variation in health care access and treatment approaches that are unrelated to V30M . Two versions of the mNIS + 7 were utilized in the analyses:

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

-CSS (p < 0.001 for each) Adverse events (Tafamidis vs placebo) Similar safety profile Dose reduction related to adverse events in 0.8% for Tafamidis vs. 2.3% for placebo Acoramidis ATTRIbute-CM [ 27 ] NCT03860935 Completed Phase III, double-blinded, placebo-controlled, randomized 2:1 Duration: 30 months n : 632 ATTR-CMv and ATTRwt-CM (90.4%) Oral Acoramidis 800 mg twice daily ( n : 421) or placebo ( n :211) Concomitant Tafamidis use: 18% Primary outcome A win ratio of 1.8, 95% confidence interval [CI] 1.4–2.2, p < 0.0001) in favor of Acoramidis over placebo for the hierarchal composite of all-cause mortality, cardiovascular-related hospitalization, change from baseline NT-proBNP, and change from baseline in 6MWT Secondary Outcomes All-cause mortality: 19.3% vs. 25.7%; hazard ratio (HR) 0.77, 95% CI 0.54–1.10 ( p = 0.15) Adjusted mean factor change in NT-proBNP from baseline: 0.529 (95% CI 0.46–0.60, p < 0.05) Improvement from baseline in 6-min walk distance: 39.6 m (95% CI 21.1–58.2, p < 0.001) CV-related hospitalization: 26.7% vs. 42.6% (p < 0.0001) Least means square change in KCCQ-OS: 9.94 points (95% CI 5.97–13.91, p < 0.001) Adverse events (Acoramidis vs. placebo) 98.1% and 97.6%, respectively Serious adverse events 54.6% and 64.9% Anti-sense oligonucleotides Eplontersen CARDIOTTRansform NCT04136171 Active, not recruiting Estimated completion in 2025 Phase III, placebo-controlled double-blinded, randomized Duration: 140 weeks n : 1436 Eplontersen and matching placebo sub

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Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

ITC methods for the included studies based on cross-trial differences in study design, baseline patient characteristics, treatment regimens evaluated, outcome definitions and availability, and time points of outcome assessment. The results of the feasibility assessment concluded that comparisons of eplontersen to relevant comparators of inotersen, partisan, and vutrisiran using MAIC and STC methods were feasible, based on the design of the NEURO-TTRansform study and the overall heterogeneity in design and patient characteristics of the studies included in the ITC (precluding network meta-analysis [NMA]). 14 ITC Designs Objectives The overall objective of the sponsor-submitted ITCs (i.e., STC and MAIC) was to compare eplontersen to other treatments available in Canada for patients with hATTR-PN (i.e., vutrisiran, patisiran, and inotersen). The specific objectives of the ITC were to: 14 • conduct feasibility assessments of pairwise ITC methods and NMAs for the comparison of eplontersen and comparators for efficacy end points of interest • if deemed feasible, conduct pairwise ITCs of eplontersen and comparators using methods deemed appropriate by the feasibility assessment and conduct an NMA of medical therapies for the treatment of patients with hATTR-PN. Study Selection Methods The sponsor-submitted ITC was informed by an SLR (search date: July 2022) to identify clinical, humanistic, and economic literature on patients with hATTR-PN. 14 Details describing the SLR methods and selection criteria are summarized in Table 17 . The authors noted that hATTR-PN is a heterogeneous disease; thus, outcomes were broadly defined in the search strategy. As such, some outcomes of interest, such as serum TTR, were not explicitly defined in the search criteria because it was known that these outcomes were not reported in relevant comparator studies (e.g., serum TTR was not reported in the APOLLO trial for patisiran). Comparators of tafamidis and diflunisal are not currently approved in Canada for hATTR-PN and, although included in the search, were not included in the submitted ITC. 14 Table 17 Study Selection Criteria and Methods for the Systematic Review Submitted by the Sponsor. ITC Analysis Methods A feasibility

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

Using the MAIC methodology, following the adjustment of select characteristics, the populations were comparable; however, the substantial reductions in the sample size of the eplontersen groups limit the precision of the findings because these suggest considerable heterogeneity between the included studies among the variables included in the weighting process. The results of the ITCs generally suggested that there was insufficient evidence to detect a difference between eplontersen and other available treatments with respect to the mNIS + 7, with patisiran only mildly favoured over eplontersen. For the Norfolk QoL-DN and serum TTR outcomes, eplontersen was mostly favoured over other treatments, although there was insufficient evidence to detect a difference with vutrisiran. However, all results were associated with wide 95% CIs, often including the potential for no difference, or for either of the treatments being compared to be favoured. Overall, given the limitations outlined previously, it remains uncertain whether eplontersen provided additional benefits versus currently available therapies. Harms The safety analysis for eplontersen was based on the safety set, which included 144 patients treated with eplontersen, the 24 patients treated with inotersen from week 1 to week 37, and the 20 patients who switched to eplontersen from week 37 until the end of treatment. Harms for the 60 patients included from the external placebo group were also summarized. Harms occurred at similar frequencies across treatment groups. Overall, the clinical experts consulted for this review noted that the reported harms were in line with other treatments for hATTR and generally manageable. There was a higher frequency (> 10%) of some TEAEs in the placebo group compared to the eplontersen group, including falls (5.6% versus 21.7%), fatigue (4.9% versus 20.0%) neuralgia (2.8% versus 15.0%), asthenia (2.1% versus 13.3%), and pain (0.7% versus 13.3%). Although the reason for this is uncertain, it may be due to disease progression in the placebo group, resulting in lack of motor function and control. Vitamin A deficiency and thrombocytopenia were outcomes of special interest to eplontersen as well as this review, given that these are known safety concerns associated with inotersen treatment. As previously noted, no vitamin

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

OS-A and APOLLO studies, interim end points were reported at 9 months (range, 36 weeks to 39 weeks), and final end points were reported at 18 months (range, 79 weeks to 80 weeks). 14 Differences in baseline patient characteristics were noted across studies. These included differences in mBMI, disease stage, PND score, mNIS + 7 score at baseline, Norfolk QoL-DN score at baseline, and race (refer to Table 20 ). 14 Due to differences in the underlying patient characteristics of each trial, the authors deemed population adjustment comparisons (i.e., MAIC, STC) to be the most suitable methods of comparing treatments between trials. Given the key limitations identified with regard to the reference arms (not designed for statistical analysis and premedication difference) and placebo arms (premedication differences and heterogeneity in baseline population) across all trials, unanchored comparisons were conducted. 14 Table 19 Summary of Study Design Characteristics Across Studies Included in the ITC. Table 20 Summary of Baseline Characteristics Across Studies Included in the ITC (Before Matching and Adjustment). Results To ensure that the eplontersen patient cohort used for the analyses was as homogeneous as possible, a filtering procedure applying the comparator trial eligibility criteria was applied to patients from the NEURO-TTRansform study. Following the filtering of patients by eligibility criteria, 141 patients from the NEURO-TTRansform study were included in the analyses (except for the comparison to inotersen for the Norfolk QoL-DN outcome). 14 Baseline characteristics included in the adjustments comparing eplontersen from the NEURO-TTRansform study to vutrisiran from the HELIOS-A study, patisiran from the APOLLO and HELIOS-A studies, and inotersen from the NEURO-TTR study for outcomes included in the MAIC and STC are summarized in Table 21 , Table 22 , Table 23 , and Table 24 , respectively. Variables included in the reference models for each comparison were age, sex, race, V30M mutation, previous treatment with tafamidis or diflunisal, disease stage, cardiac involvement, and baseline measurement of the outcome of interest. Disease stage was not included in the reference model for the comparison of eplontersen and inotersen because FAP

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

study were of limited applicability to clinical practice in Canada; the clinical experts consulted for this review highlighted that these outcomes are not used to evaluate treatment effect in routine clinical practice. The NEURO-TTRansform study demonstrated that eplontersen likely resulted in a clinically meaningful decrease in serum TTR levels, but the clinical importance of this biomarker remains unknown. According to the clinical experts consulted for this review, disease stabilization is among the most important outcomes of treatment. In the NEURO-TTRansform study, neuropathy symptoms and neurologic function were measured using the mNIS + 7; these results suggested that patients treated with eplontersen experienced stabilization of disease, whereas those in the placebo group experienced deterioration. Lastly, improved HRQoL was an outcome important to patients. The results of the NEURO-TTRansform study suggest that patients treated with eplontersen may have clinically meaningful improvements in HRQoL (per the Norfolk QoL-DN) compared to placebo. Outcomes that are clinically relevant to practice in Canada, including the COMPASS-31 and R-ODS, were consistent with the suggested stabilization from the coprimary end points, but were generally considered supportive of the overall effect of eplontersen, given that the results were noncomparative. There were few safety concerns with eplontersen relative to other treatments for hATTR-PN. The frequency of thrombocytopenia AEs was lower versus the randomized inotersen group. There were more frequent ocular AEs related to vitamin A deficiency; however, the clinical experts noted that this was manageable in clinical practice. There were important limitations in the conduct of the ITCs: the included studies varied in design, including outcome definitions and time of assessment. Additionally, there were notable differences in patient characteristics before adjustment, and the removal of patients in the weighting process substantially reduced the precision of treatment-effect estimates. Overall, the ITCs suggest that there was insufficient evidence to detect a difference between eplontersen and other treatments, or that eplontersen may be favoured over some treatments; however, conclusions could not be drawn with any certainty owing to methodological limitations and imprecision, as evidenced by wide 95% CIs. Abbreviations AE adverse event AIC Akaike information criterion ANCOVA analysis of covariance ASO

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

1 pivotal study that was selected according to the sponsor’s systematic review protocol. The CDA-AMC assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second main section includes indirect evidence from the sponsor. No long-term extension studies or additional studies that were considered to address important gaps in the systematic review evidence were submitted by the sponsor. Included Studies Clinical evidence from the following are included in the CDA-AMC review and appraised in this document: • 1 pivotal study identified in the systematic review (the NEURO-TTRansform trial) 12 , 13 • 2 ITCs (a MAIC and an STC). 14 Systematic Review The contents within this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the CDA-AMC review team. Description of Studies Characteristics of the included study are summarized in Table 5 . One study was included in the review. The NEURO-TTRansform study was an 85-week, phase III, multicentre, randomized, open-label study evaluating the efficacy and safety of eplontersen in patients with hATTR. In total, 168 patients were randomized 6 to 1 using an interactive voice or web response system, stratified by V30M TTR mutation, previous treatment, and disease stage to receive 45 mg eplontersen SC once every 4 weeks (n = 144) or 300 mg inotersen SC once per week for up to 34 weeks; these patients were then switched to eplontersen SC once every 4 weeks from week 37 to week 81 (n = 24). All patients continued dosing with eplontersen until week 81, with end-of-treatment assessments occurring at week 85. The NEURO-TTRansform study also included 2 external control groups (placebo [n = 60] and inotersen [n = 112]) from the NEURO-TTR study (described later). (Results comparing eplontersen to the historical inotersen comparison are not described in this section of the report, but are included in the indirect evidence.) The NEURO-TTRansform study was conducted at 40 sites in 15 countries in North America, Europe, South America, Australasia, and Asia, including 2 sites in Canada (

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

VEF is earlier in placebo (6 months) than in the Tafamidis 80 mg group which only became apparent at 30 months. Garcia-Pavia et al. [ 25 ] investigated the efficacy of Tafamidis among octogenarian patients with ATTR-CM using data from the ATTR-ACT trial and ongoing LTE studies. Efficacy was comparable in both age groups with Tafamidis treatment. There was a significant trend in increased median survival in those < 80 on continuous Tafamidis compared to those who were initially in the placebo treatment group. In contrast, continuous Tafamidis had no significant increase in survival in the > 80 subgroups in the LTE. Two studies analyses extracted and evaluated data from the NYHA Class III subset of ATTR-ACT [ 26 , 27 ]. Sperry et al. found that Tafamidis treatment resulted in better health status compared to placebo in patients with NYHA Class III symptoms. Tafamidis was associated with stability and improved health status at 30 months, regardless of NYHA Class [ 26 ]. An extrapolation model revealed that patients spend more years in lower NYHA Classes than standard care, suggesting its crucial role in slowing disease progression. From a NYHA Class I/II baseline, the projected increase in life years and quality-adjusted life years (QALYs) is 5.49 and 3.29 to 4.62, respectively, with Tafamidis compared to the standard of care (SoC). Even at a baseline of NYHA Class III, Tafamidis treatment projected a 27.4% improvement compared to the standard of care [ 26 ]. Safety profile from clinical trials In the ATTR-ACT trial, the proportion of treatment-related treatment-emergent adverse events (TEAEs) reported by the Tafamidis 80 mg, 20 mg, and placebo groups were (44.9%), (38.6%), and (50.8%), respectively. A greater proportion of deaths was observed in the placebo group (40.7%) and the majority of deaths in the Tafamidis groups were attributed to the result of disease severity. Cardiac failure was the most common cause of TEAEs in all groups. The most common TEAE associated with Tafamidis 80 mg dose was diarrhea (18%) and urinary tract infection with Tafamidis 20

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

idis): NYHA Class III: 64% vs 81% NYHA Class I/II: 41% vs. 61% N/A Open in a new tab Main text Rationale for an in-depth analysis of clinical trials and real-world evidence Further study and analysis of the use of Tafamidis in the management of ATTR-CM is pivotal as there is still a lot to learn. With the median overall survival on Tafamidis not attained since its approval in 2019, the full potential of this disease-modifying therapy is yet to be discovered [ 19 ]. While the impact of Tafamidis on all-cause mortality and cardiovascular-related hospitalization is remarkable little is known about the autonomic effect, post-therapeutic quality of life, and other cardiovascular parameters, and lack of evidence of the degree of stabilization to which approved doses exhibit fullest potential [ 13 ]. Most real-world studies lack large sample sets, sufficient follow-up periods, and equal representation of the subtypes precluding the availability of evidence regarding long-term efficacy and generalizability associated with Tafamidis treatment [ 20 ]. A noteworthy lack of real-world studies evaluating changes in a comprehensive set of echocardiographic parameters after Tafamidis treatment at follow-up exists in the literature. Subsets like advanced age and patients in more advanced stages of disease can benefit from longer follow-up analysis. Despite the burden of ATTR-CM on black populations, there remains a paucity of studies focusing on the efficacy and safety of this drug in that subset. Notably, more than 30% of the world [ 21 ] are without access to this costly drug creating a void in knowledge on the impact of Tafamidis on these diverse populations. This geographical disparity stems from a lack of available clinical registries/cohorts on ATTR-CM in countries outside of Europe and North America [ 22 ]. Mechanism of action of Tafamidis Tafamidis is a small molecule that stabilizes the transthyretin (TTR) protein, preventing its dissociation into monomers, which can misfold and form amyloid fibrils. In the context of cardiac amyloidosis, Tafamidis binds selectively to the thyroxine-binding sites of TTR tetramers, enhancing their stability. This binding inhibits the dissociation of TTR into monomers, which is a critical step in the amyl

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

control and the open-label design, which increases the risk of baseline confounding, selection bias, and performance bias. Key outcomes evaluated in the NEURO-TTRansform study were of limited applicability to clinical practice in Canada; the clinical experts consulted for this review highlighted that these are not used to evaluate treatment effect in routine clinical practice. The NEURO-TTRansform study demonstrated that eplontersen likely resulted in a clinically meaningful decrease in serum TTR levels; however, the clinical importance of this biomarker remains unknown. According to the clinical experts consulted for this review, disease stabilization is among the most important outcomes of treatment. In the NEURO-TTRansform study, neuropathy symptoms and neurologic function were measured using the mNIS + 7; the findings suggested that patients treated with eplontersen experience stabilization of disease, whereas those in the placebo group experience deterioration. Lastly, improved HRQoL was an outcome important to patients. In the NEURO-TTRansform study, the results suggested that patients treated with eplontersen may have clinically meaningful improvements in HRQoL (per the Norfolk QoL-DN) compared to placebo. Outcome measures that are clinically relevant to practice in Canada, including the COMPASS-31 and R-ODS, were consistent with the suggested stabilization from the coprimary end points, but were generally considered supportive of the overall effect of eplontersen because the results were noncomparative. There were few safety concerns with eplontersen relative to other treatments for hATTR-PN, including a lower frequency of thrombocytopenia AEs compared to the randomized inotersen group; however, there were more frequent ocular AEs related to vitamin A deficiency. The clinical experts noted that this was manageable in clinical practice. There were important limitations in the conduct of the ITCs: the included studies varied in design, including outcome definitions and time of assessment. Additionally, there were notable differences in patient characteristics before adjustment, and the removal of patients in the weighting process substantially reduced the precision of treatment-effect estimates. Overall, the ITCs suggested that there was insufficient evidence to detect a difference between eplontersen and other treatments or to suggest that eplontersen may be favoured over some treatments. However, conclusions could not be drawn with any certainty, owing to

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

█████████ ██ ████████ ███ ████████ ██ █████ ████████ ████ █████ ██ ███████ ██████████ ██ ████████ ████ ████ ████████ ████████ ████ █████ ██ ███████ ██████████ ██ ████████ ████ █████ ████ ██ ████████ ████ █████ ██ ███████ ██████████ ██ ████████ ████ ████████ █████████ ████ █████████ ██ ██████████ ████████ ████ █████ ██ ███████ ██████████ ██ ████████ ████ █████ █ ████████ ████ █████ ██ ██████ ███ █████ ██ ████████ ████ █████ ██ ██████ ████████ ██ ████ ██ ███████████ ██ ███████ ███████ ██████ ████ Table 19 . Given that there were multiple comparator trials, separate ITCs were conducted for comparisons of eplontersen to each of the relevant comparators. When conducting a MAIC or STC, the inclusion criteria for the index study should be the same as or broader than the comparator study to allow for matching on inclusion and exclusion criteria. After applying the exclusion criteria of the comparator trials to the NEURO-TTRansform trial, the original sample size of 144 patients from the eplontersen arm was reduced to ███ ████████ for most comparisons and outcomes, and to ███ ████████ for 1 outcome in the comparison to inotersen. It was unclear which criteria from the comparator studies were applied to the NEURO-TTRansform study; as such, the implications for the generalizability of the results are uncertain. A reference and alternative matching model were then conducted to optimize the ESS for each comparison. In the reference models, comparisons of eplontersen to vutrisiran resulted in further sample-size decreases of 31.9% to 45.4% across outcomes. Comparisons of eplontersen to patisiran from the APOLLO and HELIOS-A trials resulted in sample-size decreases of █████ ██ █████ ███ █████ █

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

and their standard errors were combined using Rubin’s rules. The ANCOVA model adjusted by propensity score included the effects of treatment (eplontersen or NEURO-TTR study placebo), disease stage (stage 1 or stage 2), V30M mutation (yes or no), previous treatment with tafamidis or diflunisal (yes or no), and the baseline value of the end point. Note that in these analyses, efficacy assessments that were within the analysis window but more than 52 days after last dose were included. This differs from the primary analysis, in which data after 52 days from the last dose were excluded. The number of imputed datasets may have been increased after reviewing results if the simulation error was considered large. 12 A random seed to be used by a random number generator with value of 2,855 was used to initiate data imputation for all 3 methods. 12 Harms Analysis Unless otherwise specified, all safety analyses were performed on the safety population, and all analyses were summarized descriptively by treatment by system organ class, preferred term, and severity. All AEs were coded using the MedDRA (Version 25.0 or later). For the inotersen-eplontersen group, TEAEs that first occurred or worsened on or after dosing at week 37 are defined as TEAEs after the switch to eplontersen. Otherwise, these are defined as TEAEs before the switch to eplontersen. 12 Table 8 Statistical Analysis of Efficacy End Points. Analysis Populations A description of the analysis populations in the NEURO-TTRansform study can be found in Table 9 . Table 9 Analysis Populations of the NEURO-TTRansform Study. Protocol Amendments and Deviations The original study protocol was dated June 28, 2019. The final, global study protocol was dated August 12, 2021 (amendment 5). There were 18 protocol amendments in total across the global and country-specific protocols. Key amendments to the global protocol included the addition of exploratory efficacy assessments for EQ-5D-5L and COMPASS-31 (as of September 18, 2019) and Patient Global Impression of Change and Patient Global Impression of Severity (as of January 30, 2020) and amendments to improve study safety, decrease patient burden, and support recruitment during the COVID-19 pandemic by allowing selected visits and procedures to

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

the outcome of mNIS + 7, there was generally insufficient evidence to determine whether eplontersen or the comparator treatments was favoured given the wide 95% CIs that included the potential for no difference or that either treatment could be favoured. For the Norfolk QoL-DN and change from baseline in serum TTR outcomes, eplontersen was often favoured statistically over other treatments, though uncertainty remained, given the wide 95% CIs. For example, the upper bounds of the 95% CIs for between-group differences in Norfolk QoL-DN scores often included effects that appeared small. In the absence of known MIDs, it is uncertain whether these would be considered clinically important differences. Studies Addressing Gaps in the Systematic Review Evidence No studies addressing gaps in the systematic review evidence were submitted by the sponsor. Discussion Summary of Available Evidence The evidence included in this review consisted of 1 pivotal study (the NEURO-TTRansform study) and 1 sponsor-submitted ITC. The NEURO-TTRansform study was an 85-week, phase III, multicentre, randomized, open-label study to evaluate the efficacy of eplontersen after 65 weeks compared to placebo in adult patients with genetic confirmation of hATTR-PN. Patients were randomized 6 to 1 to eplontersen 45 mg SC once every 4 weeks (n = 144) or to 300 mg inotersen SC once per week for up to 34 weeks before switching to eplontersen SC once every 4 weeks from week 37 to week 81 (n = 24). The NEURO-TTRansform study also included an external control group using the placebo arm (n = 60) from the NEURO-TTR study, with adjustment for a select set of baseline covariates using propensity scores. The NEURO-TTR trial was a phase II and III, double-blind, placebo-controlled study that compared the efficacy and safety of inotersen 300 mg SC injection weekly with placebo in patients with stage 1 or 2 hATTR-PN. The eligibility criteria for the NEURO-TTR and NEURO-TTRansform studies were identical. The coprimary end point of the NEURO-TTRansform study was the percentage change from baseline in serum TTR and change from baseline in mNIS + 7 at

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

trials referenced earlier in this section were funded by the drug manufacturer. Independent case reports may show a slight deviation from the results obtained by case reports obtained by manufacturer-backed reports. Tafamidis is a strong contender for the treatment of ATTR. Patients have a higher chance of survival and have longer periods of symptom suppression while on Tafamidis. However, there is still some uncertainty when it comes to the reproducibility of clinical trial results in individual patients, thus the need for more widespread use of Tafamidis in clinical practice. Challenges and limitations Clinical trials for rare conditions like ATTR-CM yield small sample sets. This is shown in the ATTR-ACT trial where only 24% of patients represented the ATTR-CMv disease subtype. The parent trial, ATTR-ACT was not a dose-specific assessment as patient-requested dose reductions were allowed. Furthermore, a protocol amendment requiring all patients to switch to the 61 mg tablet (80 mg bioequivalent) resulted in unique durations for each dose. Seven post hoc analyses are reviewed in this article [ 10 , 11 , 16 , 23 – 25 , 27 ]. A limitation of post hoc analysis is its rigidity; extracted data from a predetermined sample are used to generate hypotheses based on events that have already occurred. This limits the power of the sub-analysis. One of the studies that evaluated extracted echocardiographic data from the original sample cited a small sample of the ATTRv disease subtype and the inability to infer results over a longer duration as major limitations [ 23 ]. A few studies excluded the Tafamidis 20 mg cohort as the 80 mg dose was FDA-approved, causing the lack of generalizability of these results to the 20 mg dose [ 23 , 25 , 26 ]. The analysis did not distinguish between the 20 mg and 80 mg Tafamidis doses; hence, individualized efficacy measures were not ascertained. Patients who discontinued for a reason other than death were assigned as a deterioration, further limiting the power of this study [ 59 ]. As with any open-label study, non-blinding bias is high and will affect the integrity of the results. The pre-specified inclusion criteria of the ATTR-ACT trial automatically excluded elderly and immobile patients, further decreasing the statistical power of this sub-analysis. Low numbers of patients in the > 80 age group joined the LTE study due to expected

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

isiran in those patients also on Tafamidis (25% of the cohort). Studies have supported Patisiran's superiority over Tafamidis regarding treatment effects in patients with hATTR-PN but no comparative study for ATTR-CM between these two exists [ 38 ]. Vutrisiran: Another promising small interfering RNA, Vutrisiran which is now being evaluated for its clinical efficacy and safety in ATTR-CM in the HELIOS-B Trial, has a potential for "99% TTR knockdown with once annual dosing." Vutrisiran was approved in June 2022 for the treatment of hATTR-PN [ 39 ]. Vutrisiran significantly improved neuropathy scores and QOL at nine months in patients with hATTR-PN and had an acceptable safety profile [ 40 ]. Resuviran: In the ENDEAVOUR trial, evaluating another small interfering RNA, Resuviran was terminated due to high treatment-related mortality compared to placebo [ 41 ]. Both Patisiran and Tafamidis have acceptable safety profiles and no monitoring is required during studies [ 42 ]. On the other hand, treatment with Diflunisal and Inotersen warrants close monitoring of platelet count and renal function prior to and throughout treatment. In the first comparison of efficacy and safety between Tafamidis and Diflunisal, there was no significant difference in the progression of biomarkers (NYHA p :0412, BNP p :0.890, Troponin: 0.015) at 1 year between groups. Diflunisal was associated with a significantly higher transthyretin trend and greater reduction in estimated glomerular filtration rate (EGFR) ( p : 0.009, 0.008, respectively) [ 43 ]. Overall, a paucity of head-to-head studies comparing the efficacy and safety of these novel therapies precludes an effective comparison. Real-world evidence (Table 2 ) Real-world data on the outcomes and efficacy of Tafamidis outside of clinical trials for ATTR-CM is lacking A meta-analysis of 15 studies comprising 2765 patients revealed a significant Tafamidis-associated reduction in the composite endpoint of all-cause death, heart transplant, heart assist device implantation, heart failure exacerbations, and hospitalization in both ATTR types [ 20 ]. A predomin

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

80 mg dose in the Japanese retrospective study [ 53 ], but no reduction in the ATTR-ACT trial. This could underline the possibility of heterogeneous responses to Tafamidis in unique populations. Real-world studies evaluating efficacy and safety of Tafamidis in diverse populations Though the most common variant (Val122Ile) in patients of West African descent, there remains a clear discrepancy in access and availability to this drug in developing countries, primarily Africa and the Caribbean [ 21 ]. Two observational studies (one retrospective and the other prospective) evaluated the efficacy of Tafamidis in the Japanese population [ 53 , 54 ]. Even though Nakamura et al.'s study was limited by a small, single-center sample and short follow-up period, there were some noteworthy findings: Unlike the ATTR-ACT trial which showed an increased rate of rehospitalization in NYHA Classes I and II, this study showed worsening of heart failure symptoms, leading to rehospitalization with longer stays in NYHA Class III patients who were otherwise relatively event-free for one year prior to starting Tafamidis. Interventricular septal thickness (IVS) worsened with treatment in three patients. Surrogate markers (NT-proBNP) and echocardiographic data remained unchanged from the baseline. An 83-year-old Korean female with a history of heart failure with preserved ejection fraction (NYHA II) and status post MitraClip intervention presented to the hospital with decreased tolerance during the previous year [ 55 ]. The patient was diagnosed with ATTRwt and was started on Tafamidis 20 mg in addition to heart failure therapy. Using magnetocardiography (MCG), the patient was monitored over 4 months. The initial MCG vector was 0.052 before initiation of therapy and after 4 months of therapy, the vector normalized to 0.037. There was an increase in the dose of Tafamidis to 61 mg when the efficacy of the drug seemed to decrease after 27 months of treatment. 18 months later on 61 mg of Tafamidis, the patient reported an improvement in exercise tolerance and an overall improvement in the quality of life during therapy. Restoration of euvolemia and QOL improvement in this patient emphasized the clinical importance of empiric Tafamidis treatment in the early stages of suspecting ATTR-CM [ 56 ]. This stabilizing effect of Tafam

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

anchored comparisons, data from the eplontersen arm of the NEURO-TTRansform study were used in the stepwise selection process to derive the alternative model, which was subsequently used to adjust the eplontersen data from the NEURO-TTRansform study to the aggregate data for comparators. In the alternative model for anchored comparisons, eplontersen data from the NEURO-TTRansform study and external placebo data (i.e., from NEURO-TTR) were used in the stepwise process to derive the models with the lowest AIC; these were then combined to form a model that was the sum of the lowest AIC models. The variables selected in the combined model were used to adjust the eplontersen data from the NEURO-TTRansform study to the population characteristics of the comparator trial treatment group (e.g., vutrisiran, patisiran or inotersen) and the placebo arm to the comparator trial placebo group characteristics. 14 For the mNIS + 7 composite score and Norfolk QoL-DN total score, both the mean change-from-baseline outcome and the response outcome were analyzed. For these 2 measures, the alternative model was estimated separately. 14 For comparisons versus vutrisiran and patisiran, the definition of cardiac involvement from the NEURO-TTRansform study was altered to match that of the HELIOS-A and APOLLO trials. The definition for the cardiac group for these comparisons was a diagnosis of TTR CM at study entry (defined as familial amyloid CM), baseline interventricular septum thickness greater than or equal to 13 mm on echocardiogram, no medical history of hypertension (i.e., no 2 consecutive systolic blood pressure readings ≥ 150 mm Hg at either of these 2 visits), and no medical history of aortic valve disease. However, for comparisons versus inotersen, the original definition of cardiac involvement from the NEURO-TTRansform study was retained. This was defined as a diagnosis of TTR CM at study entry (defined as familial amyloid CM) or baseline interventricular septum thickness greater than or equal to 13 mm on echocardiogram and no medical history of hypertension (i.e., no

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

, and vutrisiran). The clinical decision between eplontersen and other available disease-modifying therapies would be based on AE profile and convenience. The clinical experts also noted that patients should be able to switch between approved treatments based on tolerance and/or convenience, and that failure of other disease-modifying drugs would not be a prerequisite. The clinical experts noted that there is no evidence to support combining disease-modifying treatments for hATTR because the mechanism of action is similar across therapies; combining TTR silencers is unlikely to provide much additional clinical benefit, though the theoretical rationale of combining TTR silencers and TTR stabilizers could be explored. The clinical experts highlighted that existing patients are likely to have tried pharmacotherapies such as inotersen, patisiran, or tafamidis, or to have undergone liver transplant. The clinical experts noted that eplontersen may be favoured over the newly available vutrisiran, given its less frequent dosing requirements. Overall, the experts highlighted that, based on the mechanism of action, eplontersen may offer improvements in efficacy, safety, and patient convenience that could position it favourably against existing treatments. Patient Population According to the clinical experts, the patients most suitable for eplontersen treatment are those with confirmed neuropathy and a pathogenic mutation in the TTR gene (i.e., confirmed diagnosis of hATTR) confirmed by genetic testing. The clinical experts noted that accessibility of genetic testing in Canada has improved significantly, with initiatives by pharmaceutical companies and provincial labs now offering free testing that includes methods such as saliva or cheek swabs in addition to traditional blood tests. (However, awareness of genetic testing is inconsistent across Canada.) Enhancing the reliability and accessibility of these diagnostic assessments is essential to accurately identify candidates for eplontersen and prevent both underdiagnosis and overdiagnosis in the clinical setting. The ideal patients for treatment with eplontersen are those who mirror the participants in the relevant clinical trials: specifically, adults with confirmed neuropathy determined through reliable and objective assessments. These assessments should ideally involve diagnostic tools, such as nerve conduction studies or evaluations of small fibres, to accurately ascertain the presence and extent of neuropathy. Patients with confirmed neuropathy and TTR mutation who experience rapid progression of neuropathy are generally most in need of intervention and should be offered treatment as soon as possible. The clinical experts noted that

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

2765 patients revealed a significant Tafamidis-associated reduction in the composite endpoint of all-cause death, heart transplant, heart assist device implantation, heart failure exacerbations, and hospitalization in both ATTR types [ 20 ]. A predominance of the ATTRwt vs. ATTRv subtype (1060 vs. 78) is noteworthy and underscores unequal representation in studies. Findings support a significant decrease in LVEF (SMD: − 0.17; 95% confidence interval (CI) − 0.31 to − 0.03; p = 0.02) but no significant difference in interventricular septal thickness or global longitudinal strain after Tafamidis treatment over a mean follow-up duration of 18.7 ± 17.1 months. A significant decrease in the primary endpoint of all-cause mortality and heart transplantation was associated with Tafamidis treatment compared to placebo (the pooled RR 0.44; 95% CI 0.31–0.65; p < 0.01) although no significant difference in primary endpoint occurred between wtATTR or hATTr. (RR 0.44; 95% CI 0.27–0.73 vs. 0.21; 95% CI 0.11–0.40, p = 0.08; I 2 = 68%). These studies all agreed with the study by Maurer et al. [ 5 ] which demonstrated a smaller decline in LVEF with Tafamidis treatment compared to placebo. Real-world studies evaluating changes in myocardial function and echocardiographic features at follow-up after Tafamidis treatment are also lacking. Ichikawa et al. [ 44 ] analyzed changes in LVEF, left ventricular mass index (LVMI), the ratio of peak early diastolic mitral flow velocity, and pulsed-wave Doppler-derived early diastolic velocity from the septal mitral annulus ( E / e ′), LA volume index, GLS, and relative apical sparing from baseline in 41 patients with biopsy-proven ATTR-CM before and mean 16 = /–8 months after Tafamidis treatment with standard speckle-tracking. Subgroup comparisons of NYHA class and age (>

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

specified inclusion criteria of the ATTR-ACT trial automatically excluded elderly and immobile patients, further decreasing the statistical power of this sub-analysis. Low numbers of patients in the > 80 age group joined the LTE study due to expected mortality in this age group, as enrollment occurred 5 years after the parent trial [ 61 ]. Patient-reported data for studies assessing long-term impact on health status were used in two studies [ 24 , 27 ]. There needs to be further studies with clinically objective measures of QOL improvement. Short follow-up periods in real-world studies cannot support the long-term efficacy of Tafamidis. Meta-analysis comprised mainly retrospective and prospective cohort studies with small samples. Furthermore, the under-representation of hATTR subtypes across the board precluded the generalizability of these findings. Most trials and real-world studies used different doses of Tafamidis preventing consistency in data for a specific dose. Small sample sizes in single-center studies precluding large-scale utilization of Tafamidis have been attributed to its high cost [ 48 , 49 ]. Two studies [ 18 , 28 ] used a model-based approach to simulate disease progression; however, this method and the limited pre-specified sample sizes induce variability in survival data. Future directions Despite ATTR-CM's poor prognosis, the current challenge is enhancing awareness of the red flags of the disease. The future of ATTR-CM management is focused on prevention and early diagnosis. Algorithms involving noninvasive, multimodality cardiac imaging, histologic, genetic, and hematological assessments can lead to earlier detection of the disease. Biomarker-based ATTR-CM staging systems have not been thoroughly validated. There is a paucity of data on imaging and biological parameters to support their use in longitudinal follow-up [ 61 ]. Therefore, no single staging system is currently in use consistently. Recent research has highlighted the importance of inflammation, oxidative stress, reduced NO availability, thrombosis risk, endothelial dysfunction, and altered vasculature structure, all of which contribute to myocardial remodeling and fibrosis, in addition to amyloid deposition. Unearthing alternative interactions of Tafamidis with the amyloidogenesis pathway and identifying new mediators in its pathophysiology can pave the way forward. In vivo, DNA editing technologies and anti-TTR monoclonal antibody therapies are on the

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

p = 0.005), Septal E / e ′ ( p = 0.01), and Lateral E / e ′ ( p = 0.006) were observed with Tafamidis treatment. There was also a comparable safety profile to placebo [ 5 ]. An LTE study sought to determine the long-term efficacy and safety profiles of Tafamidis in ATTR-CM. Hence, endpoints from the parent trial were monitored over a prolonged follow-up period of a median of 58.5 months in the continuous Tafamidis group and 57.1 months in the placebo-to-Tafamidis group. Unlike the parent trial, there were no dose reductions related to adverse events. Continuous Tafamidis treatment was associated with a lower rate of death than in the placebo-to-Tafamidis group [ 10 ]. Damy et al. [ 11 ] investigated the efficacy and safety of different doses of Tafamidis in the ATTR-ACT trial and its LTE. Even though both doses had comparable safety and efficacy endpoints, greater survival benefit was shown with the 80 mg dose. Rapezzi et al. evaluated the efficacy of Tafamidis in patients with both wild-type ATTR-CM (ATTRwt-CM) and hereditary ATTR-CM (ATTRv-CM) and found comparable reduction in 6MWT, KCCQ-OS scores and mortality reduction between the subgroups [ 10 ]. Hanna et al.'s [ 24 ] study investigated Tafamidis' efficacy in health-related quality of life and concluded that Tafamidis significantly reduced the decline in all 4 KCCQ-OS domains ( p < 0.0001 for each). A larger proportion of Tafamidis-treated reported their health status as "improved" at 6-month checkpoints until month 30. Shah et al.'s [ 23 ] pre-specified analysis focused on the Tafamidis (80 mg dose) impact on echocardiographic parameters and regional strain patterns that were not fully explored in prior studies of other ATTR-CM therapeutics. The onset of decline in LVEF is earlier in placebo (6 months) than in the Tafamidis 80 mg group which only became apparent at 30 months. Garcia-Pavia et al. [ 25 ] investigated the efficacy of Tafamidis among

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

ose reduction related to adverse events: 0.8% for Tafamidis vs. 2.3% for placebo Treatment-related TEAEs were reported by 44.9%, 38.6%, 50.8% of patients in the Tafamidis 80 mg, 20 mg, and placebo groups Long-term extension (LTE) study Elliot et al. [ 18 ] NCT02791230 LTE of ATTR-CT Open Label Study Assessing long-term efficacy of Tafamidis Duration: Median 58.5 months (continuous Tafamidis) and 57.1 months (placebo-Tafamidis) 353 Continuous Tafamidis ( n :176) Placebo to Tafamidis ( n :177) ATTR-ACT Tafamidis subgroup continued on the same dose (80 mg or 20 mg) ATTR-ACT placebo group randomized in 2:1 ratio to Tafamidis 80 mg or 20 mg doses Protocol amendment caused switch to 61 mg dose Significant mortality reduction in ATTRv ( p = 0.05), TTR-wt ( p = 0.006), NYHA Class I & II ( p = 0.003), and NYHA Class III ( p = 0.06) Comparable safety profile between Tafamidis 80 mg and 20 mg No dose reductions related to adverse events Death: 44.9% in continuous Tafamidis group vs. 62.7% in placebo-to-Tafamidis group (hazard ratio: 0.59 [95% CI: 0.44–0.79]; p < 0.001) Post hoc Analysis Shah et al. [ 23 ] Exploratory post hoc analysis of ATTR-CT patients randomized to Tafamidis 80 mg daily compared to placebo Duration: 30 months n : 176 (Tafamidis 80 group) n : 177 in placebo group See ATTR-CT [ 10 ] Attenuated decline in these parameters at 30 months LVSV 7.02 mL (95% CI, 2.55–11.49; p = .002) LV GLS − 1.02% (95% CI, − 1.73 to − 0.31; P = .005

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

.4% across outcomes. Comparisons of eplontersen to patisiran from the APOLLO and HELIOS-A trials resulted in sample-size decreases of █████ ██ █████ ███ █████ ██ ██████ █████████████ . Comparisons of eplontersen to inotersen resulted in sample-size decreases of █████ ██ ██████ Sample-size decreases were generally smaller in the alternative models, given that fewer variables were included in the adjustment. Interestingly, there was a large reduction in sample size for the reference model for the comparison to inotersen, despite the uniform eligibility criteria. Given the reduction in ESS, there was likely considerable heterogeneity between studies among the variables included in the weighting process. Despite the substantial reduction in ESS for nearly all comparisons following the matching and adjustment, the populations in all MAIC and STC analyses were relatively balanced. Substantial reductions in ESS have implications for generalizability and the precision of effect estimates. The key limitation of the sponsor-submitted MAIC and STC, which is a limitation inherent to all unanchored MAICs and STCs, is that it assumes that all treatment-effect modifiers and prognostic factors are accounted for in the model. This assumption is largely considered impossible to meet, according to the National Institute for Health and Care Excellence (NICE) Decision Support Unit Technical Guidance report on methods for population-adjusted ITCs. A list of prognostic factors and treatment-effect modifiers identified through appropriate channels was included in the report, and based on discussions with the clinical experts consulted for this review, were considered relevant; however, it was noted by the clinical experts that the exclusion of region as a factor may bias the results because there may be regional variation in health care access and treatment approaches that are not related to the V30M mutation. Additionally, the clinical experts noted the heterogeneity in the number and type of mutations in hATTR, each potentially influencing disease progression and treatment response; however, the impact of this remains uncertain. Further, the treatment-effect modifiers and prognostic factors accounted for in the models included only those that were reported within the included trials; unknown (measured or unmeasured) and known, unmeasured treatment-effect modifiers and/or prognostic factors could not be accounted for using the MAIC or STC methods. Methodological or design differences across trials — such as in blinding

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy - PubMed

CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial registration: ClinicalTrials.gov Identifier: NCT04136184 ; EU Clinical Trials Register: EudraCT 2019-001698-10. PubMed Disclaimer Conflict of interest statement Conflict of Interest Disclosures: Dr Coelho reported receiving consulting fees (to institution) from Ionis and AstraZeneca and receiving support for scientific meetings attendance from Sobi, Pfizer, and Alnylam. Dr Marques Jr reported receiving personal fees for participation in meetings, lectures, and advisory boards from Alnylam, PTC Therapeutics, and Pfizer. Dr Dasgupta reported receiving personal fees for serving on the advisory board of NorvoNordisk, Eidos, Alnylam, AstraZeneca, and Intellia/Regeneron; receiving nonfinancial writing assistance from Eidos; receiving nonfinancial travel support from the American Society of Hematology; and receiving grants from Ionis. Dr França Jr reported receiving personal fees for participation in in meetings, lectures, and advisory boards from Alnylam, PTC Therapeutics, and Pfizer and receiving research grants from Pfizer and PTC. Dr Wixner reported receiving consulting fees from Akcea Therapeutics, AstraZeneca, Alnylam Pharmaceuticals, Pfizer, and Intellia Therapeutics. Dr Calandra reported receiving clinical research honoraria from Ionis Pharmaceuticals. Dr Kowacs reported receiving for regular research activities from

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

populations. Because the treatments being studied pertain to a rare disease, the sample size of the included study was small; however, it was adequately powered for the coprimary end points. A larger sample size was likely infeasible due to the rare nature of the condition. The clinical experts consulted for this review also highlighted that the characteristics of the enrolled patients were generally similar to patients in real-world clinical practice despite the small sample sizes. The primary outcomes of the NEURO-TTRansform study were consistent with the outcomes used in trials for hATTR-PN; however, the clinical experts consulted for this review highlighted that the use of serum TTR, mNIS + 7, and Norfolk QoL-DN as outcome measures in clinical practice is very limited. Additionally, considering the nonrandomized study design utilizing an external control arm, the potential for bias resulting from confounding, and the potential for selection bias, the certainty of evidence for the GRADE assessment started at low. The overarching aim of treatment in hATTR-PN is stabilization of the disease, such that functional outcomes (e.g., mobility and lower extremity function) do not progressively deteriorate. For the coprimary end point of percentage change from baseline in serum TTR, there was a substantial improvement in circulating TTR levels compared to placebo, indicating that there is some drug activity with eplontersen. The clinical experts consulted for this review noted that a 50% reduction in serum TTR is generally considered clinically meaningful; this was achieved in the eplontersen group, as well as compared to placebo. However, the relationship between circulating TTR and functional outcomes remains unknown because change in TTR is not a validated surrogate for clinical outcomes. Results for the within-group change from baseline in mNIS + 7 composite score at the interim and final analyses were generally unchanged for patients treated with eplontersen, while those treated with placebo experienced deterioration, suggesting stabilization of disease and lesser neurologic impairment relative to placebo. As noted by the clinical experts, clinician groups, and patient groups, stabilization is important because improvements or reversal of disease are unlikely for these patients. For the Norfolk QoL-DN, results were consistent with the findings for the mNIS + 7 in that the difference compared to placebo favoured eplontersen at both time points, suggesting improvements in daily living, physical functioning, neuropathy symptoms, and HR

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

follow-up revealed statistically divergent curves of survival benefit in the NYHA Class III subset that had little benefit in the original trial [ 18 ]. Methodology A literature search was conducted to identify relevant studies and publications on Tafamidis' efficacy in managing ATTR-CM. Table 1 . Databases such as PubMed, MEDLINE, EMBASE, and Cochrane Library were searched. The search strategy included keywords such as "Tafamidis," "transthyretin cardiac amyloidosis," "cardiac disease," "Tafamidis efficacy," "clinical trials," "cardiac disease treatment," and related terms. Inclusion criteria include studies reporting on the use of Tafamidis in managing ATTR-CM, including clinical trials and observational studies. Non-English language studies were excluded. No time limit was placed on the search. Two reviewers conducted the selection process independently, with disagreements resolved through discussion or consultation with a third reviewer. A qualitative narrative analysis approach was employed to explore and synthesize the narrative elements present in the selected studies. This involved identifying common themes and patterns. Table 1. Studies from clinical trials Author and year Study design Duration Population/sample size Intervention Outcomes Adverse events Parent Clinical Trial Maurer et al. [ 5 ] NCT01994889 Phase III, double-blind, placebo-controlled, multicenter, randomized 2:1:2 Duration: 30 months n : 441 ATTRv-CM (24%) Oral Tafamidis 80 mg daily, Tafamidis 20 mg daily, or placebo Primary outcomes: Lower all-cause mortality (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI] 0.51–0.96) Secondary Outcomes: Lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81) A lower rate of decline for the 6MWT and the KCCQ-CSS ( p < 0.001 for each) Dose reduction related to adverse events: 0.8% for Tafamidis vs. 2.3% for placebo Treatment-related TEAEs were reported by 44.9%, 38.6%, 50.8% of patients in the T

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence - PMC

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

NIS + 7, there were no statistically significant differences detected between eplontersen and vutrisiran in the HELIOS-A trial, patisiran in the HELIOS-A trial, or inotersen in the NEURO-TTR trial. ███████ ███ ███ ██████████ ██ ███████████ ███ █████████ ████ ███ ██████ █████ ████ █████████████ ███████████ ██ ██████ ██ █████████ █████ ██████████ █████ █████ ████ ███ ████ ██ ████████ ██████████ ████ █████████ ███████ ██ █ ███████ ███████████ ██ ███████████ In the alternative models, there were no statistically significant differences detected between eplontersen and vutrisiran in the HELIOS-A trial or patisiran in the HELIOS-A trial, but there was a statistically significant improvement in the mNIS + 7 composite score compared to inotersen ████ █████ ████ ███ ██████ ██ ████████ ██ ████ ███ █████████ ██████ █████████ ████ ███ ██████ █████ ███ ████████ ████ ███████████ ████ ████ ████ ███ ████ ██ ███████ For the change from baseline in Norfolk QoL-DN, comparisons of eplontersen to vutrisiran in the HELIOS-A trial and to inotersen in the NEURO-TTR trial demonstrated a statistically significant improvement in Norfolk QoL-DN total score ████ ████████ ████ █████ ████ ███ ██████ ██ ██████ ███ ███ █████ ████ ███ ██████ ██ ███████ ██████████████ ██ ██████ ██ ████████████ ██████████ ███████ ████████████ ██ █████ ████ ████████████ ███████████ ██ ███████████ ██ █████████ ████ ███ ██████ ██ ████████ ██████ ███ ███ ███████████ █ █████████████ ███████████ ██████████ ██ ██████ ████ ████████ ██

Clinical Review - Eplontersen (Wainua) - NCBI Bookshelf

█████████ ████ ███ ██████ ██ ████████ ██████ ███ ███ ███████████ █ █████████████ ███████████ ██████████ ██ ██████ ████ ████████ ██ ███████ ██████ █████ ██████ ███████ ███ ███ ███████████ ██████ ████ ██████████ ████ ███ █████████ ███████ ██████ ███ ███ ██████████ ██ ███████████ ███ █████████ ████ ███ ████████ ██████ ███████████ ███ ████████ ████ █████████ ████ █████ ████ ███ ██████ ██ ██████ For the change from baseline in serum TTR concentration, ███ ██████████ ██ ███████████ ███ █████████ ████ ███ ████████ █████ and eplontersen and inotersen in the NEURO-TTR trial demonstrated statistically significant reductions in serum TTR concentration ████ █████ ████ ███ █████ ██ ███████ ███ ███ █████ ████ ███ ██████ ██ ███████ ██████████████ in favour of eplontersen, which suggested that eplontersen results in greater reductions in serum TTR levels. However, there was no statistically significant difference detected between eplontersen and vutrisiran. Results for the alternative model were generally consistent with the reference model; however ██ █████████████ ███████████ ██████████ ███ ████████ ███ ███ ██████████ ██ ███████████ ███ █████████ ████ ███ ████████ █████ ████ █████ ████ ███ █████ ██ ███████. Percentage change from baseline in serum TTR concentration was not evaluated in the comparison of eplontersen and patisiran in the APOLLO trial. 14 Critical Appraisal The sponsor-submitted MAIC and STCs were informed by an adequately conducted systematic literature review (SLR) that included planned searches of multiple databases and standard screening and extraction methods. Risk-of-bias assessments of the included studies were conducted per the University of York Centre for Reviews and Dissemination criteria; however, the results of this quality assessment were not provided. Thus, the