Vutrisiran 25mg/0.5ml solution for injection pre-filled syringes

BACKGROUND: The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. METHODS: HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months. RESULTS: ), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. CONCLUSIONS: Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile. CLINICALTRIALS.GOV: NCT03759379.

Abstract licence: CC BY-NC-ND 4.0

BackgroundHereditary transthyretin (ATTRv) amyloidosis, a multifaceted disorder affecting multiple systems, substantially diminishes patients’ physical capabilities and overall quality of life. Patisiran and Vutrisiran, two Ribonucleic acid (RNA) interference therapies, target reducing both pathogenic and wild-type transthyretin (TTR) protein levels. This systematic review assesses the effectiveness and safety of these treatments in managing ATTRv.MethodsA comprehensive, thorough literature search across databases including Embase, PubMed, Web of Science, Cochrane Central, and Google Scholar yielded 858 studies. Following removing duplicate and irrelevant articles, 676 distinct studies underwent review. These studies, conducted on a global scale, encompassed a range of methodologies, including clinical trials and indirect treatment comparisons.ResultsTen studies, spanning a total population of 756 patients, were selected for in-depth analysis. Patisiran and Vutrisiran consistently demonstrated significant improvements in primary and secondary endpoints related to neuropathy, quality of life, and cardiac function. Both medications were well-tolerated, with primarily mild to moderate adverse events. Indirect treatment comparison studies indicated Vutrisiran’s superiority over Tafamidis in treating ATTRv amyloidosis.ConclusionThis systematic review recommends using Patisiran and Vutrisiran to treat ATTRv amyloidosis. The findings suggest that these RNA interference therapies improve neuropathy, quality of life, and cardiac symptoms. The results indicate sustained benefits over prolonged treatment, with satisfactory safety profiles. However, potential biases, conflicts of interest in the studies, and limited follow-up periods in some trials necessitate cautious interpretation. Future research should address these limitations and provide more robust evidence for the long-term efficacy and safety of Patisiran and Vutrisiran in ATTRv treatment.

Abstract licence: CC BY 4.0

Background: Transthyretin amyloidosis (ATTR) is a progressive disease that causes a restrictive cardiomyopathy. Vutrisiran, a subcutaneous RNA interference (RNAi) therapy, is an approved treatment. This systematic review and meta-analysis evaluates its efficacy and safety with respect to transthyretin (TTR) reduction, functional capacity, quality of life, mortality, and adverse events. Methods: We identified 1,032 records, of which three randomized controlled trials — HELIOS-A, HELIOS-B, and a Phase 1 study — comprising 976 participants (508 vutrisiran; 468 comparator) met the inclusion criteria. Comparator participants received placebo, patisiran (an active reference comparator in HELIOS-A), or external placebo from the APOLLO trial. Outcomes assessed were TTR reduction, functional capacity, quality of life, mortality, and adverse events, pooled using random-effects models reporting mean differences and risk ratios. Results: Vutrisiran achieved a rapid, durable TTR reduction of up to 97% in healthy volunteers at the highest dose, and a sustained steady-state reduction in the HELIOS-A and HELIOS-B trials. QoL outcomes showed a protective effect of vutrisiran, with slowed deterioration in the intervention group. Functional outcomes (10-MWT, 6-MWT) suggested slower decline in mobility and functional capacity. Mortality showed a non-significant reduction (RR 0.51; p=0.29; I²=62%), with most deaths considered unrelated to treatment. The safety analysis showed fewer falls (RR 0.62; p=0.001; I²=0%) but no significant difference in overall adverse events (AEs) (RR 1.01; p=0.76) or serious AEs (RR 0.82; p=0.23). A sensitivity analysis supported the adverse-event findings. Conclusions: Vutrisiran consistently suppressed TTR and showed signals of benefit in quality of life, function, and mortality, though most of these outcomes did not reach statistical significance. It reduced fall risk without increasing adverse events, indicating a favourable safety profile. Larger, long-term RCTs are needed to confirm survival and functional benefits.

Abstract licence: CC BY 4.0

BackgroundWe used network meta-analyses to evaluate the pharmacological interventions for Hereditary Transthyretin-related Amyloidosis with Polyneuropathy (ATTRv-PN).MethodsWe searched Medline, Embase, and Cochrane (June 2025) for randomized trials assessing pharmacological interventions in ATTRv-PN adults. Two reviewers independently screened, extracted data, and assessed risk of bias. Primary efficacy outcomes were mNIS+7 and Norfolk-QoL-DN. Primary safety outcome was serious adverse events (SAE). We used Bayesian hierarchical models. Evidence certainty was assessed using GRADE.ResultsSix trials (n = 989) were included (3 at high-risk of bias). Participant ages and disease duration ranged from 52.8 to 62.0 and 1.4 to 3.9 years, respectively. For mNIS+7, data were available for all interventions except tafamidis. All demonstrated statistically significant improvements versus placebo. Vutrisiran (standardized mean difference [SMD] vs. placebo: -1.66; 95% credible interval [CrI]: -2.13 to -1.17) and patisiran (SMD vs. placebo: -1.56; 95% CrI: -1.88 to -1.25) demonstrated improvements compared with diflunisal, eplontersen, and inotersen. For Norfolk-QoL-DN, data were available for all interventions except diflunisal. All except tafamidis demonstrated statistically significant improvements versus placebo. Patisiran (MD vs. placebo: -17.39; 95% CrI: -23.22 to -11.57), vutrisiran (MD vs. placebo: -16.99; 95% CrI: -25.24 to -8.72), and eplontersen (MD vs. placebo: -15.56; 95% CrI: -21.97 to -9.15) demonstrated improvements compared with tafamidis. For SAE, there were no differences between active interventions versus placebo. Confidence in the evidence varied from very low to moderate.ConclusionGene-silencing therapies were more efficacious, although these findings should be regarded as hypothesis-generating given the scarcity of data, lack of head-to-head trials, and clinical heterogeneity across trials.

Abstract licence: CC BY-NC-ND

Abstract Aims Transthyretin cardiac amyloidosis (ATTR-CA) is an important cause of heart failure (HF). Several therapies demonstrated an efficacy in reducing hard and surrogate endpoints. We compared the relative efficacy of therapies evaluated in completed phase III trials. Methods and results We conducted a network meta-analysis using data from ATTR-ACT, ATTRIBUTE-CM, APOLLO-B, and HELIOS-B. The primary endpoint was a composite of all-cause mortality and cardiovascular hospitalizations. Secondary endpoints were changes in the 6-minute walk distance (6MWD) and Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) scores. For the primary endpoint, tafamidis and vutrisiran demonstrated a significant survival benefit over placebo; acoramidis approached significance. In indirect comparisons, there was no clear evidence of a larger absolute risk reduction for any drug. Tafamidis was associated with the lowest risk for the primary endpoint (surface under the cumulative ranking, SUCRA 82%), followed by vutrisiran monotherapy (70%). Regarding changes in 6MWD, tafamidis and acoramidis had the highest SUCRA curve values (97% and 69%, respectively). For KCCQ-OS changes, tafamidis also had the highest SUCRA (87%), followed by acoramidis (79%) and vutrisiran monotherapy (67%). When the ATTR-ACT trial was excluded from the analysis, vutrisiran monotherapy consistently showed the highest probability of being ranked better than other treatments in terms of primary end-point. Conclusion Although differences in trial design and study populations complicate direct efficacy comparisons, tafamidis demonstrated the highest efficacy in improving survival, reducing cardiovascular hospitalizations, and enhancing functional capacity and quality of life in patients with ATTR-CA, but also vutrisiran and acoramidis emerged as viable options.

Abstract licence: CC BY-NC 4.0

Abstract In the HELIOS-B randomized clinical trial, the RNA interference therapeutic agent vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). In this secondary analysis of HELIOS-B, we evaluated vutrisiran’s effects on echocardiographic measures of cardiac structure and function in patients with ATTR-CM receiving vutrisiran or placebo (n = 654, 93% men). At 30 months after treatment, as compared to the placebo group, vutrisiran treatment attenuated increases in mean left ventricular (LV) wall thickness (least squares mean difference: −0.4 mm; 95% confidence interval (CI): −0.8, 0.0; P = 0.03) and LV mass index (−10.6 g m− 2; 95% CI: −18.0, −3.3; P < 0.01). Vutrisiran treatment also attenuated declines in LV ejection fraction (2.0%; 95% CI: 0.3, 3.7; P = 0.02), absolute global longitudinal strain (1.2%; 95% CI: 0.7, 1.7; P < 0.01) and LV stroke volume (4.1 ml; 95% CI: 1.7, 6.4; P < 0.01), and decreased both the average ratio of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity (−2.0; 95% CI: −2.9, −1.2; P < 0.01) and the early to late diastolic transmitral flow velocities ratio (−0.3; 95% CI: −0.6, −0.0; P = 0.04), as compared to placebo. Consistent with its clinical benefits, these echocardiographic findings indicate favorable effects of vutrisiran on cardiac structure and function in patients with ATTR-CM. ClinicalTrials.gov registration: NCT04153149.

Abstract licence: CC BY 4.0

Background Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis.Research design and methods Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI).Results Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: −5.3 [95% confidence interval (CI): −9.4, −1.2; p = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: −18.3 [95% CI: −28.6, −8.0; p < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p = 0.020]).Conclusions This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy.

Abstract licence: CC BY-NC-ND 4.0