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.

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Background: Hereditary 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. Methods: A 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. Results: Ten 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. Conclusion: This 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.

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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.

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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 .

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Abstract Aims HELIOS-A was a Phase 3, open-label study of vutrisiran, an RNA interference therapeutic, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. This analysis evaluated vutrisiran's impact on exploratory cardiac endpoints in HELIOS-A patients. Methods and results Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months or intravenous patisiran 0.3 mg/kg every 3 weeks (reference group) for 18 months. Exploratory cardiac endpoints included change from baseline in N-terminal prohormone of brain-type natriuretic peptide (NT-proBNP) and echocardiographic parameters versus external placebo (APOLLO study). The modified intent-to-treat (mITT) population comprised randomized patients receiving any study drug (n = 122). A cardiac subpopulation with evidence of cardiac amyloid involvement (n = 40) was prespecified. 99mTc scintigraphy exploratory assessments in a planned vutrisiran-treated cohort at select sites were compared with baseline. At Month 18, vutrisiran demonstrated beneficial effects on NT-proBNP versus external placebo in the mITT and cardiac subpopulations (adjusted geometric mean fold change ratio [95% confidence interval] 0.480 [0.383–0.600], p = 9.606 × 10−10 and 0.491 [0.337–0.716], p = 0.0004, respectively). Benefits or trends towards benefit in echocardiographic parameters versus external placebo were observed for both populations. In 99mTc scintigraphy assessments, 32/47 (68.1%) and 31/48 (64.6%) patients exhibited reduced normalized left ventricular total uptake and heart-to-contralateral lung ratio, respectively. Perugini grade was reduced or unchanged versus baseline in 55/57 (96.5%) evaluable patients. No increase in cardiac adverse events was observed with vutrisiran versus external placebo. Conclusions Vutrisiran demonstrated evidence of potential benefit on cardiac manifestations in patients with ATTRv amyloidosis with polyneuropathy, with an acceptable safety profile.

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BACKGROUND: Patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) have high mortality and morbidity. Vutrisiran, a subcutaneous RNA interference therapeutic, reduced the composite of all-cause mortality (ACM) and cardiovascular (CV) events (CV hospitalizations and urgent heart failure [HF] visits) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy) in patients with ATTR-CM. OBJECTIVES: Here we present data from HELIOS-B evaluating the impact of vutrisiran on ACM and CV mortality with additional patient follow-up through 42 months, and CV events such as CV hospitalizations, HF hospitalizations, and urgent HF visits. METHODS: The HELIOS-B trial randomized 655 patients to vutrisiran 25 mg or placebo once every 3 months for up to 33 to 36 months in the double-blind (DB) period, followed by an open-label extension. Prespecified mortality and CV mortality analyses used data through 39 to 42 months of follow-up (DB period and up to 6 months of the open-label extension). CV hospitalizations and HF events were evaluated over the DB period of 33 to 36 months. Differences between vutrisiran and placebo were evaluated in the overall population, and in those stratified by baseline tafamidis use. RESULTS: In the overall population, vutrisiran reduced the risk of ACM (HR: 0.64; 95% CI: 0.46-0.88) and CV mortality (HR: 0.67; 95% CI: 0.47-0.96) vs placebo. Vutrisiran also reduced the risk of a composite of CV mortality and CV events (HR: 0.72; 95% CI: 0.55-0.94), and lowered rates of CV hospitalizations (rate ratio [RR]: 0.75; 95% CI: 0.62-0.91), urgent HF visits (RR: 0.54; 95% CI: 0.30-0.98), and HF hospitalizations (RR: 0.67; 95% CI: 0.52-0.86) vs placebo. Consistent trends were seen regardless of baseline tafamidis use. CONCLUSIONS: Consistent with the primary trial results, vutrisiran reliably reduced the risk of ACM, CV mortality, CV hospitalizations, HF hospitalizations, and urgent HF visits vs placebo in patients with ATTR-CM. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149).

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