Eplontersen

According to NICE's 2024 technology appraisal guidance (TA1020), eplontersen has been recommended as an option for treating hereditary transthyretin-related amyloidosis in adults with stage 1 or stage 2 polyneuropathy. This guidance was concluded after evaluating eplontersen's efficacy in comparison to existing treatments such as vutrisiran, which is currently a usual treatment for the condition. Eplontersen offers the convenience of self-administration at home with a monthly injection, whereas vutrisiran requires administration every three months. Evidence from clinical trials indicated that eplontersen is more effective than placebo in reducing transthyretin levels and delaying the progression of polyneuropathy. While direct comparisons between eplontersen and vutrisiran in clinical trials are unavailable, indirect evidence suggests comparable efficacy between the two treatments. The 2024 guidance also includes a cost analysis, which demonstrates that eplontersen provides cost savings over vutrisiran. NHS funding arrangements mandate the implementation of this guidance within stipulated timeframes, reflecting NHS England's and Wales's commitment to making eplontersen available to eligible patients promptly. [1]

Vutrisiran

The 2025 ACC Concise Clinical Guidance provides a detailed framework on the evaluation and management of transthyretin cardiac amyloidosis (ATTR-CM), reflecting advancements in diagnostic and therapeutic strategies. The pharmacological agents tafamidis, acoramidis, and vutrisiran are used to manage transthyretin amyloid conditions by slowing the progression of the disease. However, these medications do not reverse any end-organ damage that may have occurred. Consequently, while they can help maintain a patient's current level of functional status and quality of life, they are not anticipated to enhance these parameters. Their primary role is to stabilize the condition rather than to ameliorate pre-existing organ damage or improve the overall health status of affected individuals. Transthyretin silencers, including small-interfering ribonucleic acids and antisense oligonucleotides, are designed to degrade transthyretin messenger RNA in hepatocytes, thereby reducing transthyretin production. Vutrisiran, a specific transthyretin silencer, received FDA approval in 2022 for transthyretin-mediated amyloidosis with polyneuropathy (ATTRv), and subsequently for transthyretin amyloid cardiomyopathy (ATTR-CM) in 2025. The HELIOS-B trial evaluated the efficacy of vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy, involving a cohort of 655 individuals. Participants received either 25 mg of vutrisiran subcutaneously every 12 weeks or a placebo. The study demonstrated that vutrisiran significantly reduced the risk of death from any cause and recurrent cardiovascular events compared to placebo. Given that transthyretin is a primary transporter of retinol, it is crucial to administer vitamin A supplementation alongside any therapy that diminishes transthyretin production. The recommended FDA-approved dosage of vutrisiran is 25 mg administered subcutaneously every three months in conjunction with vitamin A supplementation to mitigate potential deficiencies. [2]

Olezarsen

A 2024 randomized, controlled, phase 2b clinical trial investigated the efficacy of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (APOC3), for the management of hypertriglyceridemia in patients at high cardiovascular risk. This multicenter study involved 154 adults with either moderate hypertriglyceridemia (triglyceride levels ranging from 150 to 499 mg per deciliter) or severe hypertriglyceridemia (triglyceride levels ≥500 mg per deciliter). These participants were randomly assigned into two cohorts receiving either a 50-mg or 80-mg dose of olezarsen, in a 3:1 ratio of olezarsen to placebo. The primary endpoint was the percent reduction in triglyceride levels from baseline to six months. Additional secondary endpoints included changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. The trial results demonstrated significant reductions in triglyceride levels, with the 50-mg and 80-mg olezarsen doses achieving reductions of 49.3 and 53.1 percentage points, respectively, compared to placebo (P<0.001 for both groups). Furthermore, both doses led to significant decreases in APOC3, apolipoprotein B, and non-HDL cholesterol levels, while LDL cholesterol levels remained unchanged. Adverse events were comparable across the olezarsen and placebo groups, with no significant hepatic, renal, or platelet abnormalities observed. These findings highlight olezarsen's potential as a safe and effective treatment option for hypertriglyceridemic patients at elevated cardiovascular risk. [3]

A 2024 phase 3, double-blind, placebo-controlled trial evaluated the efficacy of olezarsen in patients with familial chylomicronemia syndrome, a genetic condition characterized by severe hypertriglyceridemia and acute pancreatitis. The trial randomly assigned 66 patients with genetically confirmed familial chylomicronemia syndrome to receive either 80 mg or 50 mg of olezarsen or a placebo subcutaneously every four weeks for 49 weeks. Two primary endpoints were set: the percent change in fasting triglyceride levels from baseline to six months between the 80 mg olezarsen group and the placebo group, followed by the comparison between the 50 mg olezarsen group and the placebo group if the first endpoint was significant. Secondary endpoints included the mean percent change from baseline in apolipoprotein C-III levels and the incidence of independently adjudicated acute pancreatitis episodes. The results demonstrated that, at six months, patients receiving the 80 mg dose of olezarsen experienced a significant reduction in triglyceride levels compared to those receiving a placebo, with a difference of -43.5 percentage points; the 95% confidence interval ranged from -69.1 to -17.9, with a P-value of less than 0.001. However, the 50 mg dose did not show a statistically significant difference compared to the placebo, with a reduction of -22.4 percentage points and a P-value of 0.08. Significant reductions were also observed in apolipoprotein C-III levels for both olezarsen groups compared to placebo, with the 80 mg group showing a change of -73.7 percentage points and the 50 mg group showing -65.5 percentage points. By 53 weeks, the placebo group experienced 11 episodes of acute pancreatitis, contrasted with a single episode in each of the olezarsen groups, yielding a rate ratio of 0.12 (95% CI, 0.02 to 0.66) for the pooled olezarsen groups versus placebo. Moderate severity adverse events deemed related to the study drug occurred in four patients receiving the 80 mg dose. These findings suggest that olezarsen may serve as a promising new therapy for reducing plasma triglyceride levels in individuals affected by familial chylomicronemia syndrome. [4]

A 2026 clinical trial, involving two randomized, double-blind, placebo-controlled studies (CORE-TIMI 72a and CORE2-TIMI 72b), explored the efficacy and safety of olezarsen, an antisense oligonucleotide, for managing severe hypertriglyceridemia and its associated pancreatitis risk. The trial enrolled 1061 patients, randomizing them in a 1:1:1 ratio to receive either olezarsen at doses of 50 mg or 80 mg, or a placebo, monthly for 12 months. The primary endpoint was the percentage change in triglyceride levels at 6 months, with secondary endpoints encompassing changes in levels of apolipoprotein C-III, remnant cholesterol, and non-high-density lipoprotein cholesterol at both 6 and 12 months. In the CORE-TIMI 72a trial, olezarsen resulted in a placebo-adjusted triglyceride reduction of -62.9 percentage points for the 50 mg dose and -72.2 percentage points for the 80 mg dose, while in the CORE2-TIMI 72b trial, reductions were -49.2 percentage points and -54.5 percentage points respectively. Efficacy was significant with P-values less than 0.001. Furthermore, the incidence of acute pancreatitis was markedly lower among those receiving olezarsen, with a mean rate ratio of 0.15 (95% CI, 0.05 to 0.40; P<0.001). Adverse event rates were similar across study groups, though the 80 mg dose was associated with increased liver enzyme levels, thrombocytopenia, and a dose-dependent rise in hepatic fat fraction. The findings highlight olezarsen's potential as a promising therapeutic for reducing triglyceride levels and acute pancreatitis risk in this patient population. [5]

A 2024 study rigorously evaluated the clinical outcomes of switching from inotersen to eplontersen among patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). Conducted as part of the phase 3 NEURO-TTRansform trial, this research focused on a cohort of participants initially randomized to receive inotersen 300 mg subcutaneously on a weekly basis. At week 37, the treatment regimen transitioned to eplontersen 45 mg every four weeks, continuing until week 81. The primary metrics of assessment included changes in serum transthyretin (TTR) levels, neuropathy impairment, quality of life (QoL), and treatment-emergent adverse events (TEAEs) up to week 85. The study's methodology incorporated a comprehensive array of assessments, including the modified Neuropathy Impairment Score+7 and the Norfolk Quality of Life-Diabetic Neuropathy total score, alongside nutritional status evaluation via modified body mass index. Results from the Journal of Neurology article highlighted significant efficacy and safety improvements following the transition to eplontersen. Of the 24 initial participants receiving inotersen, 83% transitioned smoothly to eplontersen, with a marked reduction in serum TTR levels from 74.3% at week 35 to 80.6% at week 85. Notably, the condition of neuropathy impairment and QoL remained stable post-transition, indicating halted disease progression, while nutritional status did not deteriorate. The incidence of TEAEs reduced to 95% with eplontersen compared to 100% with inotersen, accompanied by stabilized platelet counts and no recorded cases of thrombocytopenia or glomerulonephritis during eplontersen treatment. This study underscores a favorable benefit-risk profile for eplontersen as a treatment option for ATTRv-PN, suggesting significant enhancements in patient outcomes compared to inotersen. [6]

A 2025 secondary analysis from the NEURO-TTRansform trial explored the effects of eplontersen on symptoms of autonomic neuropathy in patients diagnosed with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). This investigation aimed to evaluate the efficacy of eplontersen, an antisense oligonucleotide, in ameliorating autonomic impairment over an 85-week treatment duration. The trial involved 141 patients receiving eplontersen compared to an external placebo group derived from the previously conducted NEURO-TTR trial (involving 59 subjects). Autonomic impairment was assessed using standardized instruments, including the modified Neuropathy Impairment Score +7 (mNIS+7), the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score, and the Neuropathy Symptoms and Change (NSC) total score. Additionally, the Composite Autonomic Symptom Score-31 (COMPASS-31) was employed to measure varied autonomic dysfunction components comprehensively. Profound autonomic dysfunction was reported at baseline in both the eplontersen and placebo groups. The analysis revealed that patients treated with eplontersen experienced significant improvements over the specified period in autonomic components of mNIS+7, Norfolk QoL-DN, NSC, and mBMI scores compared to placebo. Improvements were consistent up to Week 85, highlighting eplontersen's potential to maintain autonomic function and general health-related quality of life. The study also reported preserved nutritional status, as indicated by stable modified body mass index (mBMI) scores, contrasting with the deterioration observed in the placebo group. These results underscore eplontersen's capability to slow the progression of autonomic symptoms associated with ATTRv-PN, suggesting a positive impact on patient quality of life when conventional treatments might result in substantial progression of the disease. [7]

A 2024 clinical trial evaluated the effects of eplontersen on cardiac structure and function in patients with hereditary transthyretin amyloidosis (ATTRv). The NEURO-TTRansform, an open-label trial, included 144 adults presenting with ATTRv polyneuropathy, with a notable 34% also diagnosed with cardiomyopathy. These patients were treated with eplontersen, compared to a historical placebo group consisting of 60 subjects, of which 50% had cardiomyopathy. The primary goal of the investigation was to discern the therapeutic impact of eplontersen on the cardiac ejection fraction and stroke volume over a period of 65 weeks, with adjustments made for variables such as age, sex, region, baseline values, ATTRv disease progression, prior ATTRv therapies, and the presence of the V30M transthyretin variant. The findings revealed that treatment with eplontersen was associated with a significant improvement in left ventricular ejection fraction, showing a mean difference of 4.3% (95% confidence interval 1.40-21.01; P = .049) when contrasted with placebo controls. Additionally, the stroke volume increased by 10.64 mL (95% confidence interval 3.99-17.29; P = .002), while other echocardiographic markers remained stable. These results indicate that eplontersen may contribute to either stabilization or enhancement of cardiac measures in individuals with ATTRv polyneuropathy and cardiomyopathy, warranting further exploration of its efficacy in transthyretin amyloid cardiomyopathy within the ongoing CARDIO-TTRansform trial. [8]

A 2024 multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluated the safety and efficacy of givinostat in treating Duchenne muscular dystrophy across 41 tertiary care sites in 11 countries. Participants in the trial were ambulant, male, and aged at least 6 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy. These boys had completed two four-stair climb assessments with an average time of 8 seconds or less and demonstrated time-to-rise values between 3 and 10 seconds. They had also been on a regimen of systemic corticosteroids for a minimum of six months. Participants were stratified by concomitant steroid use and were randomly assigned in a 2:1 ratio to receive either oral givinostat or a matching placebo twice daily over 72 weeks. A flexible dosing schedule, based on weight, was used and doses were adjusted if not tolerated. The primary endpoint focused on the change in the four-stair climb assessment from baseline to 72 weeks in the intention-to-treat, group A population, segmented by vastus lateralis fat fraction. Safety assessments were conducted for all participants who received at least one dose of the study drug. Results published in 2024 indicated that between June 2017 and February 2022, 179 boys were enrolled, with 95% completing the study. In the primary analysis, the geometric least squares mean ratio for the four-stair climb at 72 weeks compared to baseline was 1.27 for the givinostat group and 1.48 for the placebo group, yielding a ratio of 0.86 (p=0.035), indicating a smaller decline in the givinostat group. Common adverse events included diarrhea and vomiting, observed in a higher proportion among participants receiving givinostat. The trial noted that while both groups showed worsened four-stair climb assessment results over the study duration, the decline was significantly less severe in the givinostat group. An ongoing extension study aims to evaluate the long-term safety and efficacy of givinostat, providing valuable insights into its potential role in managing Duchenne muscular dystrophy. [9]

A 2013 multicenter, randomized, open-label phase II study evaluated the safety and efficacy of the histone deacetylase inhibitor Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera (PV) who were unresponsive to hydroxycarbamide monotherapy. The study included 44 patients with confirmed JAK2 V617F-positive PV, median age 65 years, who had not responded to the maximum tolerated dose (MTD) of hydroxycarbamide for at least three months. Participants were randomly assigned to receive 50 mg or 100 mg of Givinostat daily alongside their individual MTD of hydroxycarbamide. The primary endpoint was hematological response rate at week 12 per European LeukemiaNet criteria, with secondary endpoints including response rate at week 24 and safety assessments. After 12 weeks, a complete or partial response was noted in 55% of patients receiving 50 mg and 50% of those receiving 100 mg of Givinostat. Notably, pruritus, a common symptom in PV patients, was controlled in 64% and 67% of the 50 mg and 100 mg groups, respectively. The combination was generally well tolerated with few grade 3 adverse events reported, and no significant differences in safety profiles between the two dosing regimens. Overall, the combination of Givinostat and hydroxycarbamide demonstrated promising safety and clinical effectiveness in PV patients who were previously unresponsive to hydroxycarbamide alone, with a significant number experiencing reduced symptom burden and improved hematological parameters. [10]

A 2025 randomized, double-blind trial evaluated the efficacy and safety of vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). In this trial, 655 patients were randomly assigned in a 1:1 ratio to receive either 25 mg of vutrisiran or a placebo every 12 weeks over a 36-month period. The primary endpoint was the composite of death from any cause and recurrent cardiovascular events, assessed both in the overall population and in a subgroup of patients receiving vutrisiran as monotherapy, excluding those on baseline tafamidis treatment. Secondary endpoints included overall mortality, changes in the 6-minute walk test distance, and the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, with hierarchical testing of efficacy endpoints. Results from this investigation demonstrated that vutrisiran significantly reduced the risk of death and recurrent cardiovascular events compared to placebo, with a hazard ratio of 0.72 in the overall population and 0.67 in the monotherapy group. Additionally, at 42 months, there was a lower risk of death from any cause in the vutrisiran group, reflected by a hazard ratio of 0.65. Furthermore, patients receiving vutrisiran showed less decline in physical function and quality of life, as evidenced by a 26.5-meter least-squares mean difference in the 6-minute walk test and a 5.8-point difference in the KCCQ-OS score. The incidence of adverse events was comparable between groups, although serious adverse events were slightly lower in the vutrisiran group (62% versus 67% in the placebo group). The findings suggest that vutrisiran provides significant clinical benefits in reducing mortality and preserving functional and quality of life metrics in patients with ATTR-CM. [11]

A 2022 phase 3, global, open-label, randomized clinical trial evaluated the efficacy and safety of vutrisiran, an RNA interference (RNAi) therapeutic administered subcutaneously every 3 months, in adult patients with hereditary transthyretin-mediated (ATTRv) amyloidosis with polyneuropathy. The HELIOS-A trial enrolled 164 patients randomized in a 3:1 ratio to receive either vutrisiran 25 mg every 3 months or patisiran 0.3 mg/kg intravenously every 3 weeks for an 18-month treatment duration. An external placebo group, derived from the previously conducted APOLLO study, served as the comparator arm and permitted assessment of efficacy endpoints without incorporating a concurrent placebo-controlled population. Patients eligible for inclusion had confirmed TTR variants, a Neuropathy Impairment Score (NIS) between 5–130, and a polyneuropathy disability (PND) score of ≤IIIb. At month 9, vutrisiran achieved statistically significant improvements in the primary outcome of modified Neuropathy Impairment Score +7 (mNIS+7), demonstrating a least squares (LS) mean change from baseline of –2.24 versus +14.76 in the external placebo group, with a treatment difference of –17.00 (95% CI: –21.78 to –12.22, p = 3.54 × 10–12). These benefits were sustained at month 18, with an LS mean change of –0.46 compared to +28.09 in placebo, corresponding to a treatment difference of –28.55 (95% CI: –34.00 to –23.10, p = 6.50 × 10–20). Vutrisiran also demonstrated statistically significant improvements across all hierarchical secondary endpoints, including Norfolk QOL-DN score, 10-meter walk test (10-MWT), modified body mass index (mBMI), and Rasch-built Overall Disability Scale (R-ODS), consistently outperforming the external placebo group at both 9- and 18-month timepoints. Mean serum TTR reduction with vutrisiran reached 87.6% at peak and 81.0% at trough, proving non-inferior to within-study patisiran and exhibiting a more stable pharmacodynamic profile due to reduced peak-trough fluctuation. The safety profile of vutrisiran was favorable, with most adverse events mild to moderate in severity and a low incidence of drug-related discontinuations or deaths. [12]

A 2025 randomized controlled trial assessed the effects of the RNA interference therapeutic agent vutrisiran on cardiac function and outcomes in patients with transthyretin amyloidosis and cardiomyopathy (ATTR-CM). Conducted as part of the HELIOS-B study, 655 patients were randomly assigned to receive vutrisiran (25 mg subcutaneously every 12 weeks) or placebo. Echocardiographic evaluations were performed at baseline and at 12, 18, 24, and 30 months. The investigational approach utilized modified Andersen-Gill models which adjusted for variables such as age, sex, ATTR disease type, and National Amyloidosis Centre stage, with stratification by baseline tafamidis use and treatment assignment. Landmark analyses were then employed to compare changes in cardiac function from baseline to month 18 between the treatment groups. Results from the trial indicated that among the 654 participants with echocardiographic data, baseline measures of left and right ventricular systolic and diastolic function were significant predictors of the primary outcome, which encompassed all-cause death and recurrent cardiovascular events. Notably, at 18 months, vutrisiran was shown to mitigate declines in left ventricular and right ventricular systolic function, evidenced by improvements in left ventricular ejection fraction, absolute global longitudinal strain, and tricuspid annular systolic myocardial velocity. Furthermore, the trial highlighted that patients experiencing worsening cardiac parameters at 18 months faced an increased risk for primary outcomes. The 2025 findings underscore the prognostic value of echocardiographic measures and suggest that the beneficial effects of vutrisiran on cardiac function contribute to its positive impact on clinical outcomes in ATTR-CM. [13]

A 2022 randomized, single-ascending-dose, phase 1 clinical trial assessed the safety, pharmacokinetics, pharmacodynamics, and exposure-response of nedosiran in a cohort of 25 healthy participants and 18 patients diagnosed with primary hyperoxaluria types 1 or 2 (PH1 or PH2). The trial, identified as PHYOX1, was conducted with participants receiving subcutaneous doses ranging from 0.3 to 12.0 mg/kg in Group A and open-label doses of 1.5, 3.0, or 6.0 mg/kg in Group B. Nedosiran, an RNA interference agent targeting hepatic lactate dehydrogenase, was tested to explore its potential in inhibiting oxalate production, a critical factor in primary hyperoxaluria. The results indicated no significant safety concerns, with injection site reactions observed in 13.3% of Group A and 27.8% of Group B participants. Importantly, a marked reduction in 24-hour urinary oxalate excretion was seen, with a mean maximum reduction of 55% from baseline by Day 57 across the patient cohorts. The detailed exposure-response modeling and simulation indicated that a fixed monthly dose of 160 mg nedosiran (equivalent to 170 mg sodium salt) could offer optimal therapeutic benefits for adult patients, achieving the highest proportion of individuals with normalized or near-normal urinary oxalate levels. The data emphasized the pharmacodynamic efficacy of nedosiran, aligning with its mechanism of action to inhibit the final enzymatic step in oxalate production. These findings suggest that nedosiran offers a promising therapeutic option for individuals with PH1 and PH2, highlighting both its safety profile and potential to reduce hyperoxaluria effectively. [14]

A 2023 randomized controlled trial explored the efficacy of nedosiran, an investigational RNA interference agent, in patients with primary hyperoxaluria types 1 and 2 (PH1 and PH2). The trial involved 35 participants with an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m², randomly assigned in a 2:1 ratio to receive subcutaneous nedosiran or placebo once monthly over a period of six months. The primary endpoint was the area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion between days 90-180. The results demonstrated a substantial improvement in the nedosiran group, with a least squares mean difference of 5172 (95% CI 2929-7414; P <0.001) favoring nedosiran over placebo. Further analysis revealed that 50% of participants receiving nedosiran achieved normal or near-normal Uox excretion on two or more consecutive visits after day 90, compared to 0% in the placebo group (P = 0.002). Notably, the PH1 subgroup exhibited a significant and sustained reduction in Uox, with 64.7% achieving targeted Uox excretion levels (P <0.001), whereas such effect was not consistently observed in the PH2 subgroup. Additionally, nedosiran-treated individuals with PH1 experienced a marked reduction in plasma oxalate levels compared to those receiving a placebo (P = 0.017). Safety assessments indicated that nedosiran was generally well-tolerated, with only mild and self-limiting injection-site reactions observed in 9% of participants administered nedosiran. These findings suggest that nedosiran may offer a promising therapeutic option for managing oxalate overproduction in primary hyperoxaluria, particularly for PH1 patients. [15]