A review of Eplontersen use in hereditary transthyretin amyloidosis

ABSTRACT

Hereditary transthyretin amyloidosis is a progressive life-threatening disease characterized by deposition of abnormally folded amyloid fibrils into tissues leading to polyneuropathy and cardiomyopathy. Eplontersen, an antisense oligonucleotide has been FDA approved for the treatment of hereditary transthyretin amyloidosis with polyneuropathy in the United States. Eplontersen inhibits the translation of both variant and wildtype transthyretin in the liver, thereby preventing deposition in tissues. In the pivotal Phase III NEURO-TTRansform trial, Eplontersen significantly lowered serum transthyretin concentrations, improving neuropathic impairment and quality of life. Eplontersen was generally well tolerated in the treatment group, with the primary safety effects not significantly different from the control group. Eplontersen is suitable for long term use in patients with disease related polyneuropathy and is currently being studied for use in patients with cardiomyopathy. In this review, we discuss the clinical efficacy, mechanism of action, pharmacology, tolerability, and social determinants of health affecting the use of Eplontersen.

1. Introduction

Hereditary or variant transthyretin amyloidosis (ATTRv) is a rare autosomal dominant, life-threatening genetic disorder caused by a single-nucleotide mutation in the transthyretin gene [1,2]. The transthyretin gene encodes the tetramer protein of transthyretin (TTR), produced primarily in the liver and responsible for transporting thyroxine (thyroid hormone) and retinol (Vitamin A) [3,4]. Small amounts of TTR (< 10%) are also produced by the brain choroid plexuses and retinal pigment epithelium (RPE) of the eye [5,6]. This mutation leads to destabilization of the native TTR tetramer into misfolded monomers that self-assemble into amyloid fibrils. Destabilization of the TTR tetramer can also occur in the absence of genetic mutation in older individuals for unknown reasons leading to wildtype ATTR. Extracellular deposition of amyloid fibrils in various organs including the heart, peripheral and autonomic nerves, kidneys, and gastrointestinal tract causes deterioration and end organ impairment. This manifests primarily as a polyneuropathy and/or cardiomyopathy leading to significant sensorimotor disturbances, carpal tunnel syndrome, spinal stenosis, severe cachexia, nephropathy, autonomic dysfunction and cardiac dysfunction such as heart failure, arrythmias, or sudden cardiac death [7]. Abnormal deposition from the RPE lead to vitreous humor opacities causing blindness, while choroid plexus deposition in cerebrospinal fluid causes central nervous system manifestations [5,6]. Mixed phenotypes with both cardiomyopathy and neuropathy are the most common. The extent of each organ’s involvement is variable and depends on how early the disease is diagnosed and treated, as well as the specific mutation involved. The overall average life expectancy of untreated disease from symptom onset is 3 to 15 years [1,8]. Without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximal 5 years [1].

Hereditary amyloidosis affects about 1–9 per 1,000,000 individuals worldwide according to the Transthyretin Amyloidosis Outcomes Survey (THAOS database) [9]. More than 130 different inherited genetic variants in TTR exist [7,10]. The most common genetic variants in the United States (US) are the Val122Ile (isoleucine substituted for valine at position 122 of TTR protein), the Val30Met (methionine substituted for valine) and the Thr60Ala (alanine substituted for threonine) variants [11]. The Val122lle allele originates from West Africa and is present in 3% to 4% of African Americans [12]. It presents more frequently in the elderly with cardiomyopathy but may present earlier than other mutations with a more aggressive phenotype [10]. Worldwide, and in most European countries, the Val30Met mutation is the most prevalent hereditary mutation [1,13]. It is also the most common mutation associated in patients with ATTR polyneuropathy. Patients with Leu111Met (methionine substituted for leucine) mutation are most seen in Denmark while the Ile68Leu (Leucine substituted for isoleucine) is common in Italy. Both alleles typically present with an aggressive cardiomyopathy at a younger age [10].

Treatment of ATTRv has progressed rapidly over the past decade [7]. Liver transplantation historically was the best method to slow disease progression in patients with polyneuropathy. Diflunisal, a nonsteroidal anti-inflammatory drug approved for treatment of arthritis, was shown to slow the progression of neuropathy in patients with hereditary amyloidosis. However, its use was limited by cardiac, gastrointestinal, and renal side effects [14,15]. Recent advancement in gene therapy have led to multiple FDA (Food and Drug Administration) approved drugs. Patisiran, a small-interfering RNA (siRNA) was the first disease modifying agent approved for ATTRv polyneuropathy in the United States following results of the APOLLO-A trial [7,16]. This siRNA selectively binds to a genetically conserved sequence in the 3’-untranslated region of both mutant and wildtype TTR mRNA, leading to direct, sequence-specific degradation of TTR mRNA in the liver [17]. This was followed shortly by the approval of inotersen (NEURO-TTR Trial), an antisense oligonucleotide (ASO) in 2018 [18]. Vutrisiran a second-generation siRNA was studied in both wildtype and hereditary patients in the HELIOS-A/B trials and approved for use in polyneuropathy (2022) and cardiomyopathy (2025) [19,20]. Recently, the second generation ASO, Eplontersen was approved in 2023 for use in polyneuropathy after results of the NEURO-TTRansform Trial [21]. TTR tetramer stabilizers (Tafamidis and Acoramidis) were approved for use in cardiomyopathy, but not in polyneuropathy following results of the ATTR-ACT trial (2018) and the ATTRibute-CM (2024) [22,23]. In Europe, Tafamidis is approved for use in early-stage polyneuropathy. Other approaches currently under investigation include the use of CRISPR/Cas-9 gene editing technology with NTLA-2001 (MAGNITUDE-CM Trial, NCT06128629) which provides the advantage of administering a single drug dose. The use of monoclonal antibody amyloid depleter (ALXN2220) to deplete preexisting amyloid deposits in the heart (DEPLETTR-CM Trial, NCT06183931) is also being investigated [17].

Eplontersen (marketed as Wainua^TM) is an ASO currently FDA approved for the treatment of ATTRv polyneuropathy [21]. The drug is currently in Phase III trials for the treatment of cardiomyopathy (CARDIO-TTRansform Trial) [24]. This review discusses the pharmacological properties, clinical efficacy, tolerability, and social determinants of health affecting Eplontersen in the treatment of adults with ATTRv.

2. Mechanism of action

Eplontersen is a ligand-conjugated ASO meant to silence the TTR gene and lead to the degradation of the messenger RNA of both the wildtype and variant proteins in the liver [21]. The oligonucleotide sequence used is identical to that of its first-generation drug, inotersen, previously FDA approved for treatment of variant amyloidosis with polyneuropathy [18,25,26]. The ASO is conjugated to a ligand consisting of three N-acetyl galactosamine (GalNAc) residues. This ligand targets the drug to hepatocytes, through asialoglycoprotein receptor mediated uptake [25,27–29]. After endocytosis, the GalNAc moiety is metabolized and ASO is able to bind TTR mRNA [30]. ASOs work to reduce mRNA levels through multiple mechanisms, including recruitment of ribonucleases (RNases), splicing of pre-mRNAs to skip exons, and hindering mRNA function [31,32] (Figure 1). This decreases TTR production and reduces protein deposits in tissues, thereby slowing disease progression and improving neuropathy. This is the same conjugation used by Vutrisiran to enhance its stability and tolerability [19].

Figure 1.

Mechanism of action of Eplontersen.

Eplontersen is an antisense oligonucleotide conjugated to N-acetylgalactosamine (GalNAc). GalNac binds to hepatocyte asialoglycoprotein receptor and is endocytosed. Eplontersen is translocated into the nucleus where it binds with target mRNA of both wild-type transthyretin (WT-TTR) and variant transthyretin (TTRv). Drug-target complex leads to RNAse-mediated mRNA degradation. This causes less transthyretin protein (TTR) translation, thus leading to less unstable TTR monomers and less misfolded protein, decreasing systemic amyloid deposition.

3. Pharmacokinetics of Eplontersen

After subcutaneous administration, Eplontersen is absorbed with a time to maximum plasma concentration (Tmax) of 2 hours [33]. It binds highly to plasma proteins (> 98% with invitro studies) and is primarily distributed to the liver and kidney cortex. It is then metabolized in the liver by endo- and exonucleases into shorter oligonucleotide fragments [29,32,34]. The central volume of distribution is around 12 L, while the peripheral volume of distribution is estimated to be 11,100 L. Less than 1% of the drug dose is eliminated in urine within 24 hours of administration. The terminal elimination half-life is about 3-weeks, and no significant accumulation of drug was observed with monthly dosing. Eplontersen does not interact with cytochrome P450 enzymes and also does not interact with high plasma protein bound drugs, giving it a low potential of drug-to-drug interactions [32]. During its clinical trials, there was no clinically significant difference in drug pharmacology by age, body weight, sex, race or Val30Met variant status [33]. No dose adjustment is necessary for patients with mild to moderate renal impairment GFR $\ge$ 30, mild hepatic impairment (total bilirubin ≤ 1 × ULN and AST > 1 × ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST) or Age $\ge$ 65. The drug has not been studied in pediatric patients, pregnant or lactating patients, patients with moderate to severe hepatic impairment or prior liver transplant [35].

4. Pharmacodynamics of Eplontersen

During Phase 1 clinical studies, 45 mg (four doses total) subcutaneously of Eplontersen once every 4 weeks produced dose-dependent and prolonged decreases in TTR levels over time compared to placebo. The mean reduction in serum TTR at the lowest tested dose (45 mg) reduced TTR formation by 86%. These reductions were maintained up to three months after the last administered dose, supporting an infrequent dosing schedule. Dose dependent and prolonged reductions in retinol binding protein 4 also occurred. Therefore, vitamin A supplementation (about 3000 IU daily) is recommended for patients on eplontersen therapy [33,35] (Table 1).

Table 1.

Clinical comparison between eplontersen and Inotersen.

	Eplontersen	Inotersen
Nucleic Acid Sequence	Same	Same
N-acetylgalactosamine	Present	Absent
Route of Administration	Subcutaneous	Subcutaneous
Dosage	45 mg	284 mg
Dosing Schedule	Every 4 weeks	Every week
CYP Interactions	None	None
TTR Reduction	85%	74%
Co-administration	Daily allowance of Vitamin A	Daily allowance of Vitamin A
Complications	Injection site reactions Low vitamin A	Injection site reactions Low vitamin A Thrombocytopenia Glomerulonephritis Elevated Liver Enzymes Stroke or cervicocephalic arterial dissection
Safety Monitoring	Patients with ocular symptoms concerning for Vitamin A deficiency should be referred to an ophthalmologist	Weekly platelet count, Bi-Weekly UPCR/creatinine/eGFR/UA, Monthly Liver Function Test, Patients with ocular symptoms concerning for Vitamin A deficiency should be referred to an ophthalmologist

CYP Cytochrome P450 enzymes TTR Transthyretin UPCR Urine Protein Creatinine, eGFR estimated glomerulus filtration rate, UA Urinalysis.

Pharmacodynamics of GalNAc conjugation showed an increase in fraction of drug delivered to the liver, allowing for greater potency and lower dosage of drug administered compared to ASO alone (like Inotersen). This makes eplontersen about 30 to 50-fold more potent than inotersen based on their median effective doses (ED₅₀ values) [29,33,36,37]. Preferential uptake of ligand-conjugated drug into the liver was also demonstrated by mice models, further showing the improved pharmacodynamic profile compared with unconjugated models [33,38].

The initial pharmacokinetic and pharmacodynamic modeling of eplontersen showed that injection site and weight were two measures that impacted the pharmacokinetics. There was a 29.6% greater rate of absorption when injected into the abdomen compared to the arm, but this did not have statistically significant differences on TTR reduction [36]. There were slight differences in pharmacokinetics based on patient weight in simulations, but there was no difference in TTR reduction across all quartiles. Race was not found to have a significant impact [36].

5. Dosage and administration of eplontersen

During Phase 1 studies, dosing every 4 weeks and simulations of dosing every 8 weeks both achieved greater than 80% TTR reduction [33,36]. However, dosing every 4 weeks maintains greater TTR reduction compared to dosing every 8 weeks. TTR reductions were also maintained up to 3 months after receiving the last dose in the multi-dose cohort during the Phase 1 study of eplontersen [33].

The Eplontersen subcutaneous injection is packaged as a clear, colorless-to-yellow solution in a single-dose auto injection with a concentration of 45 mg/0.8 mL. The dose is administered as a monthly injection. If there is a missed dose, Eplontersen should be administered as soon as possible and the monthly interval resumed from the most recently administered dose. The dose is administered into the abdomen or upper thigh region. The back of the upper arm can also be used for injections if provided by a caregiver or healthcare provider. Patients should maintain adequate Vitamin A supplementation (3000 IU). Patients should see a specialist or ophthalmologist if they experience any ocular symptoms concerning for vitamin A deficiency [35].

6. Clinical efficacy of Eplontersen

Current evidence for the therapeutic efficacy of eplontersen in the treatment of ATTRv comes from the multinational, open-label, phase III NEURO-TTRansform trial, conducted between December 2019 and April 2023 [21]. This trial met significant improvement in all primary and secondary endpoints, as discussed in detail below. Findings from this study led to the FDA’s approval of eplontersen for the treatment of polyneuropathy associated with hereditary TTR amyloidosis (ATTRv-PN) in December 2023. Since the conclusion of this trial, there is an ongoing open-label extension (NCT05071300) scheduled for completion in 2029.

Eplontersen may also show efficacy in the management of hereditary TTR amyloidosis with cardiomyopathy (ATTRv-CM), though it is not currently FDA approved for this indication. ASO provide a targeted approach to treat ATTR cardiomyopathy by interfering with the production of abnormally folded TTR protein, preventing cardiac deposition and disease progression. Secondary analyses of the NEURO-TTRransform cohort explored the effects of eplontersen on echocardiographic parameters, showing improvement in left ventricular function and stroke volume after 65 weeks of treatment. Another study showed a significant decrease in volumetric heart and lung ratios when quantified using technecium-99 m-pyrophosphate single‐photon emission computed tomography [39,40]. There are several ongoing Phase III clinical trials, including the multinational CARDIO-TTRansform trial and the EPIC-TTR trial in China aimed at investigating the effects of eplontersen in hereditary and wildtype transthyretin cardiomyopathy. These studies are discussed in detail below.

Although Eplontersen was effective in reducing serum TTR concentrations, it is not known to have any effect on TTR produced by other organs, specifically the eye or brain. Progression of ocular involvement of ATTR has been reported in patients after liver transplantation despite the inability of plasma TTR to cross the blood-retina barrier suggesting ocular production of mutant TTR. A recent study showed that lipid-modified siRNAs are potent inhibitors of TTR expression in the eye when injected into the vitreous humor of mice [6]. This lipid modification has not been tried with ASOs, nor has this been tested in humans, but provides a potential strategy for treating ocular findings in ATTR. Patients receiving subcutaneous Eplontersen monotherapy may therefore present with long term ocular or central nervous system amyloid complications not currently appreciated in the current studies.

7. Efficacy in ATTRv-PN

The NEURO-TTRansform trial enrolled 168 adult patients, 144 were assigned to subcutaneous eplontersen (45 mg every 4 weeks, mean age 53.0 years; 69% male) and included 60 historical placebo patients (mean age 59.5 years; 68% male) from the NEURO-TTR trial, a phase III randomized-controlled clinical trial of inotersen with similar inclusion criteria and end points [18]. Eligibility criteria for NEURO-TTRansform included Coutinho stage 1 or 2 (ambulatory without or with assistance, respectively) ATTRv-PN, a documented TTR gene variant, and a neuropathy impairment score of 10–130 (scored from 0 to 244, high scores indicate worse function). Patients enrolled were aged 18 years to 82 years.

The efficacy end points were measured at week 65 or 66. The three primary endpoints included change from baseline serum TTR concentration, modified Neuropathy Impairment Score +7 (mNIS +7), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN). Secondary end points included Neuropathy Symptoms and Change total score (NSC), 36-item Short Form Survey physical component summary score (SF-36), Polyneuropathy Disability (PND) Score, and modified body mass index (mBMI, product of serum albumin concentration and BMI).

In the eplontersen-treatment arm, 136 (94.4%) completed follow up. In the placebo arm, 52 (86.7%) completed follow up. At week 65, mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference −70.4%, [95% CI, −75.2 to −65.7%]; p < 0.001). The mean change from baseline mNIS +7 was significantly improved with eplontersen versus placebo at week 66 (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6]; p < 0.001). Norfolk QoL-DN was also significantly improved in the eplontersen arm versus placebo (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; p < 0.001) (Table 2).

Table 2.

Efficacy of eplontersen in the treatment of ATTRv-PN.

	Eplontersen Group (n = 144)	Historical Placebo (n = 60)	Difference
Primary Endpoints
Change in serum transthyretin concentration	−81.7%	−11.2%	−70.4%, [95% CI, −75.2 to −65.7%]; p < 0.001
mNIS +7 Score	0.3	25.1	24.8 [95% CI, −31.0 to −18.6]; p < 0.001
Norfolk QOL-DN Score	−5.5	14.2	−24.8 [95% CI, −31.0 to −18.6]; p < 0.001
Secondary Endpoints
NSC Score	−0.03	8.2	−8.2 [95% CI, −10.7 to − 5.8]; p < .001
SF-36 Score	0.9	−4.5	5.3 [95% CI, 3.2–7.4]; p < .001
mBMI	−8.1 kg/m2 × g/L	−90.8 kg/m2 × g/L	82.7 kg/m2 × g/L [95% CI, 54.6–110.8]; p < .001

Data from the Phase III NEURO-TTRansform Trial. Polyneuropathy disability scores not included here. Treatment arm given 45 mg subcutaneous eplontersen every 4 weeks. Endpoints measured at weeks 65/66.

ATTRv-PN hereditary transthyretin amyloidosis with polyneuropathy; mNIS7+, modified Neuropathy Impairment Score + 7; QOL-DN, Quality of Life Questionnaire-Diabetic Neuropathy; NSC, neuropathy symptom and change total score; SF-36, Short Form Survey physical component summary score; mBMI, modified body mass index.

Regarding secondary endpoints, the difference between eplontersen and historical placebo in NSC score at week 66 was −8.2 (95% CI, −10.7 to −5.8; p < 0.001). SF-36 score at week 65 was improved by 5.3 (95% CI, 3.2–7.4; p < 0.001) when compared to placebo. The proportion of patients who could walk without assistance (PND score stage 1) were unchanged from baseline for the Eplontersen group (39.6%) but decreased from 37.3% to 29.4% in the historical placebo group. The proportion of patients with PND score stage IIIb (walking with two sticks or crutches) decreased slightly in the Eplontersen group (6.7% to 6.0%) but increased in the placebo group (5.9% to 11.8%) at week 65 compared to baseline. The change in mBMI at week 65 was an increase of 82.7 kg/m² x g/L (95% CI, 54.6–110.8; p < 0.001) in the treatment group versus historical placebo (Table 2).

In addition to meeting statistical significance, the degree of change of end points in NEURO-TTRansform met clinical significance. Investigators set to establish changes in neuropathic impairment and quality of life that are clinically meaningful to patients with ATTRv-PN using anchor-based method to define the minimal important clinical difference [41]. Clinically meaningful improvement in mNIS +7 was estimated at −4.0, Norfolk QoL-DN were estimated at −12.8 to −4.0 points, NSC was estimated at −2.4 to −1.3 points, and mBMI was estimated at 9.8 kg/m² x g/L. All the end points met clinical significance as defined by the investigators (Table 2).

Wixner et. al. published secondary analysis of the NEURO-TTRansform trial that analyzed the primary endpoints until end-of-treatment date at week 85, revealing sustained improvements of the primary endpoints [42]. In addition, the study examined improvement in markers of autonomic dysfunction through the Composite Autonomic Symptom Score-31 (COMPASS-31) tool. This is a 31-item questionnaire evaluating symptoms of dysautonomia in 6 categories: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor. The tool was administered at weeks 37 and 81, showing a mean improvement of 2.6 points at week 81. Due to being absent from the NEURO-TTR trial, there was no placebo-control for COMPASS-31 score. The authors note that control-arms of other ATTRv-PN trials have shown worsening COMPASS-31 scores, suggesting that the natural history of ATTRv-PN involves progressive worsening of autonomic symptoms. For example, the APPOLO trial of Patisiran demonstrated worsening of COMPASS-31 score by 2.2 points at 81 weeks in the control group [16]. HELIOS-A study of vutrisiran did not include COMPASS-31 as an outcome [19].

While initial results are encouraging, several limitations of the NEURO-TTRansform trial must be acknowledged. The use of a historical placebo group introduces potential bias through multiple mechanisms. Changes in the standard of care over time may have improved background management, potentially exaggerating the apparent benefit of the investigational drug. The absence of randomization with a contemporaneous control arm also raises concerns about residual confounding and unmeasured variables, which can lead to unpredictable bias. Furthermore, the trial lacks hard clinical endpoints such as hospitalizations and mortality, likely due to the relatively small sample size and limited duration of follow-up in this rare disease population. Continued investigation through ongoing and future studies will be essential to fully characterize the efficacy and long-term impact of this therapy.

8. Efficacy in ATTRv-CM

While there are currently no published clinical trials examining the efficacy of eplontersen in the management of ATTRv-CM, investigators have analyzed a small subset (N = 49, 34%) of patients in the NEURO-TTRansform eplontersen treatment arm with ATTRv-CM who have polyneuropathy.

Work by Masri et al. sought to explore the effects of eplontersen on echocardiographic measures of the heart [39]. This study compared 49 patients from NEURO-TTRansform against a subset of the NEURO-TTR historical placebo group with concomitant cardiomyopathy (N = 30, 50%). Results were adjusted for age, sex, region, baseline value, ATTRv disease stage, previous treatment, and Val30Met variant. At week 65, they analyzed echocardiographic parameters including ejection fraction, end-diastolic volume, end-systolic volume, stroke volume, lateral early diastolic myocardial velocity, mean LV wall thickness, left atrial volume, global longitudinal strain, lateral E/e,’ and LV mass. While all echocardiographic measures favored improvement in eplontersen treatment arm, statistical significance was reached only with the ejection fraction (+4.30% in treatment arm, [95% confidence interval: 1.40–21.01; p = 0.049]), and stroke volume (+10.64 mL [95% confidence interval: 3.99–17.29; p = 0.002]) [39]

Another retrospective analysis of the NEURO-TTRansform cohort was done by Yu et al. evaluating change in technetium-99 m-pyrophosphate cardiac uptake in response to eplontersen [40]. Inclusion criteria included patients with symptoms of heart failure or noninvasive diagnostic evidence of amyloid cardiomyopathy such as intraventricular septal wall thickness >12 mm without another cause of hypertrophy, and a pretherapeutic technetium-99 m-pyrophosphate scan showing myocardial enhancement with a visual score >2 and planar heart to contralateral lung ratio >1.3. Exclusion criteria included patients with light chain disease, patients who died or were lost to follow-up within 1 year, or patients without complete baseline and follow-up imaging. Thirteen patients were enrolled, 6 received eplontersen and 7 in the control group. The median follow-up time was 544 days. The eplontersen group showed a clinically significant reduction in volumetric heart and lung ratio (3.774 to 2.979, p = 0.028), whereas the control group showed no significant change (4.079 to 3.915, p = 0.237). Furthermore, the eplontersen group showed a significantly greater reduction in volumetric heart and lung ratio compared to the control group. (−20.7% vs −3.4%, p = 0.007).

These findings suggest the potential efficacy of eplontersen, and to a greater extent, ASO in treating both ATTRv-CM and ATTRwt-CM. Inotersen, for example, showed promising cardiac effects in patients with ATTRv-CM in smaller studies/subgroup analysis. In a small single-center analysis by Dasgupta et al., 33 subjects with variant or wildtype ATTR-CM were treated with inotersen (300 mg, weekly, subcutaneous injections). After 2 years, the mean left ventricular mass decreased by 8.4% by cardiac Magnetic Resonance Imaging (CMR) and exercise tolerance increased by 20.2 meters by the 6-minute walk test [43]. This suggests the potential long-term effects of ASO in inhibiting progression and potentially reversing amyloid burden. In another recently published study, a metanalysis of nine randomized controlled trials involving 2713 patients, the effects of specific therapies in amyloid cardiomyopathy were investigated. TTR specific therapies were associated with a significant reduction in all-cause mortality (RR 0.7, 95% confidence interval: 0.6–0.8; p < 0.01) with both TTR stabilizers and gene knock-down therapies showing equally effective reductions (p = 0.97). TTR specific therapies improved LV longitudinal strain (Standardized Mean Difference −0.22; 95% confidence interval −0.34 to −0.10; p < 0.01) and reduced LV mass (Standardized Mean Difference −9.11; 95% confidence interval −16.4 g to −1.84, p = 0.01). There was no significant difference in cardiovascular mortality, all cause hospitalization or HF hospitalization between TTR specific therapies and placebo [44]. Patisiran was investigated in the APPOLO-B trial and showed statistical improvement in the 6-minute walk test and the Kansas City Cardiomyopathy Questionnaire. At 12 months, there was not a statistically significant benefit in the composite secondary endpoint of all-cause mortality, cardiovascular events, and change from baseline in 6-minute walk test. Patisiran was not approved by the FDA for ATTR-CM due to insufficient data to prove clinical meaningfulness. Vutrisiran was FDA approved after HELIOS-B trial results for use in cardiomyopathy in patients with wildtype and hereditary amyloidosis.

The ongoing CARDIO-TTRansform Trial (NCT04136171) is a Phase III, multicenter, double-blind randomized, placebo-controlled trial aimed at investigating the safety and efficacy of Eplontersen use in patients with wildtype and hereditary ATTR-CM. It has finished enrolling patients, totaling 1438 participants making it the largest study in this patient population to date and is scheduled to conclude before the end of 2026. The investigational dose is 45 mg every 4 weeks subcutaneously plus daily Vitamin A supplementation. The primary outcome is cardiovascular mortality and recurrent cardiovascular clinical events up to week 140 [24]. In addition, the CMR subgroup analysis has enrolled 157 patients from the CARDIO-TTRansform trial to measure the change in amyloid burden by utilizing CMR with extracellular volume mapping, and echocardiography with strain analysis to tract changes in cardiac structure and function. A sub study from the CMR subgroup analysis will utilize scintigraphy to analyze amyloid deposition in the heart [45].

EPIC-TTR (NCT06194825) is another phase III clinical trial currently ongoing and scheduled to end in 2027. It is a randomized controlled, double-blind and placebo-controlled trial in China, also investigating the effects of Eplontersen on the reduction of TTR in patients with hereditary and wildtype cardiomyopathy. The initial study duration is 24 weeks, followed by an 80-week open-label extension. The primary outcome measure is percent change of serum TTR concentration from baseline after 24 weeks. The secondary outcomes include changes from baseline in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin T (hs-cTnT), changes in plasma concentrations of eplontersen at specific time-points and changes in plasma concentrations of anti-drug antibodies at specific time points. Sixty-four patients are currently enrolled, and recruitment is completed.

Wildtype patients with cardiomyopathy commonly have neuropathy. While there are no clinical trials that have looked at improvement in neuropathy in wildtype patients with cardiomyopathy, there could be potential benefit from treatment with gene silencers.

9. Tolerability and side Effects

Subcutaneous eplontersen is generally well tolerated. In contrast to similar in-class medications such as inotersen, eplontersen is conjugated to a ligand that target the drug to hepatocytes, which are the primary TTR producers in the body [46]. This allows for lower dosage of eplontersen needed for efficacy and current data suggests improved safety when compared with inotersen [29]. TTR is a transport of vitamin A-retinol binding complexes, explaining the vitamin A-deficiency seen in TTR gene silencing medications [21].

Most of the available eplontersen safety data stems from the NEURO-TTRansform trial. All patients in the treatment arm were required to supplement with 3000 IU vitamin A. Adverse events of special interest include thrombocytopenia, glomerulonephritis, and vitamin A-deficiency related ocular events as these required special monitoring during treatment with inotersen. Thrombocytopenia was seen in only 2% of patients, similar to the incidence in the historical placebo group, and did not require discontinuation of the medication. Glomerulonephritis was not seen in the treatment arm. As a result, thrombocytopenia and glomerulonephritis do not require monitoring with Eplontersen treatment. Ocular events were reported in 17% of patients in the eplontersen group compared to 15% of patients in the historical placebo group. No patients experienced an ocular event that was attributed to vitamin A deficiency after evaluation by an ophthalmologist.

The most reported adverse events of eplontersen include vitamin A deficiency (15%), followed by vomiting (9%), proteinuria (8%), injection site reactions (7%), blurry vision (6%), and cataracts (6%). Atrioventricular block occurred in 2% of patients, including one case of complete heart block. Two deaths were reported in the eplontersen group (cardiac arrhythmia, intracerebral hemorrhage) however these deaths were attributed to ATTRv and not related to the study drug. Long-term tolerability and side effects will be released in the long-term extension of the NEURO-TTRansform study (NCT05071300).

10. Social determinants of health affecting eplontersen use

African Americans (AA) or Black Americans have a disproportionately higher prevalence of amyloid cardiomyopathy compared to White Americans. Specifically, the Val122lle (valine to isoleucine) allele is known to be present in 50% of Black people with biopsy confirmed amyloid and has been estimated to be present in 3%−4% of AA in the United States [47,48]. In addition, ATTRv has been found in >10% of Black people older than 65 years of age with severe congestive heart failure, and the Compass Genetic Testing Program identified a pathogenic TTR variant in 19.4% of black patients [11,49,50]. However, Black people remain underrepresented in many of the large clinical therapeutic trials. This makes it difficult to ascertain the true safety and effectiveness of therapies in this patient population. The NEURO-TTRransform trial only enrolled 3% of AA in both treatment and control groups and the NEURO-TTR trial for inotersen enrolled 2% AA. Similarly, most of the other major drug investigation trials included <10% of AA in the study population (Table 3). In addition, participants were frequently enrolled from the Americas, Europe, Asia, Australia, but rarely from Africa, despite current evidence linking the origin of the Val1222lle variant to West Africa. A recent systematic epidemiologic review of TTR amyloidosis reported no studies that exclusively focused on ATTR amyloidosis in Africa or South America [8]. This regional disconnect further contributes to the disparity in study population. With respect to gender differences, female sex only accounted for about a third of the study participant in most of the major studies (Table 3). The Clinical Trials Transformation Initiative (CTTI), a member-based group dedicated to modernizing clinical trials and disseminating best practices for trial design, has provided some recommendations for improving diversity in clinical trials. Some of these recommendations include building bidirectional community partnerships that inform the creation of research strategies and formation of diverse clinical trial programs. Engaging patients and caregivers at all stages of medical product development, prioritizing equitable access to care, prioritizing inclusion of diverse populations into trials, hiring dedicated personnel and developing data driven approaches to identify needs and interest of diverse populations impacted by disease [51].

Table 3.

Socioeconomic disparities affecting use of selected ATTR therapies.

Drug Trial	Drug	Mechanism	Number of Participants	Percent of women	Percent of African Americans	Estimated Cost Per Year
NEURO-TTR	Inotersen	ASO	172	31.0%	2.0%	$370,000
NEURO-TTRansform	Eplontersen	ASO	168	32.0%	3.0%	$570,000
APOLLO-A	Patisiran	siRNA	225	26.0%	2.0%	$451,000
APOLLO-B	Patisiran	siRNA	360	10.0%	9.0%	$451,000
HELIOS-A	Vutrisiran	siRNA	164	35.4%	4.9%	$477,000
HELIOS-B	Vutrisiran	siRNA	655	8.0%	7.0%	$477,000
ATTR-ACT	Tafamidis	TTR Stabilizer	441	8.7%	14.0%	$261,000
ATTRibute-CM	Acoramidis	TTR Stabilizer	632	9.8%	4.7%	$244,000
Berk et al.	Diflunisal*	TTR Stabilizer	130	32.8%	1.6%	$600

ASO Antisense oligonucleotides, siRNA small interfering ribonucleic acid TTR Transthyretin.

*Not FDA approved for use in transthyretin amyloidosis.

Another major concern is the cost and socioeconomic impact of affording medical treatment with Eplontersen and other TTR gene therapies. Currently, the annual out of pocket cost per patient for treatment with eplontersen is about $570,000 in the US. The cost for a single dose (subcutaneous injection) is about $45,000. This cost is similar to vutrisiran ($477,000) and patisiran ($451,430 to $677,145 depending on patient’s weight (Canadian study)), with patients expected to pay between $1083–$1250 in monthly co-pays [52]. These estimates do not include other costs associated with in-clinic infusion of patisiran and pre-infusion drugs like dexamethasone, acetaminophen, diphenhydramine, and ranitidine [53]. Inotersen has an annual cost estimated at $370,000, and this also does not include drug monitoring cost such as monthly blood tests (complete blood count, renal function test) [54]. The relatively well established tafamidis has a list price of $225,000 per year with a mean monthly out of pocket cost of $250 ($39 - $1763) [53,55]. Of note, inotersen is no longer manufactured for market in the US and not comemercially available as of September 2024.

Affordability is an issue and the actual cost per patient depends on their insurance status, type of insurance, copays, coinsurance and deductibles. AstraZeneca has a patient assistance program for eplontersen called AstraZeneca Access 360^TM for Wainua^TM (Wainua^TM Savings Program) which covers copays for eligible patients [56]. However, patients are required to have private insurance with a copay and need to be enrolled by their healthcare provider. In 2025, Medicare began offering a Medicare prescription payment plan for Medicare drug plans which limits the annual patient out of pocket expenses for formulary medications to $2000, and may reduce the out-of-pocket expenses for some patients [57]. The cost of medications can affect patient outcomes; higher cost of medical care in patients with ATTRv-CM has been shown to be associated with shorter life expectancies and therefore presents a significant barrier to patient care [58]. More drug ascertainment studies are needed to identify the true pharmacoeconomic impact of these newer generation drugs.

Social and community support systems are essential in the management of ATTRv. In patients with advanced neuropathy, self-administration of eplontersen might be difficult, requiring the assistance of caregivers. Similarly, presence of support groups and community resources for rare diseases can provide valuable information. Lack of adequate social and emotional support can impact treatment accessibility and duration. Barriers to genetic testing in clinical practice also exist and include lack of knowledge about genetic testing, type of health insurance coverage, access to care and testing locations [11]. Other factors like diagnostic delays, lack of specialized treatment centers, clinical inertia, poor education and health literacy can affect equitable access to Eplontersen [49]. Addressing these social determinants of health is crucial for improving outcomes in all patients with ATTRv [59].

Funding Statement

This paper was not funded.

Article highlights

• Eplontersen is a ligand conjugated antisense oligonucleotide FDA approved for the treatment of transthyretin amyloidosis with polyneuropathy.

• Phase III NEURO-TTRansform trial: Eplontersen significantly reduced serum transthyretin levels, improved neuropathic impairment scores, and enhanced quality of life compared to placebo. 

• CARDIO-TTRansform Trial and EPIC-TTR Trial are currently ongoing and are investigating the effectiveness of Eplontersen in transthyretin amyloidosis with cardiomyopathy.

• Eplontersen is well tolerated when administered with Vitamin A supplementation. Routine laboratory monitoring is not recommended, but long-term safety data is pending.

• Underrepresentation of minority populations in clinical trials and high cost of medications are some barriers to equitable access to care.

Author contribution

All authors contributed equally to this manuscript.

Disclosures statement

Dr. Dasgupta has participated in research studies with Ionis, AstraZeneca, Alexion, Eidos, Alnylam, and Intellia. Dr. Dasgupta has served as a consultant for Pfizer, Ionis, AstraZeneca, Eidos/BridgeBio, Alnylam, and Novo Nordisk.