WAINUA is indicated for the treatment of adult patients with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis (ATTRv). 

Treatment should be prescribed and supervised by a treating physician knowledgeable in the management of patients with amyloidosis.

Posology   

The recommended dose of WAINUA is 45 mg administered by subcutaneous injection. Doses should be administered monthly.

Missed dose 

If a dose of eplontersen is missed, then the next dose should be administered as soon as possible. Resume dosing at monthly intervals from the date of the last dose.

Special populations

Renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥45 to <90 mL/min/1.73 m²) (see section 5.2). WAINUA has not been studied in patients with eGFR<45 mL/min/1.73 m² or end-stage renal disease. 

Hepatic impairment

No dose adjustment is necessary in patients with mild hepatic impairment (see section 5.2). WAINUA has not been studied in patients with moderate or severe hepatic impairment. 

Elderly population

No dose adjustment is required in elderly patients (≥65 years of age) (see section 5.2). 

Paediatric population

The safety and efficacy of WAINUA in children and adolescents below 18 years of age have not been established. No data are available.

Method of administration 

Subcutaneous use only.

The first injection administered by the patient or caregiver should be performed under the guidance of an appropriately qualified health care professional. Patients and/or caregivers should be trained in the subcutaneous administration of WAINUA.

The autoinjector should be removed from refrigerated storage at least 30 minutes before use and allowed to reach room temperature prior to injection. Other warming methods should not be used.

Inspect solution visually before use. The solution should appear colourless to yellow. Do not use if cloudiness, particulate matter or discolouration is observed prior to administration.

If self-administered, inject WAINUA in the abdomen or upper thigh region. If a caregiver administers the injection, the back of the upper arm can also be used.

Comprehensive instructions for administration are provided in the ‘Instructions for Use’.

Reduced Serum Vitamin A Levels and Recommended Supplementation   

Based on the mechanism of action, WAINUA is expected to reduce serum vitamin A (retinol) below normal levels (see section 5.1).

Any symptoms or signs related to vitamin A deficiency should be evaluated prior to initiation of treatment with WAINUA.

Patients receiving WAINUA  should take oral supplementation of the daily recommended dose of vitamin A to reduce the potential risk of ocular symptoms due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms consistent with vitamin A deficiency, including reduced night vision or night blindness, and persistent dry eyes.

It is not known whether vitamin A supplementation in pregnancy will be sufficient to prevent vitamin A deficiency if the pregnant female continues to receive WAINUA  (see section 4.6). However, increasing vitamin A supplementation to above the daily recommended dose during pregnancy is unlikely to correct serum retinol levels due to the mechanism of action of eplontersen and may be harmful to the mother and foetus.

No formal clinical drug-drug interaction studies have been performed (see section 5.2). 

Women of child-bearing potential

WAINUA will reduce the plasma levels of vitamin A, which is crucial for normal foetal development. It is not known whether vitamin A supplementation will be sufficient to reduce the risk to the foetus. For this reason, pregnancy should be excluded before initiation of WAINUA therapy and women of child-bearing potential should practise effective contraception.

If a woman intends to become pregnant, WAINUA and vitamin A supplementation should be discontinued, and serum vitamin A levels should be monitored and have returned to normal before conception is attempted. Due to the long half-life of eplontersen (see section 5.2), a vitamin A deficit may develop even after cessation of treatment.

Contraception in males and females

Women of child-bearing potential should practise effective contraception.

Pregnancy

There are no data regarding the use of WAINUA in pregnant women.   

Administration of eplontersen or a pharmacologically-active rodent-specific surrogate at doses up to 38‑fold higher than the recommended human dose in a combined fertility and embryo-foetal development toxicity study in mice did not result in effects on male and female fertility or embryo‑foetal development (see section 5.3).   

Due to the potential teratogenic risk arising from unbalanced vitamin A levels, WAINUA should not be used during pregnancy. In case of pregnancy, close monitoring of the foetus and Vitamin A status should be carried out, especially during the first trimester.

Breast-feeding

Human or animal lactation studies have not been conducted to assess the presence of eplontersen or it’s metabolites in breast milk, the effects on the breastfed infant, or the effects on milk production for the mother. A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from WAINUA therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There is no information available on the effects of eplontersen on human fertility.

Administration of eplontersen or a pharmacologically-active rodent-specific surrogate in doses up to 38‑fold higher than the recommended human exposure in mice did not indicate any impact of eplontersen on male or female fertility. 

WAINUA has no or negligible influence on the ability to drive and use machines. 

Overall summary of the safety profile

The safety data described below reflects exposure to WAINUA in 144 patients with polyneuropathy caused by ATTRv (ATTRv-PN) randomised to WAINUA and who received at least one dose of WAINUA . Of these, 141 patients received at least 6 months of treatment and 137 patients received at least 12 months of treatment. The mean duration of treatment was 541 days (range: 57 to 582 days). 

The most frequent adverse reactions during treatment with WAINUA observed in ≥5% of patients were vomiting, and vitamin A decreased.   

Adverse Drug Reactions

Adverse drug reactions (ADRs) are organised by MedDRA System Organ Class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from available data).

Table 1: Summary of Adverse Reactions per Frequency Category

Description of selected adverse reaction

Vitamin A decreased

In the clinical study in patients with ATTRv-PN, all patients were instructed to take the recommended daily allowance of vitamin A. All patients treated with WAINUA had normal vitamin A levels at baseline, 96.5% of those developed vitamin A levels below the lower limit of normal (LLN) during the study (see section 5.1). 

Injection site reactions

In patients with ATTRv-PN treated with WAINUA, injection site erythema, injection site pain and injection site pruritus were reported in 3.5%, 3.5%, and 2.1% respectively. 

To report any side effect(s):

• Saudi Arabia:

·    Other GCC States:

-     Please contact the relevant competent authority.

There is no specific treatment for an overdose with eplontersen. In the event of an overdose, supportive medical care should be provided including consulting with a healthcare professional. 

Pharmacotherapeutic group: other nervous system drugs, ATC code: N07XX21

Mechanism of action

Eplontersen is a GalNAc conjugated 2′-O-2-methoxyethyl (2′-MOE)-modified chimeric gapmer antisense oligonucleotide (ASO) with a mixed backbone of phosphorothioate (PS) and phosphate diester (PO) internucleotide linkages. The GalNAc conjugate enables targeted delivery of the ASO to hepatocytes. The selective binding of eplontersen to the TTR messenger RNA (mRNA) within the hepatocytes causes the degradation of both mutant and wild type (normal) TTR mRNA. This prevents the synthesis of TTR protein in the liver, resulting in significant reductions in the levels of mutated and wild type TTR protein secreted by the liver into the circulation.

TTR is a carrier protein for retinol binding protein 4 (RBP4), which is the principal carrier of vitamin A (retinol). Therefore, a reduction in plasma TTR is expected to result in the reduction of plasma retinol levels to below the lower limit of normal. 

Pharmacodynamics

In the clinical study in patients with ATTRv-PN receiving eplontersen, a decrease in serum TTR concentrations was observed at the first assessment (Week 5), and TTR concentrations continued to decrease through Week 35. A sustained reduction of TTR concentration was observed throughout the duration of the treatment (85 weeks). Mean (SD) for serum TTR percent reduction from baseline was 82.1% (11.7) at Week 35, 83.0% (10.4) at Week 65 and 81.8% (13.4) at Week 85 when treated with eplontersen. Similar reduction from baseline in serum TTR concentrations compared to placebo was observed regardless of sex, race, age, region, body weight, cardiomyopathy status, previous treatment, Val30Met mutation status, disease stage, and familial amyloid cardiomyopathy (FAC) clinical diagnosis at baseline (Figures 1a and b). 

Figure 1: Forest Plot of Treatment Difference in LSM for Percent Change from Baseline in TTR (g/L) for Key Subgroups (NEURO-TTRansform Study) (full analysis set)

a) at Week 35 

* External placebo group from another randomised controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

Based on MMRM adjusted by propensity score weights with categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline and the baseline-by-time-interaction.

Subgroup models also included treatment-by-subgroup, time-by-subgroup, and treatment-by-time-by-subgroup interactions. Only data up to Week 35 are included in the Week 35 interim analysis.

CM subgroup includes patients with either diagnosis of FAC at study entry or baseline IV septum wall thickness ≥ 13 mm with no hypertension [history or diagnosis during the study].

The Week 35 LSM treatment difference (WAINUA  – Placebo) with 95% CI (unadjusted) are presented.

CI = Confidence interval; LSM = Least squares mean; MMRM = Mixed effects model with repeated measures; TTR = Transthyretin, CM = cardiomyopathy, FAC = familial amyloid cardiomyopathy.

b) at Week 65 

* External placebo group from another randomized controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

Based on MMRM adjusted by propensity score weights with categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline and the baseline-by-time-interaction.

Subgroup models also included treatment-by-subgroup, time-by-subgroup, and treatment-by-time-by-subgroup interactions.

CM subgroup includes patients with either diagnosis of FAC at study entry or baseline IV septum wall thickness ≥ 13 mm with no hypertension [history or diagnosis during the study].

The Week 65 LSM treatment difference (WAINUA  – Placebo) with 95% CI (unadjusted) are presented.

CI = Confidence interval; LSM = Least squares mean; MMRM = Mixed effects model with repeated measures; TTR = Transthyretin, CM = cardiomyopathy, FAC = familial amyloid cardiomyopathy

Cardiac Electrophysiology

Formal QTc studies have not been conducted with WAINUA . The potential for QTc prolongation with eplontersen was evaluated in a randomised, placebo-controlled trial in healthy volunteers. At a dose 2.7 times the recommended dose of 45 mg eplontersen, no clinically relevant effect on the QT interval was observed. 

Immunogenicity

In the clinical study in patients with ATTRv-PN, after an 84‑week treatment period (median treatment duration 561 days (80 weeks), range 57 to 582 days), 58 patients (40.3%) developed treatment-emergent anti-drug antibodies (ADAs).   

In the patients who tested positive for anti-eplontersen antibodies, there was no clinically meaningful impact on the efficacy, safety, pharmacokinetics, or pharmacodynamics of WAINUA . 

Clinical efficacy

The efficacy and safety of WAINUA  was evaluated in a randomised, multicentre, open-label, externally-controlled trial (NEURO-TTRansform) that included a total of 168 patients with ATTRv‑PN. Patients were randomised in a 6:1 ratio to receive subcutaneous injection every 4 weeks with WAINUA  45 mg (N=144) or weekly inotersen 284 mg (N=24) as a reference group. Of the 144 patients randomised to eplontersen, 140 (97.2 %) patients completed treatment through Week 35, 135 (93.8%) completed treatment through Week 65 and 130 (90.3%) completed treatment through Week 85. 

An external placebo control consisted of a placebo cohort of patients from the inotersen pivotal study: randomised, double-blind, placebo-controlled, multicentre clinical trial in adult patients with ATTRv-PN (NEURO-TTR). That cohort received subcutaneous injections of placebo once weekly. Both studies employed identical eligibility criteria.

The characteristics of the eplontersen and external placebo groups were generally similar, and potential imbalances in key baseline characteristics (age, Val30Met mutation status, disease stage and previous treatment) were accounted in the prespecified statistical analysis. Baseline demographic and disease characteristics are shown in Table 2.

Table 2 Baseline Demographics and Disease Characteristics in NEURO-TTRansform  Study (safety set)   

^*  External placebo group from another randomised controlled trial (NEURO-TTR).

¹ Disease stage is defined as stage 1 = does not require assistance with ambulation and stage 2 = requires assistance with ambulation.

² Includes the genotypes V30M, V50M, V50M MUTATION, VAL50MET, and P.VAL50MET.

³ Based on clinical database. Non Val30Met mutations included: GLU89GLN, LEU58HIS, PHE64LEU, SER50ARG, SER77TYR, THR49ALA, THR60ALA, VAL122LLE and other (including ALA97SER).

⁴ Familial amyloid cardiomyopathy = Hereditary transthyretin-mediated amyloidosis with cardiomyopathy (ATTRv-CM).

⁵ Denominator for the percentage calculation is the number of patients diagnosed with FAC.

Only year and months were collected from the informed consent date to calculate disease duration from diagnosis and from onset of symptoms of ATTRv-PN, FAC.

N=number of patients in the safety set; n=number of patients in a subgroup, m=number of patients with non-missing data if different from N, CRF=case report form; NT-proBNP= N-terminal proB-type natriuretic peptide; SD=standard deviation.

Week 35 analyses (interim analysis)

The primary efficacy endpoints were the change from baseline to Week 35 in serum transthyretin (TTR) concentration (see Figure 2) and in the modified Neuropathy Impairment Score + 7 (mNIS+7) composite score. The mNIS+7 composite score is an objective assessment of neuropathy and comprises the NIS and Modified +7 composite scores. In the version of the mNIS+7 composite score used in the trial, the NIS objectively measures deficits in cranial nerve function, muscle strength, reflexes, and sensations, and the Modified +7 assesses heart rate response to deep breathing, quantitative sensory testing (touch-pressure and heat-pain), and peripheral nerve electrophysiology. The validated version of the mNIS+7 composite score used in the trial had a range of ‑22.3 to 346.3 points, with higher scores representing a greater severity of disease.   

The secondary endpoint was the change from baseline in the Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) questionnaire total score. The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fibre neuropathy, activities of daily living, symptoms, small fibre neuropathy, and autonomic neuropathy. The version of the Norfolk QoL-DN total score that was used in the trial had a range from -4 to 136 points, with higher scores representing greater impairment. 

WAINUA  showed statistically significant improvement compared to external placebo control at Week 35 in reducing serum TTR with percent change of ‑66.43% (95%CI: ‑71.39%, ‑61.47%; p<0.0001) (see Figure 2). WAINUA  showed statistically significant improvement compared to external placebo control at Week 35 for mNIS+7 composite score with LSM difference of ‑9.0 (95%CI: ‑13.5, ‑4.5; p<0.0001) (see Figures 3, 4a, 7a). WAINUA  showed statistically significant improvement compared to external placebo control at Week 35 for Norfolk QoL-DN total score with LSM difference of ‑11.8 (95%CI: ‑16.8, ‑6.8; p<0.0001) (Table 3 and Figures 5, 6a, 8a). 

Week 65/66 (final analysis)

The co-primary endpoints for the primary objective at the final analysis at Week 66 included percent change from baseline in serum TTR concentration at Week 65, change from baseline in mNIS+7 composite score at Week 66 and change from baseline in Norfolk QoL-DN total score at Week 66. At Week 65, the serum TTR concentration reduction was sustained. In addition, the results at Week 66 for the mNIS+7 composite and Norfolk total scores were all consistent with Week 35 results (see Table 3 and Figures 3, 4b, 5, 6b).

The secondary endpoints were change from baseline in neuropathy symptoms and change (NSC) at Weeks 66 and 35, change from baseline in the physical component score (PCS) score of short form 36 item health survey (version 2) (SF-36) at Week 65, change from baseline in polyneuropathy disability (PND) score at Week 65, and change from baseline in modified body mass index (mBMI) at Week 65.

The NSC was a patient-answered questionnaire to quantify the type, distribution, and severity of muscle weakness, sensory symptoms, pain symptoms, and autonomic symptoms. Higher scores represent worse symptoms.

The SF-36 PCS included 4 scales assessing physical function, role limitations caused by physical problems, bodily pain, and general health. Higher scores represent better physical health.

The PND categorises disability by mobility (e.g., need for stick, crutch, wheelchair, or bed). Higher PND score represents worse disability. 

Modified BMI (BMI × serum albumin) is an acceptable method of assessing nutritional status in ATTR. Higher scores represent better nutritional status and is considered to be an indicator of longer survival in ATTRv-PN patients.   

All secondary endpoints showed statistically significant superiority to external placebo (see Table 4).

Table 3 Treatment Effect for the Primary and Key Secondary Endpoints (NEURO-TTRansform Study) (full analysis set) 

* External placebo group from another randomised controlled trial (NEURO-TTR).

¹ Based on a MMRM adjusted by propensity score weights with fixed categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30M mutation, previous treatment, and fixed covariates for the baseline value and the baseline-by-time interaction. Only data up to Week 66 are included in the Week 66 analysis.

² Based on an ANCOVA model adjusted by propensity score with the effects of treatment, disease stage, Val30M mutation, previous treatment, and the baseline value. Only data up to Week 35 are included in the interim analysis.

³ Participants with a missing mNIS+7 or Norfolk QoL-DN at Week 35 had value multiply imputed using an imputation model. Each of 500 imputed data sets was analyzed using simple ANCOVA model and the 500 ANCOVA model results were combined using Rubin’s rules.

⁴ Not formally tested due to statistically significant results at Week 35.

Analysis based on data collected up to 52 days after last dose of study drug. Week 35 data from interim analysis and Week 65/66 data from Week 66 analysis. In the Full Analysis Set, the eplontersen group included 140 participants at Week 35 and 141 participants at Week 66. One participant did not have a mNIS+7 or Norfolk QoL-DN assessment at Week 35 but did have an assessment for at least one of these at Week 66.

ANCOVA = analysis of covariance; CI = confidence interval; LSM = least squares mean; MMRM = mixed effects model with repeated measures; mNIS+7 = modified Neuropathy Impairment Score +7; N = number of participants in group; Norfolk QoL-DN = Norfolk Quality of Life – Diabetic Neuropathy questionnaire; SD = standard deviation; SE = standard error; TTR = transthyretin.

Table 4: Hierarchical Testing of Secondary Endpoints (NEURO-TTRansform Study) 

* External placebo group from another randomised controlled trial (NEURO-TTR).

N=Number of patients in Full Analysis Set at Week 66. 

n=Number of patients with non-missing data on baseline covariates and change from baseline at the time point.

Analysis based on data collected up to 28 days after last dose of study drug. Analysis visit window of Week 65 is from Day 419 to Day 479.

Based on a mixed effects model with repeated measures (MMRM) adjusted by propensity score weights with fixed categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30M mutation, previous treatment, and fixed covariates for the baseline value and the baseline-by-time interaction. Only data up to Week 65 are included in the Week 66 final analysis.

CI = confidence interval; LSM = least squares mean; mBMI = modified body mass index; NSC = neuropathy symptoms and change; PND = polyneuropathy disability; PCS = physical component score; SF‑36 PCS= short form‑36 health survey questionnaire Physical Component Score.

Figure 2: LSM Percent Change in Serum TTR Concentration from Baseline to Week 65, WAINUA  vs. External Placebo* through Week 65 (NEURO-TTRansform Study) (full analysis set) 

* External placebo group from another randomised controlled trial (NEURO-TTR).

** Treatment difference presents results from formal Week 35 interim analysis. Only data up to Week 35 are included in the Week 35 interim analysis.

Based on MMRM adjusted by propensity score weights with fixed categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline and the base-line-by-time interaction.

Analysis based on data collected up to 28 days after last dose of study treatment. Data up to Week 65 are included. Placebo was assessed at Baseline, Weeks 5, 8, 13 23, 35, 47, 57 and 65, WAINUA  assessed at Baseline, Weeks 5, 9, 13, 25, 35, 4, 59 and 65.

The Week 35 and Week 65 LS Mean treatment difference (WAINUA  – Placebo) with 95% CI (unadjusted) are presented.

CI = Confidence Interval; LSM = Least squares mean; SEM = standard error of mean, MMRM = Mixed effects model with repeated measures; TTR = Transthyretin.

Figure 3: LSM Change in mNIS+7 Composite Score from Baseline (NEURO-TTRansform Study) (full analysis set) 

* External placebo group from another randomised controlled trial (NEURO-TTR).

** Treatment difference presents results from formal Week 35 interim analysis. Based on MI ANCOVA adjusted by propensity score weights with fixed categorical effects for treatment, disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline. Only data up to Week 35 are included in the Week 35 interim analysis.
Week 66 analysis based on MMRM adjusted by propensity score weights with categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline and the baseline-by-time interaction.
Analysis based on data collected up to 52 days after last dose of study treatment. Data up to Week 66 are included.

The Week 35 and Week 65 LS Mean treatment difference (WAINUA  – Placebo) with 95% CI (unadjusted) are presented.

CI = Confidence interval; LS Mean = Least squares mean; SEM = standard error of mean, MI ANCOVA = Multiple imputation Analysis of covariance; MMRM = Mixed effects model with repeated measures.

Figure 4: Histogram of mNIS+7 Composite Score Change from Baseline (NEURO-TTRansform Study) (safety analysis set)

a) at Week 35 

mNIS +7 Composite Score Change from Baseline at Week 35

* External placebo group from another randomised controlled trial (NEURO-TTR).

b) at Week 66 

mNIS +7 Composite Score Change from Baseline at Week 66

* External placebo group from another randomised controlled trial (NEURO-TTR).

Figure 5: LSM Change in Norfolk QoL-DN Total Score from Baseline (NEURO-TTRansform Study) 

* External placebo group from another randomised controlled trial (NEURO-TTR).

** Treatment difference presents results from formal Week 35 interim analysis. Based on MI ANCOVA adjusted by propensity score weights with fixed categorical effects for treatment, disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline. Only data up to Week 35 are included in the Week 35 interim analysis.

Week 66 analysis based on MMRM adjusted by propensity score weights with categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline and the baseline-by-time interaction.

Analysis based on data collected up to 52 days after last dose of study treatment. Data up to Week 66 are included.

The Week 35 and Week 65 LS Mean treatment difference (WAINUA  – Placebo) with 95% CI (unadjusted) are presented.

CI = Confidence interval; LS Mean = Least squares mean; SEM = standard error of mean, MI ANCOVA = Multiple imputation Analysis of covariance; MMRM = Mixed effects model with repeated measures.

Figure 6: Histogram of Norfolk QoL-DN Total Score Change from Baseline (NEURO-TTRansform Study) (safety analysis set)

a) at Week 35 

Norfolk QoL-DN Total Score Change from Baseline at Week 35

* External placebo group from another randomised controlled trial (NEURO-TTR).

b) at Week 66 

Norfolk QoL-DN Total Score Change from Baseline at Week 66

* External placebo group from another randomised controlled trial (NEURO-TTR).

At both Week 35 and Week 65/66, patients receiving WAINUA  experienced similar improvements relative to placebo in the reduction of serum TTR concentration, mNIS+7 composite and Norfolk QoL-DN total scores across all subgroups including age, sex, race, region, baseline NIS score, Val30Met mutation status, cardiomyopathy status, FAC diagnosis at baseline, and disease stage (Figures 1a and b, 7a and b and 8a and b).

Figure 7: Forest Plot of Treatment Difference in LSM for Change from Baseline in mNIS+7 Composite Score for Key Subgroups (NEURO-TTRansform Study) (full analysis set)

a) at Week 35 

* External placebo group from another randomised controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

CM subgroup includes patients with either diagnosis of FAC at study entry or baseline IV septum wall thickness ≥ 13 mm with no hypertension [history or diagnosis during the study].

Difference in LS means, confidence intervals, and p-values are based on an ANCOVA model adjusted by propensity score with the effects of treatment, subgroup factors, disease stage, Val30Met mutation, previous treatment, treatment-by-subgroup interaction, and the Baseline value. Data up to Week 35 are included in the Week 35 analysis.

b) at Week 66 

* External placebo group from another randomised controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

Based on MMRM adjusted by propensity score weights with categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline and the baseline-by-time-interaction.

Subgroup models also included treatment-by-subgroup, time-by-subgroup, and treatment-by-time-by-subgroup interactions. Data up to Week 66 are included.

CM subgroup includes patients with either diagnosis of FAC at study entry or baseline IV septum wall thickness ≥ 13 mm with no hypertension [history or diagnosis during the study].

The Week 66 LSM treatment difference (WAINUA  – Placebo) with 95% CI (unadjusted) are presented.

CI = Confidence interval; LSM = Least squares mean; MMRM = Mixed effects model with repeated measures, CM = cardiomyopathy, FAC = familial amyloid cardiomyopathy.

Figure 8: Forest Plot of Treatment Difference in LSM for Change from Baseline in Norfolk QoL‑DN Total Score for Key Subgroups (NEURO-TTRansform  Study) (full analysis set)

a) at Week 35 

* External placebo group from another randomised controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

CM subgroup includes patients with either diagnosis of FAC at study entry or baseline IV septum wall thickness ≥ 13 mm with no hypertension [history or diagnosis during the study].

Difference in LS means, confidence intervals, and p-values are based on an ANCOVA model adjusted by propensity score with the effects of treatment, subgroup factors, disease stage, Val30Met mutation, previous treatment, treatment-by-subgroup interaction, and the Baseline value. Only data up to Week 35 are included in the Week 35 interim analysis.

b) at Week 66 

* External placebo group from another randomised controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.
Based on MMRM adjusted by propensity score weights with categorical effects for treatment, time, treatment-by-time interaction, and disease stage, Val30Met mutation, previous treatment, and fixed covariates for the baseline and the baseline-by-time-interaction.

Subgroup models also included treatment-by-subgroup, time-by-subgroup, and treatment-by-time-by-subgroup interactions. Data up to Week 66 are included.

CM subgroup includes patients with either diagnosis of FAC at study entry or baseline IV septum wall thickness ≥ 13 mm with no hypertension [history or diagnosis during the study].

The Week 66 LSM treatment difference (WAINUA  – Placebo) with 95% CI (unadjusted) are presented.
CI = Confidence interval; LSM = Least squares mean; MMRM = Mixed effects model with repeated measures, CM = cardiomyopathy, FAC = familial amyloid cardiomyopathy.

In an exploratory analysis of cardiac assessments with serial echocardiograms, WAINUA  demonstrated improvement in E/e’ ratio (a measure of left ventricular diastolic function) after 65 weeks of treatment in the cardiomyopathy subgroup (adjusted placebo-controlled LS mean difference: ‑3.94 [95% CI ‑6.46, ‑1.42]). Directional changes toward benefit of TRDENAME over placebo at week 66 were also observed for pre‑specified exploratory cardiac endpoints of mean LV wall thickness (LSM difference -0.04 cm, [95% CI -0.12, 0.04]), interventricular septal wall thickness (LSM difference -0.05 cm, [95% CI -0.16, 0.06]), and NT‑proBNP, a prognostic biomarker of cardiac dysfunction, (geometric LSM 0.88, [95% CI 0.68, 1.14]). Despite these observed values a clinical benefit in cardiomyopathy is yet to be confirmed. 

Week 85 (end of treatment analysis)

Week 85 data are not available for the external placebo group as the treatment period in NEURO-TTR study was only 66 weeks.   

The observed effect in the WAINUA  treated group in mNIS+7 composite score was consistent and sustained through the end of treatment at Week 85. The mean (SD) change from baseline in mNIS+7 composite score was -0.04% (16.2) at Week 35, -0.21% (17.6) at Week 66 and ‑2.9% (20.5) at Week 85. The mean Norfolk QoL-DN total score remained stable through Week 85. In the eplontersen group the mean (SD) change from baseline in Norfolk QoL-DN total score was -4.8 (16.5) at Week 35, -7.2 (18.5) at Week 66 and ‑6.2 (18.0) at Week 85. 

NSC, PND and mBMI remained stable through Week 85, while SF-36 continued to show trend towards improvement.

The pharmacokinetic (PK) properties of WAINUA  were evaluated following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with ATTRv-PN. 

Absorption

Following subcutaneous administration, eplontersen is absorbed rapidly into systemic circulation with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates. 

Distribution

Based on animal studies (mouse, rat, and monkey), eplontersen distributes primarily to the liver and kidney cortex after subcutaneous dosing. Eplontersen is highly bound to human plasma proteins (>98%). The population estimates for the apparent central volume of distribution is 12.9 L and the apparent peripheral volume of distribution is 11,100 L. 

Biotransformation

Eplontersen is metabolised by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver. There were no major circulating metabolites in humans. Oligonucleotide therapeutics, including eplontersen, are not typically metabolised by CYP enzymes. 

Elimination

Eplontersen is primarily eliminated by metabolism followed by renal excretion of the short oligonucleotide metabolites. The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose within 24 hours. The terminal elimination half-life is approximately 3 weeks based on population estimates.   

Linearity/non-linearity

Eplontersen C_max and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e., 1 to 2.7 times the recommended dose) in healthy volunteers.   

Population estimates of steady state maximum concentrations (C_max), trough concentrations (C_trough), and area under the curve (AUC_τ) were 0.218 μg/mL, 0.000200 μg/mL, and 1.95 μg h/mL, respectively, following 45 mg once every 4 weeks dosing in patients with ATTRv-PN. No accumulation of eplontersen C_max and AUC was observed in plasma after repeated dosing (once every 4 weeks). Accumulation was observed in C_trough, and steady-state is reached after approximately 17 weeks.   

Special populations

Based on the population pharmacokinetic and pharmacodynamic analysis, body weight, sex, race, and Val30Met mutation status have no clinically meaningful effect on eplontersen exposure or serum TTR reductions at steady-state. Definitive assessments were limited in some cases as covariates were limited by the overall low numbers. 

Elderly population

No overall differences in pharmacokinetics were observed between adult and elderly (≥65 years of age) patients. 

Renal impairment

No formal clinical studies have been conducted to investigate the effect of renal impairment on eplontersen PK. A population pharmacokinetic and pharmacodynamic analysis showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of eplontersen based on mild and moderate renal impairment (eGFR≥45 to <90 mL/min). Eplontersen has not been studied in patients with severe renal impairment or in patients with end-stage renal disease. 

Hepatic impairment

No formal clinical studies have been conducted to investigate the effect of hepatic impairment on eplontersen. A population pharmacokinetic and pharmacodynamic analysis showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of eplontersen based on mild hepatic impairment (total bilirubin ≤1 x ULN and AST >1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST). Eplontersen has not been studied in patients with moderate or severe hepatic impairment or in patients with prior liver transplant. 

Drug-Drug Interaction

No formal clinical drug interaction studies have been conducted. In vitro studies indicate that eplontersen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor or inducer of CYP enzymes. Oligonucleotide therapeutics, including eplontersen, are not typically substrates of CYP enzymes. Therefore, eplontersen is not expected to cause or be affected by drug-drug interactions mediated through drug transporters, plasma protein binding or CYP enzymes. 

Non-clinical/Repeat-dose toxicity

Repeated administration of eplontersen or rodent specific surrogate produced reduction in hepatic TTR mRNA levels (up to ~62% and 82% reductions in monkeys and mice, respectively), with subsequent decreases in TTR plasma protein levels (up to 70% reduction in monkeys). There were no toxicologically relevant findings related to this pharmacologic inhibition of TTR expression.

Most of the findings observed after repeated dosing for up to 6 months in mice and 9 months in monkeys were related to the uptake and accumulation of eplontersen and were not considered adverse. Microscopic findings related to uptake of eplontersen was observed by various cell types in multiple organs of all tested animal species including monocytes/macrophages, kidney proximal tubular epithelia, Kupffer cells of the liver, and histiocytic cell infiltrates in lymph nodes and injection sites. 

Severely decreased platelet counts associated with spontaneous haemorrhage were observed in a sub-chronic toxicity study in one monkey at the highest dose tested (24 mg/kg/week). Similar findings were not observed in monkeys dosed at a mid‑dose of 6 mg/kg/week which is 73‑fold the human AUC at the recommended therapeutic eplontersen dose. 

Mutagenicity and carcinogenicity

Eplontersen did not exhibit genotoxic potential in vitro and in vivo and was not carcinogenic in ras.H2 transgenic mice.

Eplontersen was negative for genotoxicity in in vitro (bacterial mutagenicity, chromosomal aberration in Chinese hamster lung) and in vivo (mouse bone marrow micronucleus) assays.

In a subcutaneous carcinogenicity study in ras.H2 transgenic mice, eplontersen was administered for 26 weeks at doses of 250, 500, and 1500 mg/kg/month. There was no evidence of carcinogenicity for eplontersen following 26 weeks of treatment in mice.

Reproductive toxicity

Embryofoetal/Developmental toxicity/Fertility

Eplontersen had no effects on fertility or embryo-foetal development in the mouse up to 38-fold to the recommended human monthly dose of 45 mg. Eplontersen is not pharmacologically active in mice. However, no effect on fertility or embryo-foetal development was noted with a mouse-specific analogue of eplontersen in mice, which was associated with >90% inhibition of TTR mRNA expression.

List of excipients 

Sodium dihydrogen phosphate dihydrate

Disodium hydrogen phosphate anhydrous

Sodium chloride

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injection

In the absence of compatibility studies, this product must not be mixed with other medicinal products. 

Store in a refrigerator (2°C – 8°C).

WAINUA  may be stored in original carton unrefrigerated for up to 6 weeks below 30°C. If not used within 6 weeks, it should be discarded.

Store in the original package in order to protect from light. 

Do not freeze. Do not expose to heat.

0.8 mL sterile solution in a single-use, type I glass syringe with a staked 27‑gauge ½ inch (12.7 mm) stainless steel needle, rigid needle shield, and siliconised chlorobutyl elastomer stopper in an autoinjector. 

Pack size of 1 pre-filled autoinjector.

WAINUA  should be inspected visually prior to administration. The solution should be clear and colourless to yellow. Do not use WAINUA  if the solution is cloudy, contains visible particulate matter or discoloured.

Single‑use pre-filled autoinjector should be discarded in a puncture-resistant sharps container.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.