Wainzua

Pharmacotherapeutic group: Other Nervous System Drugs, ATC code: N07XX21. Mechanism of action Eplontersen is a N-acetylgalactosamine (GalNAc) conjugated 2′- O -2-methoxyethyl modified chimeric gapmer antisense oligonucleotide (ASO) with a mixed backbone of phosphorothioate and phosphate diester internucleotide linkages.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ The GalNAc conjugate enables targeted delivery of the ASO to hepatocytes. The selective binding of eplontersen to the transthyretin (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. Pharmacodynamic effects 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 was observed regardless of sex, race, age, region, body weight, cardiomyopathy status, previous treatment, Val30Met mutation status, disease stage, and familial amyloid cardiomyopathy clinical diagnosis at baseline. TTR is a carrier protein for retinol binding protein 4, 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. Clinical efficacy and safety The efficacy and safety of Wainzua was evaluated in a randomised, multicentre, open-label, trial (NEURO-TTRansform) that included a total of 168 adult patients with ATTRv-PN. Patients were randomised in a 6:1 ratio to receive subcutaneous injection of Wainzua 45 mg every 4 weeks (N=144) or inotersen 284 mg weekly (N=24) as a reference group. Of the 144 patients randomised to Wainzua, 140 (97.2 %) patients completed treatment through Week 35, 135 (93.8%) completed treatment through Week 65. An external placebo control consisted of a placebo cohort of patients from the inotersen pivotal study (NEURO-TTR): randomised, double-blind, placebo-controlled, multicentre clinical trial in adult patients with ATTRv-PN. That cohort received subcutaneous injections of placebo once weekly. Both studies employed identical eligibility criteria. The characteristics of the Wainzua and external placebo groups were generally similar, and potential imbalances in key baseline characteristics (Val30Met mutation status, disease stage, and previous treatment) were accounted for in the prespecified statistical analysis. Of the 144 patients randomised to Wainzua, the median patient age at baseline was 51.5 years (range 24 to 82), 44 (30.6%) were ≥65 years old (36 patients were 65 to 74 years old and 8 patients were ≥75 years), and 69.4% of patients were male. Twenty (20) different TTR variants were represented: Val30Met (59.0%), Glu89Gln (0.7%), Leu58His (2.8%), Phe64Leu (3.5%), Ser50Arg (1.4%), Ser77Tyr (2.1%), Thr49Ala (0.7%), Thr60Ala (2.8%), Val122Ile (2.8%), and Other (24.3%, includes Ala97Ser). At baseline, 79.9% of patients had stage 1 disease (unimpaired ambulation; mild sensory, motor, and autonomic neuropathy in the lower limbs), and 20.1% had stage 2 disease (assistance with ambulation required; moderate impairment of the lower limbs, upper limbs, and trunk), and there were no patients with stage 3 disease. 69.4% of patients had prior treatment with either tafamidis or diflunisal. Of 39 (27.1%) of patients who had diagnosis of TTR cardiomyopathy at study entry, 41% of patients were classified as the New York Heart Association (NYHA) class I and 59% were NYHA class II. At Week 35 interim analysis the primary efficacy endpoints were the change from baseline in serum transthyretin (TTR) concentration and in the modified Neuropathy Impairment Score + 7 (mNIS+7) composite score, and the key secondary endpoint was the change from baseline in the Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) questionnaire total score. In Week 66 analysis the co-primary endpoints included percent change from baseline in serum TTR concentration at Week 65, change from baseline in mNIS+7 score and change from baseline in Norfolk QoL-DN total score at Week 66, all when eplontersen was compared to placebo. The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 composite scores. In the version of the mNIS+7 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 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 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 that was used in the trial had a range from -4 to 136 points, with higher scores representing greater impairment. Other secondary endpoints were formally tested hierarchically at Week 66 analysis and included change from baseline in neuropathy symptoms and change score, in the physical component summary score of short form 36-item health survey (version 2), in polyneuropathy disability score and in nutritional status (modified body mass index). Treatment with Wainzua in NEURO-TTRansform study demonstrated statistically significant improvements in all endpoints at both Week 35 and Week 66 (see Table 2 and Figures 1-3) compared to the external placebo group (all p < 0.0001). Table 2: Summary of clinical efficacy results from NEURO-TTRansform Study (full analysis set) Analysis/Endpoint Baseline, Mean (SD) LSM Change/Percent Change from Baseline, (SE) [95% CI] Wainzua - Placebo * Difference in LSM [95% CI] p-value External Placebo * Wainzua Placebo * Wainzua Week 35 N = 59 N = 140 N = 59 N = 140 Serum TTR, g/L 1 Percent change from baseline 0.15 (0.04) 0.23 (0.08) -14.8% (2.0) [-18.73, -10.80] -81.2% (1.7) [-84.55, -77.84] -66.4% [-71.39, -61.47] p < 0.0001 mNIS+7 composite score 2,3 Change from baseline 74.1 (39.0) 79.6 (42.3) 9.2 (1.9) [5.54, 12.91] 0.2 (1.9) [-3.46, 3.89] -9.0 [-13.48, -4.54] p < 0.0001 Norfolk QOL-DN total score 2,3 Change from baseline 48.6 (27.0) 43.5 (26.3) 8.7 (2.1) [4.53, 12.81] -3.1 (2.1) [-7.19, 0.96] -11.8 [-16.82, -6.76] p < 0.0001 Week 66 N = 59 N = 141 N = 59 N = 141 Serum TTR, g/L 1 Percent change from baseline 0.15 (0.04) 0.23 (0.08) -11.2% (1.9) [-15.06, -7.41] -81.7% (1.6) [-84.82, -78.48] -70.4% [-75.17, -65.66] p < 0.0001 mNIS+7 composite score 1 Change from baseline 74.1 (39.0) 79.8 (42.3) 25.1 (2.4) [20.23, 29.88] 0.3 (2.4) [-4.46, 5.06] -24.8 [-30.96, -18.56] p < 0.0001 Norfolk QOL-DN total score 1 Change from baseline 48.6 (27.0) 43.3 (26.2) 14.2 (2.4) [9.51, 18.97] -5.5 (2.3) [-10.03, -0.96] -19.7 [-25.63, -13.84] p < 0.0001 Neuropathy symptom and change score change from baseline at Week 66 8.2 [6.24, 10.12] -0.0 [-1.92, 1.86] -8.2 [-10.65, -5.76] p < 0.0001 Physical component score of short form 36 item health survey change from baseline at Week 65 -4.46 [-6.139, -2.770] 0.85 [-0.711, 2.412] 5.31 [3.195, 7.416] p < 0.0001 Modified body mass index change from baseline at Week 65 -90.8 [-112.84, -68.69] -8.1 [-28.55, 12.42] 82.7 [54.64, 110.76] p < 0.0001 * 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. 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 patients at Week 35 and 141 patients at Week 66. One patient 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. The secondary endpoint of change from baseline in PND score at Week 65 was statistically significant in favor of eplontersen (p=0.02). More patients in the eplontersen group experienced improvement from baseline in PND score than in the external placebo group (5.7% vs 3.4%) and fewer patients in the eplontersen group experienced a worsening from baseline than in the external placebo group (12.8% vs. 22.0%). Figure 1: LSM percent change in serum TTR concentration from baseline to Week 65, Wainzua vs. 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, disease stage, Val30Met mutation, previous treatment, 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, 59 and 65. Wainzua was assessed at baseline, Weeks 5, 9, 13, 25, 35, 49, 57 and 65. The Week 35 and Week 65 LS mean treatment difference (Wainzua - 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 2: Change from baseline in mNIS+7 composite score (comparison of wainzua treatment in NEURO-TTRansform study to a placebo control*) * 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 (WAINZUA – 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 3: Change from baseline in Norfolk QoL-DN total score (comparison of Wainzua treatment in NEURO-TTRansform study to a placebo control*) * 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 (WAINZUA – Placebo) with 95% CI (unadjusted) are presented. CI = confidence interval; LS mean = least squares mean; MI ANCOVA = multiple imputation analysis of covariance; MMRM = mixed effects model with repeated measures. Patients receiving Wainzua experienced similar improvements relative to placebo in the reduction of serum TTR concentration, mNIS+7 composite and Norfolk QoL-DN scores across all subgroups including age, sex, race, region, Val30Met mutation status, cardiomyopathy status, familial amyloid cardiomyopathy clinical diagnosis at baseline and disease stage. In an exploratory analysis of cardiac assessments with serial echocardiograms, eplontersen 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 eplontersen 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. Through the end of treatment with Wainzua at Week 85, reduction of TTR concentration and the observed effect in mNIS+7 composite score were sustained, and the mean Norfolk QoL-DN total score remained stable. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with eplontersen in all subsets of the paediatric population in ATTRv (see section 4.2 for information on paediatric use).