Real-World Effectiveness and Clinical Predictors of Response to First-Generation TTR Silencers in Variant ATTR Amyloidosis with Polyneuropathy

Real-World Effectiveness and Clinical Predictors of Response to First-Generation TTR Silencers in Variant ATTR Amyloidosis with Polyneuropathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Real-World Effectiveness and Clinical Predictors of Response to First-Generation TTR Silencers in Variant ATTR Amyloidosis with Polyneuropathy María Antonia Ribot-Sansó, Juan González-Moreno, Cristina Bayon-González, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9019314/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background: Transthyretin (TTR) gene-silencing therapies have transformed the management of variant transthyretin amyloidosis with polyneuropathy (ATTRv-PN). However, real-world evidence on effectiveness, safety, and durability is limited. Methods: We conducted a multicenter retrospective study across ten Spanish referral hospitals including 98 genetically confirmed ATTRv-PN patients treated with patisiran (n=81) or inotersen (n=17). Patients were classified as total, partial, or non-responders according to clinical evolution and Neuropathy Impairment Score (NIS). Baseline clinical, neurophysiological (CMAP, SNAP, ESC), and biochemical parameters were analyzed. Longitudinal NIS changes, treatment persistence, and safety were assessed. Results: Total responders had higher baseline CMAP amplitudes (p=0.045) and better renal function (eGFR, p=0.022). Compared with inotersen, patisiran showed a higher total response rate (59.3% vs. 23.5%), slower NIS progression (median +0.31 vs. +4.00 points/year; p=0.011), and greater treatment persistence (log-rank p=0.0005). No discontinuations due to adverse events occurred with patisiran, versus 41.2% with inotersen. ESC showed the highest predictive value (AUC 0.681 overall; 0.783 in the patisiran subgroup), while baseline NIS was less informative. Conclusions: In routine practice, patisiran demonstrated superior efficacy, safety, and durability compared with inotersen. Baseline motor nerve function and renal status may help guide therapeutic decisions, supporting early and personalized treatment strategies. Health sciences/Diseases Health sciences/Medical research Health sciences/Nephrology Health sciences/Neurology Biological sciences/Neuroscience ATTRv patisiran inotersen treatment response Figures Figure 1 Figure 2 Figure 3 Background Variant transthyretin (ATTRv) amyloidosis is a multisystem disorder caused by pathogenic TTR variants that promote extracellular amyloid deposition in nerves and other organs (Buxbaum et al., 2022; Poli et al., 2023). ATTRv amyloidosis encompasses a spectrum of predominantly neurologic and/or cardiac phenotypes, depending on the underlying variant (Kittleson et al., 2020; Poli et al., 2023). Although rare, ATTRv amyloidosis is underrecognized; prevalence varies by geography and founder effects, with global estimates in the low tens of thousands and marked regional clustering (Delgado et al., 2025; Poli et al., 2023). Over 240 TTR missense variants have been described ( “TTR”[GENE] - ClinVar - NCBI , n.d.) . Among the most common, p.Val50Met often manifests with neuropathy predominance, whereas p.Val142Ile, enriched in individuals of West African ancestry, often presents with cardiomyopathy, though phenotypic overlap is common (Ruberg & Maurer, 2024) . In neuropathy-predominant ATTRv amyloidosis, phenotypic heterogeneity is substantial. Early-onset disease frequently shows small-fiber and autonomic involvement, whereas late-onset disease tends toward mixed sensorimotor neuropathy with greater cardiac burden; intra-familial variability further complicates recognition (Poli et al., 2023). Carpal tunnel syndrome, gastrointestinal dysmotility, and weight loss are frequent red flags that precede diagnosis (Adams et al., 2021; Gertz et al., 2020). In these neuropathic phenotypes , natural history is characterized by rapid neurological deterioration without therapy, with meta-analytic estimates of Neuropathy Impairment Score (NIS) worsening by approximately 11.8 points per year— substantially greater than that observed in other neuropathies (Lin et al., 2021). Because neuropathy-predominant presentations often mimic more common neuropathies (for example, chronic inflammatory demyelinating polyneuropathy, or idiopathic axonal neuropathy), consensus pathways emphasize structured screening, exclusion of AL amyloidosis, appropriate imaging or biopsy with amyloid typing, and early TTR genotyping in unexplained neuropathy (Gertz et al., 2020; Kittleson et al., 2020). Clinical trial endpoints commonly include NIS and the modified NIS+7 (mNIS+7), which integrate neurologic examination and neurophysiology to sensitively detect change in ATTRv amyloidosis (P. J. Dyck et al., 2017; P. J. B. Dyck et al., 2019). Health-related quality of life is often assessed with the Norfolk QOL-DN, validated and responsive across disease stages (Vinik et al., 2014). Biomarkers have been increasingly found to be informative: neurofilament light chain (NfL) is elevated in ATTRv neuropathy and declines with patisiran, correlating with clinical improvement and supporting its role in monitoring and earlier diagnosis (Gragera-Martínez et al., 2025; Ticau et al., 2021, 2024). When cardiomyopathy coexists, cardiac biomarkers (NT-proBNP, troponin) and multimodality imaging refine risk and are often the main determinants of survival (Kittleson et al., 2020; Ruberg & Maurer, 2024) . Nutritional status is clinically relevant. Both modified BMI (calculated as BMI multiplied by serum albumin) and albumin levels alone serve as biomarkers and clinical endpoints in gene-silencing trials, and are associated with patient outcomes — including in cardiac amyloidosis (Adams et al., 2018; Dongiglio et al., 2022). Autonomic dysfunction is prevalent; electrochemical skin conductance (ESC, Sudoscan) provides a rapid, noninvasive small-fiber measure that differentiates ATTRv patients from carriers or controls and complements standard electrophysiology (Moreno-Moraleda et al., 2024; Novak, 2019). Gene-silencing therapies have transformed outcomes. In APOLLO, patisiran improved mNIS+7 and quality of life versus placebo, with favorable effects on gait speed and modified BMI (Adams et al., 2018). In NEURO-TTR, inotersen significantly slowed progression on mNIS+7 and Norfolk QOL-DN (Benson et al., 2018). The subcutaneous siRNA vutrisiran (HELIOS-A) met primary and secondary endpoints versus an external placebo, improving neuropathy, function, and nutritional status (Adams et al., 2023; Keam, 2022). Eplontersen (NEURO-TTRansform) further reduced serum ATTR and stabilized mNIS+7 with quality-of-life gains versus external placebo (Coelho et al., 2023). Despite therapeutic advances, real-world treatment responses remain heterogeneous and difficult to predict, with variability attributable to phenotype, disease stage, and concomitant cardiomyopathy. There is a clear need for clinically deployable predictors to support therapy selection, prognostication, and optimization of treatment timing in routine practice, particularly in settings constrained by access, monitoring capacity, and patient frailty. To address this evidence gap, we conducted a real-world analysis assessing baseline clinical, neurophysiological, and biochemical parameters as candidate predictors of response to TTR -silencing therapies, with the objective of translating trial efficacy into actionable guidance for everyday care. Methods Study Design and Setting This was a multicenter, retrospective, observational study conducted across ten Spanish referral hospitals for amyloidosis: Hospital Universitario Son Llàtzer, Hospital Juan Ramón Jiménez, Hospital Clínico San Carlos, Hospital universitario Vall d’Hebron, Hospital universitario Bellvitge, Hospital Clinic de Barcelona, Hospital universitario La Fe, Hospital universitario Salamanca, Hospital universitario Basurto and Hospital universitario Donosti. The study aimed to evaluate real-world effectiveness, safety, and predictors of response to first-generation TTR silencers in patients with ATTRv-PN amyloidosis. All patients provided written informed consent prior to inclusion, in accordance with ethical standards for clinical research publication. Participants We included adult patients (≥18 years) with genetically confirmed ATTRv-PN who received patisiran or inotersen for at least six months between 2015 and 2024. Diagnosis required a pathogenic TTR variant and clinical features consistent with ATTRv-PN, supported by abnormal nerve conduction studies or at least two abnormal small-fiber tests (e.g., thermotest, sympathetic skin response, R–R interval, or Sudoscan®). Patients with non- TTR amyloidosis or hematologic malignancies (e.g., multiple myeloma, lymphoma, leukemia, or macroglobulinemia) were excluded. Some patients had initiated treatment as part of clinical trials prior to commercial availability. Treatment Patients received patisiran (0.3 mg/kg intravenously every three weeks) or inotersen (284 mg subcutaneously weekly), administered according to routine clinical practice. No protocol-driven treatment changes were made. Data Collection Data were extracted from electronic medical records and entered into a secure anonymized database. Baseline variables included demographics (age, sex, family history), clinical phenotype (early-onset, late-onset, or mixed), functional staging (Coutinho and PND scores), and comorbidities (e.g., hypertension, diabetes, HIV). Neuropathy severity was assessed using the Neuropathy Impairment Score (NIS) at diagnosis, treatment initiation, and last follow-up. Quality of life was measured using the Norfolk QOL-DN questionnaire. Neurophysiological assessments included compound muscle action potential (CMAP), sensory nerve action potential (SNAP), and electrochemical skin conductance (ESC) via Sudoscan®. Laboratory parameters included NT-proBNP, troponin I, estimated glomerular filtration rate (eGFR), total protein, albumin, transthyretin (ATTR), vitamin A, and retinol-binding protein (RBP). Treatment details (start/end dates, duration, discontinuation reasons, subsequent therapies) and TTR genotype were also recorded. Definition of Treatment Response Patients were classified into three response categories based on clinical and NIS evolution: Total responders: no clinical progression and NIS increase ≤2 points. Non-responders: progression similar to natural history, defined as NIS increase >10 points/year. Partial responders: intermediate pattern, with stability of autonomic symptoms without meeting full response criteria(Monteiro et al., 2019). Outcomes The primary outcome was the association between baseline variables and treatment response. Secondary outcomes included annualized NIS progression, treatment persistence, safety, and reasons for discontinuation. Statistical Analysis Continuous variables were summarized as mean ± standard deviation or median (interquartile range), and categorical variables as frequencies and percentages. Normality was assessed using the Shapiro–Wilk test and Q–Q plots. Group comparisons used ANOVA or Kruskal–Wallis tests for continuous variables and χ² or Fisher’s exact tests for categorical variables. Receiver operating characteristic (ROC) curves were used to evaluate the predictive performance of baseline NIS, albumin, total protein, and TTR, with area under the curve (AUC). Kaplan–Meier curves and Cox proportional hazards models were used to analyze time to treatment discontinuation and identify predictors of treatment failure. Analyses were performed using Python (pandas, NumPy, SciPy, scikit-learn, lifelines, matplotlib), with p-values <0.05 considered statistically significant. Results A total of 98 patients with genetically confirmed ATTRv-PN amyloidosis were included in the study, receiving treatment with either patisiran (n = 81) or inotersen (n = 17). The mean age at treatment initiation was 64.3 years (range: 27–85), with a predominance of male patients (65.3%). In this cohort, the TTR variant Val30Met predominated, accounting for approximately 84.7% (n=83) of genotyped cases. Less frequent variants included Ser77Tyr (≈5.1%, n=5), Val122Ile (≈4.1%, n=4), Val122del (≈2.0%, n=2), Glu89Gln (≈2.0%, n=2), Val28Met (≈1.0%, n=1), and Glu61Gly (≈1.0%, n=1). . The most frequent clinical phenotype was late-onset neurological (52.0%), followed by mixed (34.7%) and early-onset neurological presentation (13.3%). As shown in Table I, no statistically significant differences were observed between response groups in terms of age, sex, clinical phenotype, or baseline functional stage (Coutinho and PND scales) (p > 0.05). However, two variables showed statistically significant differences across response groups. Patients classified as Total responders exhibited baseline higher CMAP amplitudes (mean ± SD: 7.5 ± 3.8 µV) compared to partial responders (5.3 ± 3.7 µV) and non-responders (6.3 ± 3.7 µV) (p = 0.045), suggesting better preservation of motor nerve function may be associated with a more favorable treatment response. Additionally, follow-up duration was significantly longer in Total responders (median: 37.0 months [IQR: 23.5–50.0]) than in partial (23.0 months [15.0–39.0]) and non-responders (26.0 months [14.0–45.0]) (p = 0.04), potentially reflecting greater clinical stability or sustained therapeutic benefit in this subgroup. However, this difference also reflects the study design, since patients could be enrolled with as little as 6 months of prior treatment and therapy was more often discontinued in partial and non-responders. Table 1. Baseline demographic, clinical, and electrophysiological characteristics of patients with ATTRv-PN. Values are presented as mean ± standard deviation, number (%), or median [interquartile range], as appropriate. P-values refer to comparisons across response groups using ANOVA, chi-square, or Kruskal–Wallis tests, depending on variable type. Category Characteristic Overall Total responders Partial Responders Non-Responders P-value Demographics n 98 52 29 17 - Age at treatment initiation (years) 64.3 ± 11.8 64.3 ± 12.8 65.4 ± 10.2 62.6 ± 11.7 0.734 Male, n (%) 64 (65.3) 34 (65.4) 16 (55.2) 14 (82.4) 0.174 Clinical phenotype Early-onset neurological, n (%) 13 (13.3) 8 (15.4) 2 (6.9) 3 (17.6) 0.624 Late-onset neurological, n (%) 51 (52.0) 26 (50.0) 18 (62.1) 7 (41.2) Mixed, n (%) 34 (34.7) 18 (34.6) 9 (31.0) 7 (41.2) Functional staging Coutinho stage I, n (%) 58 (59.2) 34 (65.4) 14 (48.3) 10 (58.8) 0.324 Coutinho stage II, n (%) 40 (40.8) 18 (34.6) 15 (51.7) 7 (41.2) PND stage I, n (%) 43 (43.9) 22 (42.3) 12 (41.4) 9 (52.9) 0.412 PND stage II, n (%) 22 (22.4) 16 (30.8) 4 (13.8) 2 (11.8) PND stage IIIa, n (%) 20 (20.4) 9 (17.3) 7 (24.1) 4 (23.5) PND stage IIIb, n (%) 13 (13.3) 5 (9.6) 6 (20.7) 2 (11.8) Baseline disease severity NIS, mean ± SD 34.9 ± 27.4 32.9 ± 25.8 39.7 ± 29.4 33.3 ± 29.8 0.562 Norfolk QOL-DN, mean ± SD 46.4 ± 28.6 40.8 ± 30.3 52.9 ± 27.8 50.1 ± 24.1 0.322 CMAP (µV), mean ± SD 6.7 ± 3.8 7.5 ± 3.8 5.3 ± 3.7 6.3 ± 3.7 0.045 SNAP (µV), mean ± SD 8.5 ± 11.2 7.8 ± 8.5 11.0 ± 15.3 6.1 ± 10.1 0.328 Dysautonomia, n (%) 73 (74.5) 39 (75.0) 21 (72.4) 13 (76.5) 0.947 Treatment exposure Follow-up duration (months), median [IQR] 34.5 [19.0–48.0] 37.0 [23.5–50.0] 23.0 [15.0–39.0] 26.0 [14.0–45.0] 0.04 Treatment Response Comparison Of the total patients included in the analysis, 81 (82.7%) received patisiran and 17 (17.3%) received inotersen. Response patterns differed significantly between treatment groups (χ² = 7.62, p = 0.022; see Figure 1). Among patients treated with patisiran, 48 (59.3%) achieved a complete response, 20 (24.7%) showed a partial response, and 13 (16.0%) were classified as non-responders. In contrast, the response distribution among inotersen-treated patients was notably different: 4 (23.5%) achieved a complete response, 9 (52.9%) had a partial response, and 4 (23.5%) were non-responders. Notably, patisiran was associated with a higher proportion of Total responders (59.3% vs. 23.5%), whereas inotersen showed a greater proportion of partial responders (52.9% vs. 24.7%). These findings suggest distinct response profiles between the two therapeutic approaches (p < 0.05). Baseline characteristics were analyzed within each treatment group to explore factors associated with treatment response (Table 2). In the inotersen group (n=17), total responders tended to have better functional status at baseline, with all patients in Coutinho stage I and PND stage I. Although not statistically significant, non-responders were more frequently male (100%) and younger (median age 56.5 years). Notably, the Norfolk QOL-DN score differed significantly across response categories (p = 0.016), with Total responders reporting markedly better baseline quality of life. In contrast, the patisiran group (n=81) showed a more balanced distribution of demographic and clinical features across response categories. However, CMAP values were significantly higher in Total responders (p = 0.041), suggesting better preserved motor nerve function may be associated with favorable outcomes. PND stage II was also more frequent among Total responders in the patisiran group (p = 0.04), indicating potential efficacy even in moderately advanced disease. These findings highlight distinct response profiles between the two therapies and suggest that baseline neurological function and patient-reported outcomes may influence treatment efficacy. Table 2. Comparison of baseline demographic, clinical, functional, and electrophysiological characteristics between patients treated with inotersen and patisiran, stratified by treatment response. Values are expressed as number (%), mean, or median as appropriate. P-values refer to comparisons across response categories within each treatment group, using chi-square or Kruskal–Wallis tests depending on variable type. Inotersen Patisiran Category Characteristic Overall (n=17) Total responders (n=4) Partial Responders (n=9) Non-Responders (n=4) P-value Overall (n=81) Total responders (n=48) Partial Responders (n=20) Non-Responders (n=13) P-value Demographics Male (%) 10 (59%) 2 (50%) 4 (44%) 4 (100%) 0.157 54 (67%) 32 (67%) 12 (60%) 10 (77%) 0.602 Mean Age 64.9 65.0 68.7 56.5 0.337 64.2 64.2 64.0 64.5 0.718 Clinical Phenotype Early-onset neurological (%) 1 (6%) 0 (0%) 0 (0%) 1 (25%) 0.178 12 (15%) 8 (17%) 2 (10%) 2 (15%) 0.778 Late-onset neurological (%) 10 (59%) 2 (50%) 6 (67%) 2 (50%) 0.784 41 (51%) 24 (50%) 12 (60%) 5 (38%) 0.477 Mixed (%) 6 (35%) 2 (50%) 3 (33%) 1 (25%) 0.748 28 (35%) 16 (33%) 6 (30%) 6 (46%) 0.61 Functional Staging Coutinho I (%) 10 (59%) 4 (100%) 3 (33%) 3 (75%) 0.059 48 (59%) 30 (62%) 11 (55%) 7 (54%) 0.772 Coutinho II (%) 7 (41%) 0 (0%) 6 (67%) 1 (25%) 0.059 33 (41%) 18 (38%) 9 (45%) 6 (46%) 0.772 PND I (%) 10 (59%) 4 (100%) 3 (33%) 3 (75%) 0.059 33 (41%) 18 (38%) 9 (45%) 6 (46%) 0.772 PND II (%) 3 (18%) 0 (0%) 2 (22%) 1 (25%) 0.567 19 (23%) 16 (33%) 2 (10%) 1 (8%) 0.04 PND IIIa (%) 2 (12%) 0 (0%) 2 (22%) 0 (0%) 0.365 18 (22%) 9 (19%) 5 (25%) 4 (31%) 0.615 PND IIIb (%) 2 (12%) 0 (0%) 2 (22%) 0 (0%) 0.365 11 (14%) 5 (10%) 4 (20%) 2 (15%) 0.563 Baseline Disease Severity NIS Mean 36.8 27.0 41.6 35.9 0.766 34.5 33.4 38.7 32.4 0.854 Dysautonomia (%) 14 (82%) 4 (100%) 8 (89%) 2 (50%) 0.135 59 (73%) 35 (73%) 13 (65%) 11 (85%) 0.465 Norfolk Mean 43.6 8.0 65.9 34.5 0.016 47.1 44.5 46.9 55.9 0.478 CMAP Mean (µV) 6.8 7.1 6.0 8.0 0.8 6.7 7.6 5.0 5.8 0.041 SNAP Mean (µV) 8.8 7.0 12.1 4.2 0.568 8.4 7.8 10.6 6.8 0.927 ESC (µS) 98.4 104.0 90.7 101.5 0.945 83.8 91.0 86.8 53.8 0.203 Predictive Value of Baseline Measures for Treatment Response We evaluated whether baseline neurological and electrophysiological measures predict treatment response in patients with ATTRv-PN amyloidosis receiving silencers. Focusing on Total responders versus non-responders (excluding partial responders), baseline ESC demonstrated the strongest discrimination in the overall cohort (AUC ≈ 0.68), although this did not reach statistical significance, consistent with limited sample size and overlapping distributions. CMAP showed modest discrimination (AUC ≈ 0.60), whereas NIS and SNAP performed poorly (Table 3). CMAP was statistically significant in the three-category analysis (complete, partial, none), reflecting a stepwise pattern in which partial responders fell between Total responders and non-responders. However, this gradient attenuates when restricting the analysis strictly to complete versus non-response, reducing contrast and eliminating statistical significance. Findings were directionally consistent within treatment strata. Among patisiran-treated patients, ESC remained the most informative single predictor (AUC ≈ 0.78) with a near-significant rank-based separation; CMAP was modest, and NIS/SNAP were weak. In the inotersen subgroup, no baseline measure reached statistical significance, and AUC estimates were imprecise due to very small samples. In the Val30Met subset, the pattern was broadly similar. When restricted to total responders versus non-responders, baseline NIS again showed no meaningful discrimination (AUC ≈ 0.52), whereas ESC, CMAP and SNAP displayed only modest separation. ESC provided the highest discrimination (AUC ≈ 0.71), followed by CMAP (AUC ≈ 0.62) and SNAP (AUC ≈ 0.62), but none of these differences reached statistical significance on rank-based testing, likely reflecting limited sample size and overlapping ranges between groups (Supplementary Table 1). Overall, the Val30Met analysis confirms that, even within a more genetically homogeneous subgroup, baseline neurological and electrophysiological measures offer only modest and statistically uncertain ability to distinguish patients who will later achieve complete vs no response to silencer therapy. Table 3. Comparison of baseline predictors for total and non-responders in the overall cohort and patisiran subgroup. Subset Predictor Total responders (n) Non-responders (n) Median Total responders Median Non-responders P-value AUC Overall NIS 51 16 26 22 0.797 0.522 ESC 18 6 98 69 0.205 0.681 CMAP 49 16 7.2 6.05 0.241 0.599 SNAP 47 15 3.8 2.7 0.448 0.566 Patisiran NIS 47 12 26 17 0.692 0.538 ESC 15 4 94 56.5 0.099 0.783 CMAP 45 12 7.2 5.815 0.186 0.626 SNAP 43 11 3.8 4.6 0.779 0.528 Response-Related Differences in Key Laboratory Parameters Biomarker analysis revealed a statistically significant difference in baseline estimated glomerular filtration rate (eGFR) across response groups (p = 0.022), with non-responders exhibiting the highest median eGFR and total responders the lowest (Table 4). Thus, better neurological response was not associated with better preserved renal function at baseline. A trend toward significance was observed in transthyretin (TTR) levels (p = 0.069), suggesting that higher TTR concentrations may be associated with improved treatment response, although this did not reach conventional statistical significance. Similarly, Vitamin A levels demonstrated a near-significant difference (p = 0.067), with non-responders showing the highest median concentrations. This finding may reflect alterations in retinol metabolism or transport, potentially linked to TTR and retinol-binding protein (RBP), both of which also showed non-significant but suggestive trends. No statistically significant differences were found in NT-proBNP, RBP, troponin I (TpI), or total protein levels across response groups. Table 4. Baseline biomarkers across treatment response groups showing median (min–max) with N, and Kruskal–Wallis p-values. Measure Overall Total responders Partial responders Non-responders P value NTproBNP (pg/mL) 408.0 (15.9–15569.0) [n=82] 375.5 (25.0–6582.0) [n=46] 433.0 (15.9–15569.0) [n=25] 316.0 (66.4–4012.0) [n=11] 0.995 eGFR (mL/min) 87.0 (30.0–169.0) [n=94] 80.3 (30.0–113.0) [n=52] 89.88 (31.0–108.0) [n=26] 93.0 (51.0–169.0) [n=16] 0.022 Albumin (g/L) 43.0 (29–52) [n=90] 43.0 (33.9-50.00 [n=49] 43.0 (29.0–50.0) [n=25] 41.25 (33.0–52.0) [n=16] 0.681 TTR (mg/dL) 24.95 (10.0–35.0) [n=34] 27.5 (18.1–35.0) [n=18] 23.3 (13.0–34.0) [n=7] 21.2 (10.0–29.0) [n=9] 0.069 RBP (mg/dL) 5.2 (1.8–7.7) [n=25] 5.6 (4.3–6.9) [n=13] 3.6 (2.1–7.7) [n=5] 5.02 (1.8–7.0) [n=7] 0.1 TpI (ng/L) 23.5 (1.9–102.0) [n=52] 27.0 (2.5–98.0) [n=31] 26.15 (1.9–102.0) [n=14] 21.0 (7.0–59.9) [n=7] 0.71 Total protein (g/L) 68.0 (50.0–77.0) [n=85] 68.5 (51.0–77.0) [n=44] 66.0 (50–79.9) [n=25] 69.5 (56.3–76.0) [n=16] 0.38 Vitamin A (mg/L) 0.64 (0.22–2.30) [n=24] 0.63 (0.55–0.85) [n=14] 0.42 (0.28–1.07) [n=4] 1.305 (0.22–2.3) [n=6] 0.067 Longitudinal analysis Overall, within-patient prealbumin declined substantially, expressed as percent reduction from baseline. The mean percent reduction was 80.9% (median 85.7%). In stratified analyses, Patisiran showed a mean percent reduction of 83.6% (95% CI 79.1% to 88.1%; n = 19), while Inotersen showed a mean percent reduction of 72.4% (95% CI 55.1% to 89.8%; n = 6). The between‑treatment difference favored Patisiran by 11.2 percentage points (95% CI −6.1 to 28.5), which did not reach statistical significance (Welch t‑test p = 0.165; Mann–Whitney p = 0.091). Across the cohort, annualized changes showed modest average drift with broad heterogeneity. NIS increased by an average of approximately 2.94 points per year (95% CI, 0.71 to 5.17; median 0.63), whereas Norfolk increased by 4.20 points per year (95% CI, 1.36 to 7.04; median 1.70). CMAP and SNAP declined modestly (means −0.32 and −0.67 units per year, respectively). Safety markers demonstrated small average changes with wide dispersion. Stratified by treatment, the median annualized NIS change was lower with Patisiran than with Inotersen (Patisiran median 0.31 [IQR −0.45 to 2.66] vs Inotersen median 4.00 [IQR 0.84 to 7.50]; Figure 2), with overlapping IQRs. In exploratory mean-based analyses, the mean annualized NIS change was 1.62 vs 8.69 points/year (Welch t = −1.30; p = 0.211; Hedges g = −0.67) reflecting a moderate effect size and a trend toward benefit that did not meet the threshold for statistical significance., Norfolk increased at similar rates across groups. CMAP and SNAP exhibited small declines in both groups with no significant between-group differences. Annualized changes in biomarkers were modest with broad dispersion. Cardiac biomarkers showed directionally favorable trends with Patisiran compared with Inotersen. NTproBNP declined with Patisiran (mean −246 pg/mL/year; 95% CI −533 to 42; median −20) versus an increase with Inotersen (mean +496 pg/mL/year; 95% CI −283 to 1275; median +6; Mann-Whitney p = 0.015; Welch t = −1.96, p = 0.071; Hedges g = −0.63). Similarly, troponin declined with Patisiran (mean −1.76 ng/L/year; 95% CI −4.27 to 0.76; median 0.0) versus an increase with Inotersen (mean +2.77 ng/L/year; 95% CI −2.81 to 8.35; median +1.26; Mann-Whitney p = 0.087; Welch t = −1.91, p = 0.094; Hedges g = −0.55). Albumin and total protein changes did not differ significantly between treatments, though albumin medians trended toward greater decline with Inotersen (Mann-Whitney p = 0.059). Safety and Treatment permanence In this real-world cohort, adverse event (AE)–related discontinuations were concentrated in the Inotersen group. AE-related discontinuation occurred in 7 of 98 patients (7.1%), all among those treated with Inotersen (7/17; 41.2%), and was most commonly attributed to intolerance (n = 5; 29.4%), with additional cases of intolerance plus progression (n = 2; 11.8%). No AE-related discontinuations were recorded for Patisiran (0/81; 0%). One Patisiran-treated patient experienced a serious infusion-related reaction after two doses—severe bronchospasm requiring ICU admission—in the context of substantial poliomyelitis sequelae; this event did not translate into an AE-coded discontinuation. Therefore, patients treated with patisiran exhibited greater on‑treatment persistence compared with those on inotersen (Figure 3). The continuation curves separated early and remained divergent over follow‑up. The log‑rank test confirmed a statistically significant difference favoring patisiran (χ² = 12.10, p = 0.0005). Median time on treatment was not reached in the patisiran group within the observation window, whereas earlier discontinuations were observed with inotersen. In concordance with the Kaplan–Meier findings, Cox models—adjusted for age, sex, phenotype, and clinical markers—estimated a markedly lower hazard of discontinuation with patisiran versus inotersen (adjusted HR ≈ 0.42; 95% CI ≈ 0.23–0.79; p = 0.0066), reinforcing greater on‑treatment persistence. Discussion This multicenter, real-world study across ten Spanish referral hospitals provides new evidence on the comparative effectiveness, safety, and predictors of response to first-generation TTR silencers—patisiran and inotersen—in patients with transthyretin ATTRv-PN amyloidosis. Our findings confirm and extend the results of pivotal trials, while offering practical insights into treatment selection and monitoring in routine clinical settings (Adams et al., 2018; Benson et al., 2018). Consistent with current knowledge , patisiran demonstrated superior clinical stabilization, with a significantly higher proportion of total responders (59.3% vs. 23.5%) and slower annualized NIS progression (median +0.31 vs. +4.00 points/year) compared to inotersen (Adams et al., 2018). These results align with long-term extension studies showing sustained neurological benefit and improved quality of life with patisiran (Adams et al., 2025). In contrast, inotersen-treated patients more frequently exhibited partial responses and experienced higher rates of treatment discontinuation due to adverse events, echoing safety concerns reported in NEURO-TTR (Benson et al., 2018). Our study also highlights the importance of baseline neurophysiological and biochemical markers in predicting treatment response. Higher CMAP amplitudes were significantly associated with total response, suggesting that preserved motor axonal function at treatment initiation is a key determinant of favorable outcomes. This is consistent with prior literature emphasizing the prognostic value of neurophysiological integrity (P. J. B. Dyck et al., 2019). ESC, a non-invasive marker of small fiber function, also showed promising discriminatory capacity, particularly in the patisiran subgroup, supporting its utility in clinical practice (Moreno-Moraleda et al., 2024). Although baseline CMAP values differed significantly between response groups, NIS scores did not reach statistical significance. This apparent discrepancy is likely related to the different nature and sensitivity of these measures. NIS is a clinical, semi-quantitative composite score that may be affected by inter-observer variability and ceiling effects, particularly in patients with advanced neuropathy, thereby limiting its ability to discriminate between groups in a relatively small cohort. In contrast, CMAP provides an objective, quantitative assessment of motor axonal function and may be more sensitive to differences in disease severity or treatment response, which could explain why only CMAP showed significant between-group differences. Interestingly, while baseline NIS has been shown to predict response to tafamidis in Spanish patients with Val30Met ATTRv-PN amyloidosis (Sanso et al., 2024), our study found that NIS had poor predictive value for response to silencers, with AUCs near 0.5 in both the overall and patisiran-treated subgroups. This discrepancy may reflect mechanistic differences: tafamidis stabilizes the TTR tetramer and may be more effective in early-stage disease, whereas silencers reduce TTR production and appear to retain efficacy even in more advanced stages, as evidenced by our findings in patients with PND stage II. In our cohort, baseline estimated glomerular filtration rate (eGFR) was highest in non-responders and progressively lower in partial and total responders, indicating that patients with better neurological response did not have better-preserved renal function at baseline . . Although baseline albumin and total protein did not reach statistical significance, trends suggest that nutritional status may influence therapeutic response, as previously proposed in cardiac amyloidosis and ATTRv cohorts (Adams et al., 2018; Dongiglio et al., 2022). Treatment persistence was markedly higher with patisiran, with no adverse event–related discontinuations observed, compared to 41.2% in the inotersen group. This difference likely reflects the more favorable safety profile of patisiran’s lipid nanoparticle delivery system, which avoids the thrombocytopenia and renal toxicity risks associated with inotersen (Adams et al., 2018; Benson et al., 2018). Our findings underscore the importance of early diagnosis and intervention. Patients with moderate functional impairment (e.g., PND stage II) still derived meaningful benefit from patisiran, supporting recent calls for proactive screening and early treatment to prevent irreversible nerve damage (Conceição, 2024). Limitations of this study include its retrospective design and potential selection bias. However, the multicenter nature and comprehensive phenotypic, neurophysiological, and biochemical characterization enhance the generalizability of our results. Future prospective studies should validate these findings and explore the role of emerging biomarkers such as NfL (Gragera-Martínez et al., 2025) . In conclusion, this real-world analysis confirms the superior effectiveness and tolerability of patisiran over inotersen in ATTRv-PN amyloidosis. Baseline CMAP and renal function are promising predictors of response, while NIS—predictive in tafamidis-treated patients—does not appear to guide response to silencers. These findings support early intervention and personalized treatment strategies in ATTRv-PN amyloidosis. Declarations Ethics Approval The study adhered to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Approval was obtained from Balearic Islands Research Ethics Committee [CEIm-IB] with the reference code (IB 5669/24 EOm), and all data were anonymized prior to analysis. Funding No funding was received for this study. Author Contributions M.A.R.-S., J.G.-M., C.B.-G., C.B.-G., F.M.-B., C.C.-P., A.A.., A.A.-V., T.S.-M., R.F.-T., S.K.G., L.G., R.E., F.M.-V., and I.L.-L. contributed to patient recruitment and clinical data acquisition across the participating centers. I.L.-L. and E.C.-B. conceived the study, designed the research strategy, and supervised the analytical process. D.H-S., M.V.-G., and P.H-S. contributed to data management, processing, and verification, and provided analytical support. I.L.-L. and E.C.-B. drafted the manuscript. All authors reviewed the manuscript critically for important intellectual content, contributed to revisions, and approved the final submitted version. Conflicts of Interest M.A.R.-S., J.G.-M., C.B.-G., C.B.-G., F.M.-B., C.C.-P., A.A.., A.A.-V., T.S.-M., R.F.-T., S.K.G., L.G., R.E., F.M.-V., P H.-S., I.L.-L., and E.C.-B. have received support for conference attendance and/or honoraria for advisory or speaking activities from Alnylam Pharmaceuticals and Sobi. M.V.-G. and D.H-S. declare no conflicts of interest. Data Availability The data supporting the findings of this study are available from the corresponding author upon reasonable request. References Adams, D., Ando, Y., Beirão, J. M., Coelho, T., Gertz, M. A., Gillmore, J. D., Hawkins, P. N., Lousada, I., Suhr, O. B., & Merlini, G. (2021). 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L., Chan, A., Gilbert, J. A., Erbe, D., Aldinc, E., Reilly, M. M., Adams, D., Polydefkis, M., Fitzgerald, K., Vaishnaw, A., & Nioi, P. (2021). Neurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis. Neurology , 96 (3), E412–E422. https://doi.org/10.1212/WNL.0000000000011090 “TTR”[GENE] - ClinVar - NCBI . (n.d.). Retrieved February 22, 2026, from https://www.ncbi.nlm.nih.gov/clinvar Vinik, E. J., Vinik, A. I., Paulson, J. F., Merkies, I. S. J., Packman, J., Grogan, D. R., & Coelho, T. (2014). Norfolk QOL-DN: Validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy. Journal of the Peripheral Nervous System , 19 (2), 104–114. https://doi.org/10.1111/jns5.12059 Additional Declarations Competing interest reported. M.A.R.-S., J.G.-M., C.B.-G., C.B.-G., F.M.-B., C.C.-P., A.A.., A.A.-V., T.S.-M., R.F.-T., S.K.G., L.G., R.E., F.M.-V., P H.-S., I.L.-L., and E.C.-B. have received support for conference attendance and/or honoraria for advisory or speaking activities from Alnylam Pharmaceuticals and Sobi. M.V.-G. and D.H-S. declare no conflicts of interest. 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Cisneros-Barroso","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYLCCBAMbOX4wo4BYLR8q0owlG8B6idTBOOPM4USDAyAmMVr4JdIvPuZtS0swPr868cMDAwZ5frED+LVIzsgpNuZts8kzu/F2swTQYYYzZyfg12JwIydNGmhLsdmNsxtAWhIMbhPQYn8jJ/03b9vhxM0zzm7+QZQWA4n0Y2Dvb+Dv3UacLRJn3jBLgAJZ4gbvNosEAwnCfuFvT3/4ARyV/Wc33/xRYSPPL01ACwMDDzQuJMAqJQgpBwH2B1D7DhCjehSMglEwCkYiAACZRki7pTf18gAAAABJRU5ErkJggg==","orcid":"","institution":"Hospital Universitario Son Llàtzer","correspondingAuthor":true,"prefix":"","firstName":"Eugenia","middleName":"","lastName":"Cisneros-Barroso","suffix":""}],"badges":[],"createdAt":"2026-03-03 10:53:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9019314/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9019314/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104876505,"identity":"e69380b8-5d33-4b14-ae9e-7396405aab1a","added_by":"auto","created_at":"2026-03-18 08:42:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47068,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of response categories by treatment.\u003c/strong\u003eStacked bars show the proportion of total responders, partial responders, and non-responders in each group.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9019314/v1/a19de750128453bb5e3481d1.jpg"},{"id":104876589,"identity":"790187b9-ed36-4226-aeea-82c6876e65f7","added_by":"auto","created_at":"2026-03-18 08:43:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":62668,"visible":true,"origin":"","legend":"\u003cp\u003eAnnualized NIS change per year by treatment, with individual observations overlaid . The dashed red line marks the non-responder threshold at +2 points/year.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9019314/v1/88147e03ef41b177d941abc7.jpg"},{"id":104876789,"identity":"b778289f-c226-4629-94e1-56261cee2328","added_by":"auto","created_at":"2026-03-18 08:43:39","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86415,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier estimates of on‑treatment persistence by therapy.\u003c/strong\u003eThe y‑axis reflects the probability of continuing treatment over time. Patisiran showed higher continuation compared with inotersen (log‑rank p = 0.0005).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9019314/v1/e7375c2bc7fc70dc7379857f.jpg"},{"id":105034358,"identity":"37a52dd7-36c4-4512-a88d-abbf67610787","added_by":"auto","created_at":"2026-03-20 07:23:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1642643,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9019314/v1/7a9d38d8-0bdf-4c92-b1a4-ff2ef553d937.pdf"}],"financialInterests":"Competing interest reported. M.A.R.-S., J.G.-M., C.B.-G., C.B.-G., F.M.-B., C.C.-P., A.A.., A.A.-V., T.S.-M., R.F.-T., S.K.G., L.G., R.E., F.M.-V., P H.-S., I.L.-L., and E.C.-B. have received support for conference attendance and/or honoraria for advisory or speaking activities from Alnylam Pharmaceuticals and Sobi. M.V.-G. and D.H-S. declare no conflicts of interest.","formattedTitle":"Real-World Effectiveness and Clinical Predictors of Response to First-Generation TTR Silencers in Variant ATTR Amyloidosis with Polyneuropathy","fulltext":[{"header":"Background","content":"\u003cp\u003eVariant transthyretin (ATTRv) amyloidosis is a multisystem disorder caused by pathogenic \u003cem\u003eTTR\u003c/em\u003e variants that promote extracellular amyloid deposition in nerves and other organs\u0026nbsp;(Buxbaum et al., 2022; Poli et al., 2023).\u0026nbsp;ATTRv amyloidosis encompasses a\u0026nbsp;spectrum of predominantly neurologic and/or cardiac phenotypes, depending on the underlying variant\u0026nbsp;(Kittleson et al., 2020; Poli et al., 2023). Although rare, ATTRv amyloidosis is underrecognized; prevalence varies by geography and founder effects, with global estimates in the low tens of thousands and marked regional clustering\u0026nbsp;(Delgado et al., 2025; Poli et al., 2023). Over 240 TTR missense variants have been described\u003cstrong\u003e(\u003cem\u003e\u0026ldquo;TTR\u0026rdquo;[GENE] - ClinVar - NCBI\u003c/em\u003e, n.d.)\u003c/strong\u003e. Among the most common, p.Val50Met often manifests with neuropathy predominance, whereas p.Val142Ile, enriched in individuals of West African ancestry, often presents with cardiomyopathy, though phenotypic overlap is common\u0026nbsp;\u003cstrong\u003e(Ruberg \u0026amp; Maurer, 2024)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eIn neuropathy-predominant ATTRv amyloidosis, phenotypic heterogeneity is substantial. Early-onset disease frequently shows small-fiber and autonomic involvement, whereas late-onset disease tends toward mixed sensorimotor neuropathy with greater cardiac burden; intra-familial variability further complicates recognition (Poli et al., 2023). Carpal tunnel syndrome, gastrointestinal dysmotility, and weight loss are frequent red flags that precede diagnosis\u0026nbsp;(Adams et al., 2021; Gertz et al., 2020). In these neuropathic phenotypes\u003cstrong\u003e\u003cem\u003e,\u0026nbsp;\u003c/em\u003e\u003c/strong\u003enatural history is characterized by rapid neurological deterioration without therapy, with meta-analytic estimates of Neuropathy Impairment Score (NIS) worsening by approximately 11.8 points per year\u0026mdash; substantially greater than that observed in other neuropathies\u0026nbsp;(Lin et al., 2021). Because neuropathy-predominant presentations often mimic more common neuropathies (for example, chronic inflammatory demyelinating polyneuropathy, or idiopathic axonal neuropathy), consensus pathways emphasize structured screening, exclusion of AL amyloidosis, appropriate imaging or biopsy with amyloid typing, and early \u003cem\u003eTTR\u003c/em\u003e genotyping in unexplained neuropathy\u0026nbsp;(Gertz et al., 2020; Kittleson et al., 2020).\u003c/p\u003e\n\u003cp\u003eClinical trial endpoints commonly include NIS and the modified NIS+7 (mNIS+7), which integrate neurologic examination and neurophysiology to sensitively detect change in ATTRv amyloidosis\u0026nbsp;(P. J. Dyck et al., 2017; P. J. B. Dyck et al., 2019). Health-related quality of life is often assessed with the Norfolk QOL-DN, validated and responsive across disease stages\u0026nbsp;(Vinik et al., 2014). Biomarkers have been increasingly found to be informative: neurofilament light chain (NfL) is elevated in ATTRv neuropathy and declines with patisiran, correlating with clinical improvement and supporting its role in monitoring and earlier diagnosis\u0026nbsp;(Gragera-Mart\u0026iacute;nez et al., 2025; Ticau et al., 2021, 2024). When cardiomyopathy coexists, cardiac biomarkers (NT-proBNP, troponin) and multimodality imaging refine risk and are often the main determinants of survival\u0026nbsp;\u003cstrong\u003e(Kittleson et al., 2020; Ruberg \u0026amp; Maurer, 2024)\u003c/strong\u003e. Nutritional status is clinically relevant. Both modified BMI (calculated as BMI multiplied by serum albumin) and albumin levels alone serve as biomarkers and clinical endpoints in gene-silencing trials, and are associated with patient outcomes \u0026mdash; including in cardiac amyloidosis\u0026nbsp;(Adams et al., 2018; Dongiglio et al., 2022). Autonomic dysfunction is prevalent; electrochemical skin conductance (ESC, Sudoscan) provides a rapid, noninvasive small-fiber measure that differentiates ATTRv patients from carriers or controls and complements standard electrophysiology\u0026nbsp;(Moreno-Moraleda et al., 2024; Novak, 2019).\u003c/p\u003e\n\u003cp\u003eGene-silencing therapies have transformed outcomes. In APOLLO, patisiran improved mNIS+7 and quality of life versus placebo, with favorable effects on gait speed and modified BMI\u0026nbsp;(Adams et al., 2018). In NEURO-TTR, inotersen significantly slowed progression on mNIS+7 and Norfolk QOL-DN\u0026nbsp;(Benson et al., 2018). The subcutaneous siRNA vutrisiran (HELIOS-A) met primary and secondary endpoints versus an external placebo, improving neuropathy, function, and nutritional status\u0026nbsp;(Adams et al., 2023; Keam, 2022). Eplontersen (NEURO-TTRansform) further reduced serum ATTR and stabilized mNIS+7 with quality-of-life gains versus external placebo\u0026nbsp;(Coelho et al., 2023).\u0026nbsp;Despite therapeutic advances, real-world treatment responses remain heterogeneous and difficult to predict, with variability attributable to phenotype, disease stage, and concomitant cardiomyopathy. There is a clear need for clinically deployable predictors to support therapy selection, prognostication, and optimization of treatment timing in routine practice, particularly in settings constrained by access, monitoring capacity, and patient frailty. To address this evidence gap, we conducted a real-world analysis assessing baseline clinical, neurophysiological, and biochemical parameters as candidate predictors of response to \u003cem\u003eTTR\u003c/em\u003e-silencing therapies, with the objective of translating trial efficacy into actionable guidance for everyday care. \u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Setting\u003c/strong\u003eThis was a multicenter, retrospective, observational study conducted across ten Spanish referral hospitals for amyloidosis: Hospital Universitario Son Ll\u0026agrave;tzer, Hospital Juan Ram\u0026oacute;n Jim\u0026eacute;nez, Hospital Cl\u0026iacute;nico San Carlos, Hospital universitario Vall d\u0026rsquo;Hebron, Hospital universitario Bellvitge, Hospital Clinic de Barcelona, Hospital universitario La Fe, Hospital universitario Salamanca, Hospital universitario Basurto and Hospital universitario Donosti. The study aimed to evaluate real-world effectiveness, safety, and predictors of response to first-generation \u003cem\u003eTTR\u003c/em\u003e silencers in patients with \u0026nbsp;ATTRv-PN amyloidosis. All patients provided written informed consent prior to inclusion, in accordance with ethical standards for clinical research publication.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eWe included adult patients (\u0026ge;18 years) with genetically confirmed ATTRv-PN who received patisiran or inotersen for at least six months between 2015 and 2024. Diagnosis required a pathogenic \u003cem\u003eTTR\u003c/em\u003e variant and clinical features consistent with ATTRv-PN, supported by abnormal nerve conduction studies or at least two abnormal small-fiber tests (e.g., thermotest, sympathetic skin response, R\u0026ndash;R interval, or Sudoscan\u0026reg;). Patients with non-\u003cem\u003eTTR\u003c/em\u003e amyloidosis or hematologic malignancies (e.g., multiple myeloma, lymphoma, leukemia, or macroglobulinemia) were excluded. Some patients had initiated treatment as part of clinical trials prior to commercial availability.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003ePatients received patisiran (0.3 mg/kg intravenously every three weeks) or inotersen (284 mg subcutaneously weekly), administered according to routine clinical practice. No protocol-driven treatment changes were made.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eData Collection\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eData were extracted from electronic medical records and entered into a secure anonymized database. Baseline variables included demographics (age, sex, family history), clinical phenotype (early-onset, late-onset, or mixed), functional staging (Coutinho and PND scores), and comorbidities (e.g., hypertension, diabetes, HIV). Neuropathy severity was assessed using the Neuropathy Impairment Score (NIS) at diagnosis, treatment initiation, and last follow-up. Quality of life was measured using the Norfolk QOL-DN questionnaire.\u003c/p\u003e\n\u003cp\u003eNeurophysiological assessments included compound muscle action potential (CMAP), sensory nerve action potential (SNAP), and electrochemical skin conductance (ESC) via Sudoscan\u0026reg;. Laboratory parameters included NT-proBNP, troponin I, estimated glomerular filtration rate (eGFR), total protein, albumin, transthyretin (ATTR), vitamin A, and retinol-binding protein (RBP). Treatment details (start/end dates, duration, discontinuation reasons, subsequent therapies) and \u003cem\u003eTTR\u003c/em\u003e genotype were also recorded.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eDefinition of Treatment Response\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003ePatients were classified into three response categories based on clinical and NIS evolution:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eTotal responders:\u003c/strong\u003e no clinical progression and NIS increase \u0026le;2 points.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNon-responders:\u003c/strong\u003e progression similar to natural history, defined as NIS increase \u0026gt;10 points/year.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePartial responders:\u003c/strong\u003e intermediate pattern, with stability of autonomic symptoms without meeting full response criteria(Monteiro et al., 2019).\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was the association between baseline variables and treatment response. Secondary outcomes included annualized NIS progression, treatment persistence, safety, and reasons for discontinuation.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eContinuous variables were summarized as mean \u0026plusmn; standard deviation or median (interquartile range), and categorical variables as frequencies and percentages. Normality was assessed using the Shapiro\u0026ndash;Wilk test and Q\u0026ndash;Q plots. Group comparisons used ANOVA or Kruskal\u0026ndash;Wallis tests for continuous variables and \u0026chi;\u0026sup2; or Fisher\u0026rsquo;s exact tests for categorical variables.\u003c/p\u003e\n\u003cp\u003eReceiver operating characteristic (ROC) curves were used to evaluate the predictive performance of baseline NIS, albumin, total protein, and TTR, with area under the curve (AUC). Kaplan\u0026ndash;Meier curves and Cox proportional hazards models were used to analyze time to treatment discontinuation and identify predictors of treatment failure. Analyses were performed using Python (pandas, NumPy, SciPy, scikit-learn, lifelines, matplotlib), with p-values \u0026lt;0.05 considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 98 patients with genetically confirmed ATTRv-PN amyloidosis were included in the study, receiving treatment with either patisiran (n = 81) or inotersen (n = 17). The mean age at treatment initiation was 64.3 years (range: 27\u0026ndash;85), with a predominance of male patients (65.3%). In this cohort, the TTR variant Val30Met predominated, accounting for approximately 84.7% (n=83) of genotyped cases. Less frequent variants included Ser77Tyr (\u0026asymp;5.1%, n=5), Val122Ile (\u0026asymp;4.1%, n=4), Val122del (\u0026asymp;2.0%, n=2), Glu89Gln (\u0026asymp;2.0%, n=2), Val28Met (\u0026asymp;1.0%, n=1), and Glu61Gly (\u0026asymp;1.0%, n=1). . The most frequent clinical phenotype was late-onset neurological (52.0%), followed by mixed (34.7%) and early-onset neurological presentation (13.3%). As shown in Table I, no statistically significant differences were observed between response groups in terms of age, sex, clinical phenotype, or baseline functional stage (Coutinho and PND scales) (p \u0026gt; 0.05). However, two variables showed statistically significant differences across response groups. Patients classified as Total responders exhibited baseline higher CMAP amplitudes (mean \u0026plusmn; SD: 7.5 \u0026plusmn; 3.8 \u0026micro;V) compared to partial responders (5.3 \u0026plusmn; 3.7 \u0026micro;V) and non-responders (6.3 \u0026plusmn; 3.7 \u0026micro;V) (p = 0.045), suggesting better preservation of motor nerve function may be associated with a more favorable treatment response. Additionally, follow-up duration was significantly longer in Total responders (median: 37.0 months [IQR: 23.5\u0026ndash;50.0]) than in partial (23.0 months [15.0\u0026ndash;39.0]) and non-responders (26.0 months [14.0\u0026ndash;45.0]) (p = 0.04), potentially reflecting greater clinical stability or sustained therapeutic benefit in this subgroup. However, this difference also reflects the study design, since patients could be enrolled with as little as 6 months of prior treatment and therapy was more often discontinued in partial and non-responders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e \u003cstrong\u003eBaseline demographic, clinical, and electrophysiological characteristics of patients with ATTRv-PN.\u003c/strong\u003e Values are presented as mean \u0026plusmn; standard deviation, number (%), or median [interquartile range], as appropriate. P-values refer to comparisons across response groups using ANOVA, chi-square, or Kruskal\u0026ndash;Wallis tests, depending on variable type.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal responders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePartial Responders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-Responders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eDemographics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eAge at treatment initiation (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e64.3 \u0026plusmn; 11.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e64.3 \u0026plusmn; 12.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e65.4 \u0026plusmn; 10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e62.6 \u0026plusmn; 11.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.734\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e64 (65.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e34 (65.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e16 (55.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e14 (82.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.174\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eClinical phenotype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eEarly-onset neurological, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e13 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e8 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.624\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eLate-onset neurological, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e51 (52.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e26 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e18 (62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eMixed, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e34 (34.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e18 (34.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e9 (31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eFunctional staging\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eCoutinho stage I, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e58 (59.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e34 (65.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e14 (48.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e10 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.324\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eCoutinho stage II, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e40 (40.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e18 (34.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e15 (51.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003ePND stage I, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e43 (43.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e22 (42.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e12 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e9 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.412\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003ePND stage II, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e22 (22.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e16 (30.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003ePND stage IIIa, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e20 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e9 (17.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003ePND stage IIIb, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e13 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e6 (20.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eBaseline disease severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eNIS, mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e34.9 \u0026plusmn; 27.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e32.9 \u0026plusmn; 25.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e39.7 \u0026plusmn; 29.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e33.3 \u0026plusmn; 29.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.562\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eNorfolk QOL-DN, mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e46.4 \u0026plusmn; 28.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e40.8 \u0026plusmn; 30.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e52.9 \u0026plusmn; 27.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e50.1 \u0026plusmn; 24.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eCMAP (\u0026micro;V), mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e6.7 \u0026plusmn; 3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7.5 \u0026plusmn; 3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5.3 \u0026plusmn; 3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e6.3 \u0026plusmn; 3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eSNAP (\u0026micro;V), mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e8.5 \u0026plusmn; 11.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7.8 \u0026plusmn; 8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e11.0 \u0026plusmn; 15.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e6.1 \u0026plusmn; 10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.328\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eDysautonomia, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e73 (74.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e39 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e21 (72.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e13 (76.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.947\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eTreatment exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003eFollow-up duration (months), median [IQR]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e34.5 [19.0\u0026ndash;48.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e37.0 [23.5\u0026ndash;50.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e23.0 [15.0\u0026ndash;39.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e26.0 [14.0\u0026ndash;45.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Response Comparison\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the total patients included in the analysis, 81 (82.7%) received patisiran and 17 (17.3%) received inotersen. Response patterns differed significantly between treatment groups (\u0026chi;\u0026sup2; = 7.62, p = 0.022; see Figure 1). Among patients treated with patisiran, 48 (59.3%) achieved a complete response, 20 (24.7%) showed a partial response, and 13 (16.0%) were classified as non-responders. In contrast, the response distribution among inotersen-treated patients was notably different: 4 (23.5%) achieved a complete response, 9 (52.9%) had a partial response, and 4 (23.5%) were non-responders. Notably, patisiran was associated with a higher proportion of Total responders (59.3% vs. 23.5%), whereas inotersen showed a greater proportion of partial responders (52.9% vs. 24.7%). These findings suggest distinct response profiles between the two therapeutic approaches (p \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003eBaseline characteristics were analyzed within each treatment group to explore factors associated with treatment response (Table 2). In the inotersen group (n=17), total responders tended to have better functional status at baseline, with all patients in Coutinho stage I and PND stage I. Although not statistically significant, non-responders were more frequently male (100%) and younger (median age 56.5 years). Notably, the Norfolk QOL-DN score differed significantly across response categories (p = 0.016), with Total responders reporting markedly better baseline quality of life. In contrast, the patisiran group (n=81) showed a more balanced distribution of demographic and clinical features across response categories. However, CMAP values were significantly higher in Total responders (p = 0.041), suggesting better preserved motor nerve function may be associated with favorable outcomes. PND stage II was also more frequent among Total responders in the patisiran group (p = 0.04), indicating potential efficacy even in moderately advanced disease. These findings highlight distinct response profiles between the two therapies and suggest that baseline neurological function and patient-reported outcomes may influence treatment efficacy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Comparison of baseline demographic, clinical, functional, and electrophysiological characteristics between patients treated with inotersen and patisiran, stratified by treatment response.\u003c/strong\u003e Values are expressed as number (%), mean, or median as appropriate. P-values refer to comparisons across response categories within each treatment group, using chi-square or Kruskal\u0026ndash;Wallis tests depending on variable type.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"113%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInotersen\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatisiran\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (n=17)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal responders (n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePartial Responders (n=9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-Responders (n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (n=81)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal responders (n=48)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePartial Responders (n=20)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-Responders (n=13)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003eDemographics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e10 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e54 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e32 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e12 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e10 (77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.602\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eMean Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e64.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e65.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e68.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e56.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.337\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e64.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e64.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e64.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e64.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.718\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 10px;\"\u003e\n \u003cp\u003eClinical Phenotype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eEarly-onset neurological (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e12 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.778\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLate-onset neurological (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e10 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.784\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e41 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e24 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e12 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.477\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eMixed (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e6 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e3 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.748\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e28 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e16 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 10px;\"\u003e\n \u003cp\u003eFunctional Staging\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eCoutinho I (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e10 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e3 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e3 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e48 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e30 (62%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e11 (55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e7 (54%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.772\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eCoutinho II (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e7 (41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e33 (41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e18 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e9 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.772\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ePND I (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e10 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e3 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e3 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e33 (41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e18 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e9 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.772\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ePND II (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e3 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.567\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e19 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e16 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ePND IIIa (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e2 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.365\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e18 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e9 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.615\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003ePND IIIb (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e2 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.365\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e11 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.563\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 10px;\"\u003e\n \u003cp\u003eBaseline Disease Severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eNIS Mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e36.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e27.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e41.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e35.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.766\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e34.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e33.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e38.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e32.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.854\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eDysautonomia (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e14 (82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8 (89%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e59 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e35 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e13 (65%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e11 (85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.465\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eNorfolk Mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e43.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e65.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e34.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e47.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e44.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e46.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e55.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.478\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eCMAP Mean (\u0026micro;V)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e6.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e7.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eSNAP Mean (\u0026micro;V)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e8.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e7.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e12.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.568\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e7.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.927\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eESC (\u0026micro;S)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e98.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e104.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e90.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e101.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.945\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e83.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e91.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e86.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e53.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003ePredictive Value of Baseline Measures for Treatment Response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe evaluated whether baseline neurological and electrophysiological measures predict treatment response in patients with ATTRv-PN amyloidosis receiving silencers. Focusing on Total responders versus non-responders (excluding partial responders), baseline ESC demonstrated the strongest discrimination in the overall cohort (AUC \u0026asymp; 0.68), although this did not reach statistical significance, consistent with limited sample size and overlapping distributions. CMAP showed modest discrimination (AUC \u0026asymp; 0.60), whereas NIS and SNAP performed poorly (Table 3).\u003c/p\u003e\n\u003cp\u003eCMAP was statistically significant in the three-category analysis (complete, partial, none), reflecting a stepwise pattern in which partial responders fell between Total responders and non-responders. However, this gradient attenuates when restricting the analysis strictly to complete versus non-response, reducing contrast and eliminating statistical significance.\u003c/p\u003e\n\u003cp\u003eFindings were directionally consistent within treatment strata. Among patisiran-treated patients, ESC remained the most informative single predictor (AUC \u0026asymp; 0.78) with a near-significant rank-based separation; CMAP was modest, and NIS/SNAP were weak. In the inotersen subgroup, no baseline measure reached statistical significance, and AUC estimates were imprecise due to very small samples.\u003c/p\u003e\n\u003cp\u003eIn the Val30Met subset, the pattern was broadly similar. When restricted to total responders versus non-responders, baseline NIS again showed no meaningful discrimination (AUC \u0026asymp; 0.52), whereas ESC, CMAP and SNAP displayed only modest separation. ESC provided the highest discrimination (AUC \u0026asymp; 0.71), followed by CMAP (AUC \u0026asymp; 0.62) and SNAP (AUC \u0026asymp; 0.62), but none of these differences reached statistical significance on rank-based testing, likely reflecting limited sample size and overlapping ranges between groups (Supplementary Table 1). Overall, the Val30Met analysis confirms that, even within a more genetically homogeneous subgroup, baseline neurological and electrophysiological measures offer only modest and statistically uncertain ability to distinguish patients who will later achieve complete vs no response to silencer therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Comparison of baseline predictors for total and non-responders in the overall cohort and patisiran subgroup.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubset\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePredictor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal responders (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-responders (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian Total responders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian Non-responders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 66px;\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eNIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.797\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e0.522\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eESC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e0.681\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eCMAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e7.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e6.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.241\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e0.599\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eSNAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.448\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e0.566\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 66px;\"\u003e\n \u003cp\u003ePatisiran\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eNIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e0.538\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eESC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e56.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e0.783\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eCMAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e7.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e0.626\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eSNAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e0.528\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResponse-Related Differences in Key Laboratory Parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBiomarker analysis revealed a statistically significant difference in baseline estimated glomerular filtration rate (eGFR) across response groups (p = 0.022), with non-responders exhibiting the highest median eGFR and total responders the lowest (Table 4). Thus, better neurological response was not associated with better preserved renal function at baseline. A trend toward significance was observed in transthyretin (TTR) levels (p = 0.069), suggesting that higher TTR concentrations may be associated with improved treatment response, although this did not reach conventional statistical significance. Similarly, Vitamin A levels demonstrated a near-significant difference (p = 0.067), with non-responders showing the highest median concentrations. This finding may reflect alterations in retinol metabolism or transport, potentially linked to TTR and retinol-binding protein (RBP), both of which also showed non-significant but suggestive trends. No statistically significant differences were found in NT-proBNP, RBP, troponin I (TpI), or total protein levels across response groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Baseline biomarkers across treatment response groups showing median (min\u0026ndash;max) with N, and Kruskal\u0026ndash;Wallis p-values.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"662\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMeasure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTotal responders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePartial responders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eNon-responders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNTproBNP (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e408.0 (15.9\u0026ndash;15569.0) [n=82]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e375.5 (25.0\u0026ndash;6582.0) [n=46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e433.0 (15.9\u0026ndash;15569.0) [n=25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e316.0 (66.4\u0026ndash;4012.0) [n=11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.995\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eeGFR (mL/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e87.0 (30.0\u0026ndash;169.0) [n=94]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e80.3 (30.0\u0026ndash;113.0) [n=52]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e89.88 (31.0\u0026ndash;108.0) [n=26]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e93.0 (51.0\u0026ndash;169.0) [n=16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAlbumin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e43.0 (29\u0026ndash;52) [n=90]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e43.0 (33.9-50.00 [n=49]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e43.0 (29.0\u0026ndash;50.0) [n=25]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e41.25 (33.0\u0026ndash;52.0) [n=16]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.681\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTTR (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.95 (10.0\u0026ndash;35.0) [n=34]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.5 (18.1\u0026ndash;35.0) [n=18]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.3 (13.0\u0026ndash;34.0) [n=7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21.2 (10.0\u0026ndash;29.0) [n=9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRBP (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.2 (1.8\u0026ndash;7.7) [n=25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.6 (4.3\u0026ndash;6.9) [n=13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.6 (2.1\u0026ndash;7.7) [n=5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.02 (1.8\u0026ndash;7.0) [n=7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTpI (ng/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.5 (1.9\u0026ndash;102.0) [n=52]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.0 (2.5\u0026ndash;98.0) [n=31]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26.15 (1.9\u0026ndash;102.0) [n=14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21.0 (7.0\u0026ndash;59.9) [n=7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal protein (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e68.0 (50.0\u0026ndash;77.0) [n=85]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e68.5 (51.0\u0026ndash;77.0) [n=44]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e66.0 (50\u0026ndash;79.9) [n=25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e69.5 (56.3\u0026ndash;76.0) [n=16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVitamin A (mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.64 (0.22\u0026ndash;2.30) [n=24]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.63 (0.55\u0026ndash;0.85) [n=14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.42 (0.28\u0026ndash;1.07) [n=4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.305 (0.22\u0026ndash;2.3) [n=6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eLongitudinal analysis\u003c/h2\u003e\n\u003cp\u003eOverall, within-patient prealbumin declined substantially, expressed as percent reduction from baseline. The mean percent reduction was 80.9% (median 85.7%). In stratified analyses, Patisiran showed a mean percent reduction of 83.6% (95% CI 79.1% to 88.1%; n = 19), while Inotersen showed a mean percent reduction of 72.4% (95% CI 55.1% to 89.8%; n = 6). The between‑treatment difference favored Patisiran by 11.2 percentage points (95% CI \u0026minus;6.1 to 28.5), which did not reach statistical significance (Welch t‑test p = 0.165; Mann\u0026ndash;Whitney p = 0.091).\u003c/p\u003e\n\u003cp\u003eAcross the cohort, annualized changes showed modest average drift with broad heterogeneity. NIS increased by an average of approximately 2.94 points per year (95% CI, 0.71 to 5.17; median 0.63), whereas Norfolk increased by 4.20 points per year (95% CI, 1.36 to 7.04; median 1.70). CMAP and SNAP declined modestly (means \u0026minus;0.32 and \u0026minus;0.67 units per year, respectively). Safety markers demonstrated small average changes with wide dispersion.\u003c/p\u003e\n\u003cp\u003eStratified by treatment, the median annualized NIS change was lower with Patisiran than with Inotersen (Patisiran median 0.31 [IQR \u0026minus;0.45 to 2.66] vs Inotersen median 4.00 [IQR 0.84 to 7.50]; Figure 2), with overlapping IQRs. In exploratory mean-based analyses, the mean annualized NIS change was 1.62 vs 8.69 points/year (Welch t = \u0026minus;1.30; p = 0.211; Hedges g = \u0026minus;0.67) reflecting a moderate effect size and a trend toward benefit that did not meet the threshold for statistical significance., Norfolk increased at similar rates across groups. CMAP and SNAP exhibited small declines in both groups with no significant between-group differences.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnnualized changes in biomarkers were modest with broad dispersion. Cardiac biomarkers showed directionally favorable trends with Patisiran compared with Inotersen. NTproBNP declined with Patisiran (mean \u0026minus;246 pg/mL/year; 95% CI \u0026minus;533 to 42; median \u0026minus;20) versus an increase with Inotersen (mean +496 pg/mL/year; 95% CI \u0026minus;283 to 1275; median +6; Mann-Whitney p = 0.015; Welch t = \u0026minus;1.96, p = 0.071; Hedges g = \u0026minus;0.63). Similarly, troponin declined with Patisiran (mean \u0026minus;1.76 ng/L/year; 95% CI \u0026minus;4.27 to 0.76; median 0.0) versus an increase with Inotersen (mean +2.77 ng/L/year; 95% CI \u0026minus;2.81 to 8.35; median +1.26; Mann-Whitney p = 0.087; Welch t = \u0026minus;1.91, p = 0.094; Hedges g = \u0026minus;0.55). Albumin and total protein changes did not differ significantly between treatments, though albumin medians trended toward greater decline with Inotersen (Mann-Whitney p = 0.059).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety and Treatment permanence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this real-world cohort, adverse event (AE)\u0026ndash;related discontinuations were concentrated in the Inotersen group. AE-related discontinuation occurred in 7 of 98 patients (7.1%), all among those treated with Inotersen (7/17; 41.2%), and was most commonly attributed to intolerance (n = 5; 29.4%), with additional cases of intolerance plus progression (n = 2; 11.8%). No AE-related discontinuations were recorded for Patisiran (0/81; 0%). One Patisiran-treated patient experienced a serious infusion-related reaction after two doses\u0026mdash;severe bronchospasm requiring ICU admission\u0026mdash;in the context of substantial poliomyelitis sequelae; this event did not translate into an AE-coded discontinuation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTherefore, patients treated with patisiran exhibited greater on‑treatment persistence compared with those on inotersen (Figure 3). The continuation curves separated early and remained divergent over follow‑up. The log‑rank test confirmed a statistically significant difference favoring patisiran (\u0026chi;\u0026sup2; = 12.10, p = 0.0005). Median time on treatment was not reached in the patisiran group within the observation window, whereas earlier discontinuations were observed with inotersen. In concordance with the Kaplan\u0026ndash;Meier findings, Cox models\u0026mdash;adjusted for age, sex, phenotype, and clinical markers\u0026mdash;estimated a markedly lower hazard of discontinuation with patisiran versus inotersen (adjusted HR \u0026asymp; 0.42; 95% CI \u0026asymp; 0.23\u0026ndash;0.79; p = 0.0066), reinforcing greater on‑treatment persistence.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis multicenter, real-world study across ten Spanish referral hospitals provides new evidence on the comparative effectiveness, safety, and predictors of response to first-generation \u003cem\u003eTTR\u003c/em\u003e silencers\u0026mdash;patisiran and inotersen\u0026mdash;in patients with transthyretin ATTRv-PN amyloidosis. Our findings confirm and extend the results of pivotal trials, while offering practical insights into treatment selection and monitoring in routine clinical settings (Adams et al., 2018; Benson et al., 2018). Consistent with current knowledge , patisiran demonstrated superior clinical stabilization, with a significantly higher proportion of total responders (59.3% vs. 23.5%) and slower annualized NIS progression (median +0.31 vs. +4.00 points/year) compared to inotersen (Adams et al., 2018). These results align with long-term extension studies showing sustained neurological benefit and improved quality of life with patisiran (Adams et al., 2025). In contrast, inotersen-treated patients more frequently exhibited partial responses and experienced higher rates of treatment discontinuation due to adverse events, echoing safety concerns reported in NEURO-TTR (Benson et al., 2018).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study also highlights the importance of baseline neurophysiological and biochemical markers in predicting treatment response. Higher CMAP amplitudes were significantly associated with total response, suggesting that preserved motor axonal function at treatment initiation is a key determinant of favorable outcomes. This is consistent with prior literature emphasizing the prognostic value of neurophysiological integrity (P. J. B. Dyck et al., 2019). ESC, a non-invasive marker of small fiber function, also showed promising discriminatory capacity, particularly in the patisiran subgroup, supporting its utility in clinical practice (Moreno-Moraleda et al., 2024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough baseline CMAP values differed significantly between response groups, NIS scores did not reach statistical significance. This apparent discrepancy is likely related to the different nature and sensitivity of these measures. NIS is a clinical, semi-quantitative composite score that may be affected by inter-observer variability and ceiling effects, particularly in patients with advanced neuropathy, thereby limiting its ability to discriminate between groups in a relatively small cohort. In contrast, CMAP provides an objective, quantitative assessment of motor axonal function and may be more sensitive to differences in disease severity or treatment response, which could explain why only CMAP showed significant between-group differences.\u003c/p\u003e\n\u003cp\u003eInterestingly, while baseline NIS has been shown to predict response to tafamidis in Spanish patients with Val30Met ATTRv-PN amyloidosis\u0026nbsp;(Sanso et al., 2024), our study found that NIS had poor predictive value for response to silencers, with AUCs near 0.5 in both the overall and patisiran-treated subgroups. This discrepancy may reflect mechanistic differences: tafamidis stabilizes the TTR tetramer and may be more effective in early-stage disease, whereas silencers reduce TTR production and appear to retain efficacy even in more advanced stages, as evidenced by our findings in patients with PND stage II.\u003c/p\u003e\n\u003cp\u003eIn our cohort, baseline estimated glomerular filtration rate (eGFR) was highest in non-responders and progressively lower in partial and total responders, indicating that patients with better neurological response did not have better-preserved renal function at baseline\u003cem\u003e.\u003c/em\u003e . Although baseline albumin and total protein did not reach statistical significance, trends suggest that nutritional status may influence therapeutic response, as previously proposed in cardiac amyloidosis and ATTRv cohorts\u0026nbsp;(Adams et al., 2018; Dongiglio et al., 2022).\u003c/p\u003e\n\u003cp\u003eTreatment persistence was markedly higher with patisiran, with no adverse event\u0026ndash;related discontinuations observed, compared to 41.2% in the inotersen group. This difference likely reflects the more favorable safety profile of patisiran\u0026rsquo;s lipid nanoparticle delivery system, which avoids the thrombocytopenia and renal toxicity risks associated with inotersen\u0026nbsp;(Adams et al., 2018; Benson et al., 2018).\u003c/p\u003e\n\u003cp\u003eOur findings underscore the importance of early diagnosis and intervention. Patients with moderate functional impairment (e.g., PND stage II) still derived meaningful benefit from patisiran, supporting recent calls for proactive screening and early treatment to prevent irreversible nerve damage\u0026nbsp;(Concei\u0026ccedil;\u0026atilde;o, 2024).\u003c/p\u003e\n\u003cp\u003eLimitations of this study include its retrospective design and potential selection bias. However, the multicenter nature and comprehensive phenotypic, neurophysiological, and biochemical characterization enhance the generalizability of our results. Future prospective studies should validate these findings and explore the role of emerging biomarkers such as NfL\u0026nbsp;(Gragera-Mart\u0026iacute;nez et al., 2025)\u0026nbsp;.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this real-world analysis confirms the superior effectiveness and tolerability of patisiran over inotersen in ATTRv-PN amyloidosis. Baseline CMAP and renal function are promising predictors of response, while NIS\u0026mdash;predictive in tafamidis-treated patients\u0026mdash;does not appear to guide response to silencers. These findings support early intervention and personalized treatment strategies in ATTRv-PN amyloidosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics Approval\u003c/p\u003e\n\u003cp\u003eThe study adhered to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Approval was obtained from Balearic Islands Research Ethics Committee [CEIm-IB] with the reference code (IB 5669/24 EOm), and all data were anonymized prior to analysis.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNo funding was received for this study.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eM.A.R.-S., J.G.-M., C.B.-G., C.B.-G., F.M.-B., C.C.-P., A.A.., A.A.-V., T.S.-M., R.F.-T., S.K.G., L.G., R.E., F.M.-V., and I.L.-L. contributed to patient recruitment and clinical data acquisition across the participating centers.\u003c/p\u003e\n\u003cp\u003eI.L.-L. and E.C.-B. conceived the study, designed the research strategy, and supervised the analytical process. D.H-S., M.V.-G., and P.H-S. contributed to data management, processing, and verification, and provided analytical support.\u003c/p\u003e\n\u003cp\u003eI.L.-L. and E.C.-B. drafted the manuscript. All authors reviewed the manuscript critically for important intellectual content, contributed to revisions, and approved the final submitted version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConflicts of Interest\u003c/p\u003e\n\u003cp\u003eM.A.R.-S., J.G.-M., C.B.-G., C.B.-G., F.M.-B., C.C.-P., A.A.., A.A.-V., T.S.-M., R.F.-T., S.K.G., L.G., R.E., F.M.-V., P H.-S., I.L.-L., and E.C.-B. have received support for conference attendance and/or honoraria for advisory or speaking activities from Alnylam Pharmaceuticals and Sobi. M.V.-G. and D.H-S. declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003eData Availability\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAdams, D., Ando, Y., Beir\u0026atilde;o, J. M., Coelho, T., Gertz, M. A., Gillmore, J. D., Hawkins, P. N., Lousada, I., Suhr, O. 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Rate of neuropathic progression in hereditary transthyretin amyloidosis with polyneuropathy and other peripheral neuropathies: a systematic review and meta-analysis. \u003cem\u003eBMC Neurology\u003c/em\u003e, \u003cem\u003e21\u003c/em\u003e(1). https://doi.org/10.1186/s12883-021-02094-y\u003c/li\u003e\n\u003cli\u003eMonteiro, C., Mesgazardeh, J. S., Anselmo, J., Fernandes, J., Novais, M., Rodrigues, C., Brighty, G. J., Powers, D. L., Powers, E. T., Coelho, T., \u0026amp; Kelly, J. W. (2019). Predictive model of response to tafamidis in hereditary ATTR polyneuropathy. \u003cem\u003eJCI Insight\u003c/em\u003e, \u003cem\u003e4\u003c/em\u003e(12). https://doi.org/10.1172/jci.insight.126526\u003c/li\u003e\n\u003cli\u003eMoreno-Moraleda, E., Gonz\u0026aacute;lez-Moreno, J., Cisneros-Barroso, E., Ribot-Sans\u0026oacute;, M. A., Ripoll-Vera, T., Descals, C., Uson, M., Montal\u0026agrave;, J. C., Figuerola, A., Rodr\u0026iacute;guez, A., \u0026amp; Losada, I. (2024). Validating the usefulness of Sudoscan in ATTRv: a single centre experience. \u003cem\u003eNeurological Sciences\u003c/em\u003e, \u003cem\u003e45\u003c/em\u003e(6), 2859\u0026ndash;2867. https://doi.org/10.1007/s10072-024-07311-3\u003c/li\u003e\n\u003cli\u003eNovak, P. (2019). Electrochemical skin conductance: a systematic review. In \u003cem\u003eClinical Autonomic Research\u003c/em\u003e (Vol. 29, Number 1, pp. 17\u0026ndash;29). Dr. Dietrich Steinkopff Verlag GmbH and Co. KG. https://doi.org/10.1007/s10286-017-0467-x\u003c/li\u003e\n\u003cli\u003ePoli, L., Labella, B., Cotti Piccinelli, S., Caria, F., Risi, B., Damioli, S., Padovani, A., \u0026amp; Filosto, M. (2023). Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy. In \u003cem\u003eFrontiers in Neurology\u003c/em\u003e (Vol. 14). Frontiers Media SA. https://doi.org/10.3389/fneur.2023.1242815\u003c/li\u003e\n\u003cli\u003eRuberg, F. L., \u0026amp; Maurer, M. S. (2024). Cardiac Amyloidosis Due to Transthyretin Protein. In \u003cem\u003eJAMA\u003c/em\u003e (Vol. 331, Number 9, pp. 778\u0026ndash;791). American Medical Association. https://doi.org/10.1001/jama.2024.0442\u003c/li\u003e\n\u003cli\u003eSanso, M. A. R., Rodriguez, A. R., Vicente, L. M., Sevilla, T., Garro, C. B., Mart\u0026iacute;n, J. F., Vicente, A. A., de la Prida, M. M., D\u0026aacute;vila, L. G., V\u0026aacute;zquez, L. G., Valle, F. M., Pons, C. C., Bau, A. F., Barroso, E. C., L\u0026oacute;pez, I. L., \u0026amp; Gonz\u0026aacute;lez-Moreno, J. (2024). Real life experience of tafamidis for the treatment of Spanish patients with Val30Met transthyretin amyloidosis with polyneuropathy. \u003cem\u003eMedicina Clinica\u003c/em\u003e, \u003cem\u003e162\u003c/em\u003e(9), e27\u0026ndash;e32. https://doi.org/10.1016/j.medcli.2024.01.008\u003c/li\u003e\n\u003cli\u003eTicau, S., Aldinc, E., Polydefkis, M., Adams, D., Coelho, T., Ueda, M., Hale, C., Vest, J., \u0026amp; Nioi, P. (2024). Treatment response and neurofilament light chain levels with long-term patisiran in hereditary transthyretin-mediated amyloidosis with polyneuropathy: 24-month results of an open-label extension study. \u003cem\u003eAmyloid\u003c/em\u003e, \u003cem\u003e31\u003c/em\u003e(1), 1\u0026ndash;11. https://doi.org/10.1080/13506129.2023.2232520\u003c/li\u003e\n\u003cli\u003eTicau, S., Sridharan, G. V., Tsour, S., Cantley, W. L., Chan, A., Gilbert, J. A., Erbe, D., Aldinc, E., Reilly, M. M., Adams, D., Polydefkis, M., Fitzgerald, K., Vaishnaw, A., \u0026amp; Nioi, P. (2021). Neurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis. \u003cem\u003eNeurology\u003c/em\u003e, \u003cem\u003e96\u003c/em\u003e(3), E412\u0026ndash;E422. https://doi.org/10.1212/WNL.0000000000011090\u003c/li\u003e\n\u003cli\u003e\u003cem\u003e\u0026ldquo;TTR\u0026rdquo;[GENE] - ClinVar - NCBI\u003c/em\u003e. (n.d.). Retrieved February 22, 2026, from https://www.ncbi.nlm.nih.gov/clinvar\u003c/li\u003e\n\u003cli\u003eVinik, E. J., Vinik, A. I., Paulson, J. F., Merkies, I. S. J., Packman, J., Grogan, D. R., \u0026amp; Coelho, T. (2014). Norfolk QOL-DN: Validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy. \u003cem\u003eJournal of the Peripheral Nervous System\u003c/em\u003e, \u003cem\u003e19\u003c/em\u003e(2), 104\u0026ndash;114. https://doi.org/10.1111/jns5.12059\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ATTRv, patisiran, inotersen, treatment response","lastPublishedDoi":"10.21203/rs.3.rs-9019314/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9019314/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Transthyretin (TTR) gene-silencing therapies have transformed the management of variant transthyretin amyloidosis with polyneuropathy (ATTRv-PN). However, real-world evidence on effectiveness, safety, and durability is limited.\u003c/p\u003e\n\u003cp\u003eMethods: We conducted a multicenter retrospective study across ten Spanish referral hospitals including 98 genetically confirmed ATTRv-PN patients treated with patisiran (n=81) or inotersen (n=17). Patients were classified as total, partial, or non-responders according to clinical evolution and Neuropathy Impairment Score (NIS). Baseline clinical, neurophysiological (CMAP, SNAP, ESC), and biochemical parameters were analyzed. Longitudinal NIS changes, treatment persistence, and safety were assessed.\u003c/p\u003e\n\u003cp\u003eResults: Total responders had higher baseline CMAP amplitudes (p=0.045) and better renal function (eGFR, p=0.022). Compared with inotersen, patisiran showed a higher total response rate (59.3% vs. 23.5%), slower NIS progression (median +0.31 vs. +4.00 points/year; p=0.011), and greater treatment persistence (log-rank p=0.0005). No discontinuations due to adverse events occurred with patisiran, versus 41.2% with inotersen. ESC showed the highest predictive value (AUC 0.681 overall; 0.783 in the patisiran subgroup), while baseline NIS was less informative.\u003c/p\u003e\n\u003cp\u003eConclusions: In routine practice, patisiran demonstrated superior efficacy, safety, and durability compared with inotersen. Baseline motor nerve function and renal status may help guide therapeutic decisions, supporting early and personalized treatment strategies.\u003c/p\u003e","manuscriptTitle":"Real-World Effectiveness and Clinical Predictors of Response to First-Generation TTR Silencers in Variant ATTR Amyloidosis with Polyneuropathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-18 08:39:00","doi":"10.21203/rs.3.rs-9019314/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-31T05:59:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-30T07:26:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-16T03:29:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"162000465674956237854916044174013972063","date":"2026-03-15T08:53:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"302474832848028533815583067964521291058","date":"2026-03-13T15:01:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-13T14:45:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-13T14:40:32+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-13T08:01:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-09T17:19:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-03-09T13:40:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f33a31a0-4d0a-44e6-8424-e88cdbeaaba7","owner":[],"postedDate":"March 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64545177,"name":"Health sciences/Diseases"},{"id":64545178,"name":"Health sciences/Medical research"},{"id":64545179,"name":"Health sciences/Nephrology"},{"id":64545180,"name":"Health sciences/Neurology"},{"id":64545181,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-13T16:23:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-18 08:39:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9019314","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9019314","identity":"rs-9019314","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}