Neuropathy Impairment Score-Lower Limb Research Articles

Indirect treatment comparison (ITC) of the efficacy of vutrisiran and tafamidis for hereditary transthyretin-mediated amyloidosis with polyneuropathy

ABSTRACT Background Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis. Research design and methods Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI). Results Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: −5.3 [95% confidence interval (CI): −9.4, −1.2; p = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: −18.3 [95% CI: −28.6, −8.0; p < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p = 0.020]). Conclusions This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy.

Tafamidis, a Noninvasive Therapy for Delaying Transthyretin Familial Amyloid Polyneuropathy: Systematic Review and Meta-Analysis.

Background and PurposeTafamidis functions to delay the loss of function in transthyretin familial amyloid polyneuropathy (TTR-FAP), which is a rare inherited amyloidosis with progressive sensorimotor and autonomic polyneuropathy. This systematic literature review and meta-analysis evaluated the efficacy and safety of tafamidis in TTR-FAP patients, with the aim of improving the evidence-based medical evidence of this treatment option for TTP-FAP.MethodsA systematic search of the English-language literature in five databases was performed through to May 31, 2018 by two reviewers who independently extracted data and assessed the risk of bias. We extracted efficacy and safety outcomes and performed a meta-analysis. Statistical tests were performed to check for heterogeneity and publication bias.ResultsThe meta-analysis identified six relevant studies. The tafamidis group showed smaller changes from baseline in the Neuropathy Impairment Score–Lower Limbs [mean difference (MD)=−3.01, 95% confidence interval (CI)=−3.26 to −2.75, p<0.001] and the Norfolk Quality of Life-Diabetic Neuropathy total quality of life score (MD=−6.67, 95% CI=−9.70 to −3.64, p<0.001), and a higher modified body mass index (MD=72.45, 95% CI=69.41 to 75.49, p<0.001), with no significant difference in total adverse events [odds ratio (OR)=0.69, 95% CI=0.35 to 1.35, p=0.27]. The incidence of adverse events did not differ between tafamidis and placebo treatment except for fatigue (OR=0.13, 95% CI=0.02 to 0.72, p=0.02) and hypesthesia (OR=0.16, 95% CI=0.03 to 0.92, p=0.04).ConclusionsThis systematic review and meta-analysis has demonstrated that tafamidis delays neurologic progression and preserves a better nutritional status and the quality of life. The rates of adverse events did not differ between the patients in the tafamidis and placebo groups. Tafamidis might be a safer noninvasive option for patients with TTR-FAP.

An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy

ABSTRACTBackground: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.Research design and methods: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.Results: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (–5.49) and QoL-DN (–13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.Conclusions: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.

6MWT performance correlates with peripheral neuropathy but not with cardiac involvement in patients with hereditary transthyretin amyloidosis (hATTR)

Hereditary transthyretin amyloidosis (hATTR) is a life-threatening multisystemic disease with sensory-motor peripheral neuropathy, cardiomyopathy and dysautonomia. Although the six-minute walk test (6MWT) is one of the most popular clinical tests to assess functional exercise capacity in cardiopulmonary and neuromuscular diseases, little is known about 6MWT in evaluating hATTR patients. A prospective single-center pilot study was performed in twenty hATTR patients, comparing 6MWT with widely used outcome measures. After 18 months, fourteen patients were re-evaluated. 6MWT performance was highly related with familial amyloidotic polyneuropathy stage and polyneuropathy disability score, and with CMT examination score, neuropathy impairment score-lower limbs and Kumamoto score. There was no correlation with compound autonomic dysfunction test, modified body mass index and numerous indices of heart dysfunction. After 18 months, familial amyloidotic polyneuropathy stage and polyneuropathy disability score systems were not able to reveal any significant change, whereas all other outcome measures significantly worsened. Among the outcome measures monitoring the neuropathic disturbances, neuropathy impairment score-lower limbs showed the highest responsiveness to change (adjusted effect size: 0.79), followed by CMT examination score (0.67), Kumamoto scale (0.65), 6MWT (0.62). 10MWT showed a very small value (0.21). Compound autonomic dysfunction test had a large value (0.91) whereas modified body mass index a small/moderate value (0.49). 6MWT is a simple and sensitive tool to monitor neuropathic involvement but not cardiac dysfunction in hATTR course.

Understanding the Disease Course and Therapeutic Benefit of Tafamidis Across Real-World Studies of Hereditary Transthyretin Amyloidosis with Polyneuropathy: A Proof of Concept for Integrative Data Analytic Approaches.

IntroductionHereditary transthyretin (TTR) amyloidosis with polyneuropathy (hATTR-PN) is a rare, autosomal dominant amyloidosis characterized primarily by progressive ascending sensorimotor neuropathy often associated with autonomic involvement. hATTR-PN is caused by a mutation in the TTR gene leading to protein misfolding and amyloid accumulation in peripheral nerves and vital organs. The latest global prevalence estimates point to 10,000 cases worldwide, with an upper end of about 40,000. Tafamidis has been approved in over 40 countries for delaying neurologic disease progression in early-stage hATTR-PN. Multiple observational studies have examined clinical outcomes in hATTR-PN patients treated with tafamidis in the routine clinical setting. Integrative data analysis (IDA) is a technique for optimally constructing synthetic treatment and control cohorts from multiple independent studies, which allows meta-analysis of patient-level data. Herein, we provide a proof of concept for the application of IDA to real-world and natural history hATTR-PN data. IDA permits increased understanding of outcomes in tafamidis-treated and untreated persons with hATTR-PN by optimally pooling all available information.MethodsSummary statistics corresponding to the Neuropathy Impairment Score-Lower Limb (NIS-LL) from five published studies were pooled, converted to change from baseline means and variances, and analyzed using IDA. IDA-based synthetic cohorts were generated by averaging across studies stratified on treatment versus control cohort. Trends in change from baseline in each study and the corresponding synthetic cohorts were plotted. Patient-level data were simulated from the synthetic cohort trends in a Monte Carlo simulation to highlight the ability to contrast synthetic cohort trends using the mixed model for repeated measures (MMRM).ResultsThe average sample size among the five studies was 71 (37–128) patients. The average NIS-LL trends indicated that tafamidis-treated patients experienced slower progression in neuropathy compared to untreated patients. Synthetic cohort trends reflected the trends observed in the contributing studies, while simultaneously shrinking the width of corresponding confidence bands. Monte Carlo simulation results demonstrated precise recovery of the synthetic cohort and time-dependent simulated NIS-LL means by the MMRM.DiscussionThis proof of concept demonstrates the utility of IDA-based synthetic cohorts for increased precision in characterizing and testing hypotheses about treatment outcomes and prognosis in hATTR-PN.FundingPfizer.Plain Language SummaryPlain language summary available for this article.

Tafamidis delays neurological progression comparably across Val30Met and non-Val30Met genotypes in transthyretin familial amyloid polyneuropathy.

Background and purposeTo better characterize the effects of tafamidis in non‐Val30Met patients with transthyretin familial amyloid polyneuropathy, this post hoc analysis compared the neurological results from a 12‐month, open‐label study of non‐Val30Met versus Val30Met patients at month 12 from the 18‐month, double‐blind, placebo‐controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity.MethodsNeurological function was assessed using the Neuropathy Impairment Score – Lower Limbs (NIS‐LL) in three cohorts: Val30Met tafamidis (n = 64), Val30Met placebo (n = 61) and non‐Val30Met tafamidis (n = 21). The change in NIS‐LL from baseline to month 12 for Val30Met and non‐Val30Met tafamidis‐treated patients was compared with the change from baseline at month 12 for Val30Met placebo‐treated patients using a mixed‐effects model for repeated measures (MMRM).ResultsThe baseline adjusted mean (standard error) change in NIS‐LL values at month 12 was similar for Val30Met [1.60 (0.78)] and non‐Val30Met [1.62 (1.43)] tafamidis‐treated patients and less than that observed in the Val30Met placebo‐treated group [4.72 (0.77); P = 0.0055 for Val30Met and P = 0.0592 for non‐Val30Met]. Based on the MMRM, the magnitude of change in both tafamidis‐treated cohorts was similar across the range of observed baseline NIS‐LL values, and was consistently less than that observed in the Val30Met placebo‐treated group at month 12.ConclusionsThis baseline‐adjusted analysis demonstrated that tafamidis treatment delayed neurological progression comparably in Val30Met and non‐Val30Met patients across a range of baseline NIS‐LL values. Neurological progression in these two genotype groups may be more similar than previously considered.

Organ Biomarker Responses in Patients With Light Chain Amyloidosis Treated With NEOD001 Are Independent of Previous Hematologic Response

Organ Biomarker Responses in Patients With Light Chain Amyloidosis Treated With NEOD001 Are Independent of Previous Hematologic Response

Tafamidis delays disease progression in patients with early stage transthyretin familial amyloid polyneuropathy: additional supportive analyses from the pivotal trial

Background: Tafamidis, a non-NSAID highly specific transthyretin stabilizer, delayed neurologic disease progression as measured by Neuropathy Impairment Score–Lower Limbs (NIS-LL) in an 18-month, double-blind, placebo-controlled randomized trial in 128 patients with early-stage transthyretin V30M familial amyloid polyneuropathy (ATTRV30M-FAP). The current post hoc analyses aimed to further evaluate the effects of tafamidis in delaying ATTRV30M-FAP progression in this trial.Methods: Pre-specified, repeated-measures analysis of change from baseline in NIS-LL in this trial (ClinicalTrials.gov NCT00409175) was repeated with addition of baseline as covariate and multiple imputation analysis for missing data by treatment group. Change in NIS-LL plus three small-fiber nerve tests (NIS-LL + Σ3) and NIS-LL plus seven nerve tests (NIS-LL + Σ7) were assessed without baseline as covariate. Treatment outcomes over the NIS-LL, Σ3, Σ7, modified body mass index and Norfolk Quality of Life–Diabetic Neuropathy Total Quality of Life Score were also examined using multivariate analysis techniques.Results: Neuropathy progression based on NIS-LL change from baseline to Month 18 remained significantly reduced for tafamidis versus placebo in the baseline-adjusted and multiple imputation analyses. NIS-LL + Σ3 and NIS-LL + Σ7 captured significant treatment group differences. Multivariate analyses provided strong statistical evidence for a superior tafamidis treatment effect.Conclusions: These supportive analyses confirm that tafamidis delays neurologic progression in early-stage ATTRV30M-FAP.Trial registration number: NCT00409175.

Clinical measures in transthyretin familial amyloid polyneuropathy.

This observational, cross-sectional, single-center study aimed to identify instruments capable of measuring disease progression in transthyretin familial amyloid polyneuropathy (TTR-FAP). The relationship between disease stage and Neuropathy Impairment Score-Lower Limbs (NIS-LL) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score was assessed in 61 (stages 1-3) patients with TTR-FAP (V30M variant) and 16 healthy controls. Composite measures of large- and small-nerve fiber function, and modified body mass index (mBMI) were also assessed. Ordinal-based NIS-LL and Norfolk QOL-DN scores discriminated between disease stages (P < 0.0001 for NIS-LL and Norfolk QOL-DN). Longer disease duration correlated with worse NIS-LL and Norfolk QOL-DN. Karnofsky performance score declined progressively by disease stage. Composite measures of nerve fiber function differentiated stage 1 from stage 2 disease. The mBMI declined with advancing disease. NIS-LL, Norfolk QOL-DN score, composite endpoints of nerve fiber function, and mBMI are valid, reliable measures of TTR-FAP severity. Muscle Nerve 55: 323-332, 2017.

NEOD001 Demonstrates Organ Biomarker Responses in Patients with Light Chain Amyloidosis and Persistent Organ Dysfunction: Results from the Expansion Cohort of a Phase 1/2 Study

Introduction: Systemic amyloidoses are a group of rare disorders characterized by the accumulation of misfolded proteins in tissue, resulting in the dysfunction of vital organs (eg, heart and kidneys). In amyloid light chain (AL) amyloidosis, the most common form of systemic amyloidosis, the amyloidogenic protein is a misfolded light chain (LC) or a fragment of an LC produced by clonal plasma cells. Current therapies used to treat AL amyloidosis limit LC production but do not directly target deposits underlying multiorgan failure. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits. In an interim analysis of a phase 1/2 dose-escalation study in 27 patients with AL amyloidosis and persistent organ dysfunction (NCT01707264; EudraCT2012-002683-27), monthly infusions of NEOD001 were safe, well tolerated, and associated with renal and cardiac responses.1 Here we report updated results from the escalation phase and new results from the expansion phase of this study.Patients and Methods: Inclusion criteria for this trial were that patients complete ≥1 PCD treatment before enrollment, attain partial hematologic response (HR) or better to any previous therapy, and have persistent organ dysfunction. NEOD001 was administered intravenously every 28 days. During the dose-escalation phase, 27 patients received NEOD001 at 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design. An additional 42 patients with renal, cardiac, or peripheral nerve involvement were enrolled and treated (24 mg/kg) in the expansion phase. We assessed safety/tolerability, pharmacokinetics, immunogenicity, cardiac and renal responses based on consensus criteria, and neuropathy responses using the Neuropathy Impairment Score-Lower Limb (NIS-LL).Results: The 42 additional patients enrolled in the expansion study included cohorts with renal (16 patients), cardiac (15 patients), and peripheral nerve (11 patients) involvement. In the overall population (n = 69), the median age was 60 years, and 61% of patients were men. Median (range) time since diagnosis was 2.8 (0.4-12.8) years, and 45% of patients underwent ≥3 previous plasma cell-directed regimens. The total number of infusions administered was 913 over a mean of 13.2 (range, 3-35) months. NEOD001 treatment was not associated with dose-limiting toxicities or discontinuations; patients did not develop antidrug antibodies or treatment-related serious adverse events. The most frequent treatment-emergent adverse events, regardless of relationship to study drug, were fatigue, upper respiratory tract infection, nausea, and diarrhea. In a best response analysis, 53% of cardiac-evaluable patients (N = 36) and 63% of renal-evaluable patients (N = 35) met respective criteria for organ response; no patients experienced disease progression. The median time to initial response was 2 months (cardiac) and 4 months (renal). After 9 months of treatment, 82% of patients with measurable peripheral neuropathy at baseline (N = 11) achieved a peripheral neuropathy response based on the NIS-LL score.Conclusions: Our interim results demonstrated that monthly NEOD001 infusions were safe and well tolerated and that organ response rates compared favorably with traditional chemotherapy. These updated results from the escalation phase and these new results from the expansion phase, including results from patients with peripheral nerve involvement, support the design of ongoing late-stage clinical studies. Antibody therapy may allow for effective treatment of patients with AL amyloidosis.Reference: 1. Gertz MA, Landau H, Comenzo RL, et al. First-in-human phase 1/2 study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 2016;34(10):1097-1103. DisclosuresGertz:Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Ionis: Research Funding; Annexon Biosciences: Research Funding. Comenzo:Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx/Amgen: Research Funding. Sanchorawala:Celgene: Research Funding; Takeda: Research Funding; Prothena: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:BMS: Consultancy; Celgene: Consultancy, Research Funding; Prothena: Consultancy; Array Biopharma: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy. Walling:Stealth: Consultancy; BioMarin: Equity Ownership; Apex: Consultancy; Pharm-Olam: Consultancy; NuMedii: Consultancy; Amgen: Equity Ownership, Patents & Royalties; Crown Bioscience: Consultancy; KaloBios: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Corcept: Consultancy; Prothena: Consultancy; Aduro: Consultancy; Codexis: Consultancy; Upsher Smith: Consultancy, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Schenk:Prothena: Employment, Equity Ownership, Other: Leadership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Liu:Prothena: Employment, Equity Ownership; Weston Brain Institute: Honoraria. Liedtke:Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding.

Organ Biomarker Responses in Patients with Light Chain Amyloidosis Treated with NEOD001 Are Independent of Previous Hematologic Response

Organ Biomarker Responses in Patients with Light Chain Amyloidosis Treated with NEOD001 Are Independent of Previous Hematologic Response

The VITAL Amyloidosis Study: A Randomized, Double-Blind, Placebo-Controlled, Global, Phase 3 Study of NEOD001 in Patients with AL Amyloidosis and Cardiac Dysfunction

Background: Amyloid light chain (AL) amyloidosis is caused by the deposition of misfolded light chain (LC) proteins, which may cause organ failure and death. Current treatments, which target the plasma cells that produce LC, induce organ responses in only 30% to 40% of patients. There is a substantial need for a safe and effective amyloid-directed therapy to improve recovery of organ function. NEOD001, a monoclonal antibody that targets misfolded LC, is hypothesized to neutralize circulating LC aggregates and to clear insoluble organ deposits. In an ongoing phase 1/2 study (NCT02613182; Gertz M et al. J Clin Oncol. 2016;34(10):1097-1103) in 27 patients with AL amyloidosis and persistent organ dysfunction, monthly NEOD001 infusions were well tolerated and produced no infusion-related hypersensitivity reactions. In a best response analysis of subjects who fulfilled eligibility criteria at baseline, 57% met cardiac and 60% met renal response criteria. Supported by these positive results, the current study (VITAL; NCT02312206) is a randomized, double-blind, placebo-controlled, phase 3 trial of NEOD001 in patients with cardiac AL amyloidosis. Here we present the study design for this trial in progress.Patients and Methods: Eligible patients (estimated enrollment, 236) with a diagnosis of AL amyloidosis (newly diagnosed, treatment naive) and cardiac dysfunction (N-terminal probrain natriuretic peptide [NT-proBNP] ≥650 and <8500 pg/mL, clinical signs of heart failure, left ventricular wall thickness >12 mm, or cardiac biopsy-detected amyloidosis) and with estimated glomerular filtration rate ≥30 mL/min/1.73 m2 will be randomly assigned (1:1) to receive NEOD001 (24 mg/kg q28d) plus standard of care (SOC) chemotherapy or placebo plus SOC therapy. Subjects will be stratified according to Mayo Clinic stage, renal stage, and 6-minute walk test (6MWT) distance. The primary end point is a composite, evidence-based measure consisting of all-cause mortality or cardiac hospitalization. Key secondary end points include cardiac response measured by NT-proBNP (as defined by Comenzo RL et al. Leukemia. 2012;26(11):2317-2325) and change in 6MWT distance, Short Form-36 Health Survey response, Neuropathy Impairment Score-Lower Limb and renal response (as defined by Palladini G et al. Blood. 2014;124(15):2325-2332). DisclosuresLiedtke:Gilead: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Research Funding. Merlini:Takeda and Janssen-Cilag: Honoraria. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Comenzo:Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding. Sanchorawala:Prothena: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Weiss:Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations; GlaxoSmithKline: Consultancy; Prothena: Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:Array Biopharma: Consultancy; Prothena: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy. Walling:Stealth: Consultancy; KaloBios: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Apex: Consultancy; Corcept: Consultancy; Aduro: Consultancy; Prothena: Consultancy; BioMarin: Equity Ownership; Amgen: Equity Ownership, Patents & Royalties; NuMedii: Consultancy; Pharm-Olam: Consultancy; Crown Bioscience: Consultancy; Codexis: Consultancy; Upsher Smith: Consultancy, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Gertz:Ionis: Research Funding; Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria.

Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Val30Met: A phase III, open-label study

IntroductionThe efficacy and safety of tafamidis in transthyretin (TTR) familial amyloid polyneuropathy (TTR-FAP) were evaluated in this open-label study. MethodsJapanese TTR-FAP patients (n=10; mean age 60.1years) received tafamidis meglumine (20mg daily; median treatment duration 713.5days). The primary endpoint was TTR stabilization at Week 8. Secondary endpoints included Neuropathy Impairment Score-Lower Limb (NIS-LL), Norfolk QOL-DN total quality of life (TQOL), and modified body mass index (mBMI). ResultsTTR stabilization was achieved in all patients at Weeks 8 and 26, 9 out of 10 patients at Week 52, and 8 out of 10 patients at Week 78. The percentage (95% CI) of NIS-LL responders (increase from baseline in NIS-LL<2) was 80.0% (44.4, 97.5), 60.0% (26.2, 87.8), and 40.0% (12.2, 73.8) and mean(SD) NIS-LL change from baseline was 2.1 (5.6), 3.6 (4.4), and 3.3 (4.7), at Weeks 26, 52, and 78, respectively. Mean (SD) changes from baseline in TQOL and mBMI at Weeks 26, 52, and 78 were 11.8 (20.0), 9.1 (12.5), and 10.8 (13.7) for TQOL, and 26.6 (61.9), 64.9 (80.0), and 53.7 (81.4) for mBMI, respectively. Ambulation status was preserved in 4 out of 8 patients at Week 78. Most adverse events (AEs) were mild/moderate, with no discontinuations due to AEs. ConclusionsTafamidis stabilized TTR, was safe and well-tolerated, and was effective over 1.5years in slowing neurologic progression and maintaining TQOL and nutrition status in TTR-FAP.

Tafamidis reduces disease progression in patients with transthyretin familial amyloid polyneuropathy: supportive post-hoc analyses of a pivotal trial

Background Safety and efficacy of once-daily 20 mg tafamidis, a transthyretin (TTR) stabilizer, was evaluated in an 18-month, multicentre, randomized, double-blind, placebo-controlled study in 128 patients with early symptomatic V30M TTR familial amyloid polyneuropathy (TTR-FAP). In the intent-to-treat population, a responder analysis for Neuropathy Impairment Score-Lower Limb (NIS-LL) (co-primary with Norfolk Quality of Life-Diabetic Neuropathy) favoured tafamidis (P=0.07). A pre-specified, key secondary analysis of change from baseline to Month 18 in NIS-LL continuous scores was significant (P=0.04). Placebo-corrected point estimates for 5 pre-specified and validated measures of disease progression also favoured tafamidis and were directionally consistent. Additional post-hoc analyses supporting tafamidis for delaying progression of TTR-FAP are reported here.

In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography.

Transthyretin familial amyloid polyneuropathy is a rare, autosomal-dominant inherited multisystem disorder usually manifesting with a rapidly progressive, axonal, distally-symmetric polyneuropathy. The detection of nerve injury by nerve conduction studies is limited, due to preferential involvement of small-fibres in early stages. We investigated whether lower limb nerve-injury can be detected, localized and quantified in vivo by high-resolution magnetic resonance neurography. We prospectively included 20 patients (12 male and eight female patients, mean age 47.9 years, range 26-66) with confirmed mutation in the transthyretin gene: 13 with symptomatic polyneuropathy and seven asymptomatic gene carriers. A large age- and sex-matched cohort of healthy volunteers served as controls (20 male and 20 female, mean age 48.1 years, range 30-73). All patients received detailed neurological and electrophysiological examinations and were scored using the Neuropathy Impairment Score-Lower Limbs, Neuropathy Deficit and Neuropathy Symptom Score. Magnetic resonance neurography (3 T) was performed with large longitudinal coverage from proximal thigh to ankle-level and separately for each leg (140 axial slices/leg) by using axial T2-weighted (repetition time/echo time = 5970/55 ms) and dual echo (repetition time 5210 ms, echo times 12 and 73 ms) turbo spin echo 2D sequences with spectral fat saturation. A 3D T2-weighted inversion-recovery sequence (repetition time/echo time 3000/202 ms) was acquired for imaging of the spinal nerves and lumbar plexus (50 axial slice reformations). Precise manual segmentation of the spinal/sciatic/tibial/common peroneal nerves was performed on each slice. Histogram-based normalization of nerve-voxel signal intensities was performed using the age- and sex-matched control group as normative reference. Nerve-voxels were subsequently classified as lesion-voxels if a threshold of >1.2 (normalized signal-intensity) was exceeded. At distal thigh level, where a predominant nerve-lesion-voxel burden was observed, signal quantification was performed by calculating proton spin density and T2-relaxation time as microstructural markers of nerve tissue integrity. The total number of nerve-lesion voxels (cumulated from proximal-to-distal) was significantly higher in symptomatic patients (20 405 ± 1586) versus asymptomatic gene carriers (12 294 ± 3199; P = 0.036) and versus controls (6536 ± 467; P < 0.0001). It was also higher in asymptomatic carriers compared to controls (P = 0.043). The number of nerve-lesion voxels was significantly higher at thigh level compared to more distal levels (lower leg/ankle) of the lower extremities (f-value = 279.22, P < 0.0001). Further signal-quantification at this proximal site (thigh level) revealed a significant increase of proton-density (P < 0.0001) and T2-relaxation-time (P = 0.0011) in symptomatic patients, whereas asymptomatic gene-carriers presented with a significant increase of proton-density only. Lower limb nerve injury could be detected and quantified in vivo on microstructural level by magnetic resonance neurography in symptomatic familial amyloid polyneuropathy, and also in yet asymptomatic gene carriers, in whom imaging detection precedes clinical and electrophysiological manifestation. Although symptoms start and prevail distally, the focus of predominant nerve injury and injury progression was found proximally at thigh level with strong and unambiguous lesion-contrast. Imaging of proximal nerve lesions, which are difficult to detect by nerve conduction studies, may have future implications also for other distally-symmetric polyneuropathies.

Tafamidis: A Review of Its Use in Familial Amyloid Polyneuropathy

Oral tafamidis (Vyndaqel(®)) is indicated in the EU for the treatment of transthyretin (TTR) amyloidosis in adult patients with early stage symptomatic polyneuropathy to delay peripheral neurologic impairment and, in Argentina, Japan and Mexico, for delaying the peripheral neurological impairment of TTR familial amyloid polyneuropathy (TTR-FAP). It is the first disease-modifying pharmacotherapy to be approved for use in adult patients with early-stage TTR-FAP. The drug acts to kinetically stabilize the variant TTR tetramer and thereby prevent tetramer dissociation, the rate-limiting step in TTR misfolding and amyloidogenesis. In the 18-month Fx-005 study in adult patients with early-stage V30M TTR-FAP, there were no statistically significant differences between tafamidis and placebo recipients for the coprimary endpoints, the Neuropathy Impairment Score-Lower Limb (NIS-LL) response rate (increase in NIS-LL score of <2) and the least-square mean change in Norfolk Quality-of-Life (QOL) Diabetic-Neuropathy Questionnaire total scores at 18 months, based on modified intent-to-treat analyses. However, in prespecified per-protocol analyses of efficacy evaluable patients, tafamidis recipients experienced significantly better outcomes in terms of these coprimary endpoints, with most (98%) tafamidis recipients showing stabilization of TTR tetramers at study end. Secondary endpoint outcomes also favoured tafamidis treatment over placebo. The beneficial effects of tafamidis in slowing deterioration of neurological function and health-related-QOL were maintained in long-term extension studies (up to 66 months). Tafamidis also stabilized TTR tetramers in patients with non-V30M TTR-FAP. Tafamidis was generally well tolerated, with most treatment-emergent adverse events being of mild to moderate intensity and very few patients discontinuing treatment because of these events. No new safety signals have emerged during long-term extension studies and post-marketing experience.

Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy

The aim of this study was to assess the effect of Tafamidis, which slows the progression of early stages of Met30 transthyretin (TTR) familial amyloidosis polyneuropathy (FAP) in more advanced cases. The study was a prospective, non-randomized controlled trial carried out at the French national reference centre for FAP with follow-up at 1 year. Thirty-seven consecutive Met30-TTR-FAP patients were enrolled between December 2009 and July 2011, with NIS-LL (Neuropathy Impairment Score-lower limbs) > 10 and Karnofsky score > 60. Their mean (SD) age was 56.4 (19) years. Seventy-seven per cent of patients had a walking disability. Seven patients (19%) were withdrawn for adverse effects. The primary study outcome measurements, planned before data collection began, were NIS-LL and NIS-UL (upper limbs) scores and disability scores. Of the 37 patients entered into the study, 29 were evaluated at 6 months and 13 at 12 months. During the first 6 months of treatment, the mean progression of NIS-LL score was 4.8 and was similar to that during the period before treatment. Among the 45% of patients without NIS-LL progression, the NIS-UL score worsened in 55%. During the first year, 55% deteriorated with respect to disability and 38% with respect to NIS only; only two patients (7%) remained stable. Four (out of 20; 20%) patients who were previously stage 1 reached stage 2 (walking with aid) after this period. Two out of nine patients who were initially normotensive developed orthostatic hypotension. There were a total of 19 adverse events, including four febrile urinary tract infections and three severe diarrhoeas, with faecal incontinence in two. In most patients with advanced Met30 TTR-FAP, Tafamidis is not able to stop disease progression, in respect of both NIS-LL and disability. Other anti-amyloid medicines should be assessed in this context.

Tafamidis for transthyretin familial amyloid polyneuropathy

To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.