Transthyretin-mediated Amyloidosis Research Articles

P-48 Neurofilament light chain as a biomarker in hereditary transthyretin-mediated amyloidosis: 36-month data from the patisiran global open-label extension

P-48 Neurofilament light chain as a biomarker in hereditary transthyretin-mediated amyloidosis: 36-month data from the patisiran global open-label extension

A retrospective survey of patients with hereditary transthyretin-mediated (hATTR) amyloidosis treated with patisiran in real-world clinical practice in Belgium

IntroductionHereditary transthyretin-mediated (hATTR) amyloidosis, a genetic disease caused by mutations in the transthyretin gene, leads to progressive sensory and autonomic neuropathy and/or cardiomyopathy and is associated with renal and ophthalmologic manifestations and a poor prognosis.MethodsThis is a retrospective study based on data collected from the medical records of patients with hATTR amyloidosis treated with patisiran between 01 July 2018 and 01 February 2021. Six Belgian neuromuscular reference centers participated, covering all patisiran-treated hATTR amyloidosis patients at the study time. This study was conducted to collect data requested in the context of the reimbursement of patisiran in Belgium.ResultsThirty-one patients were diagnosed with hATTR amyloidosis with polyneuropathy, Coutinho stage 1 or 2, and eligible for active treatment during the data collection period. Of the hATTR amyloidosis patients treated with patisiran (n = 12), seven and five had polyneuropathy stages 1 and 2, respectively. Six patients had cardiac symptoms (New York Heart Association class 2 or above). Follow-up information was available for nine patients. Following patisiran treatment, eight patients showed stable or improved assessments for most neurological or cardiological parameters. Only one patient presented with worsening statuses at the end of the data collection period.ConclusionsThe patients with hATTR amyloidosis in Belgium have similar baseline demographics and disease characteristics to those studied in the patisiran APOLLO study and show a similar therapeutic response in the real-world, altering the expected disease progression in most patients.

Effect of patisiran on stroke volume in hereditary transthyretin-mediated amyloidosis: insights from pressure-volume analysis of the APOLLO study.

Transthyretin-mediated (ATTR) amyloidosis is caused by deposition of transthyretin protein fibrils in the heart, nerves, and other organs. Patisiran, an RNA interference therapeutic that inhibits hepatic synthesis of transthyretin, was approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy based on the phase 3 APOLLO study. We use left ventricular (LV) stroke volume (SV) to quantify LV function overtime and non-invasive pressure-volume techniques to delineate the effects of patisiran on LV mechanics in the pre-specified cardiac subpopulation of the APOLLO study. Left ventricular SV was assessed by transthoracic echocardiography at baseline, and after 9 and 18 months of therapy. To determine the mechanisms underlying changes in LV SV, non-invasive pressure-volume parameters, including the end-systolic and end-diastolic pressure-volume relationship, were derived using single beat techniques. At baseline, the mean SV was 51 ± 14ml. At 9months, the least-squares mean change in SV was -0.3 ± 1.2ml for patisiran and -5.4 ± 1.9ml for placebo (p= 0.021). At 18 months, the least-squares mean change in SV was -1.7 ± 1.3ml for patisiran and - 8.1 ± 2.3ml for placebo (p= 0.016). Decline in LV SV was driven by diminished LV capacitance in placebo relative to patisiran. Patisiran may delay progression of LV chamber dysfunction starting at 9months of therapy. These data elucidate the mechanisms by which transthyretin-reducing therapies modulate progression of cardiac disease and need to be confirmed in ongoing phase 3 trials.

Effect of RNAi therapeutics patisiran and vutrisiran on orthostatic hypotension due to dysautonomia in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy

Effect of RNAi therapeutics patisiran and vutrisiran on orthostatic hypotension due to dysautonomia in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy

HELIOS-A: 18-month exploratory cardiac results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis

HELIOS-A: 18-month exploratory cardiac results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis

Patisiran for the Treatment of Transthyretin-mediated Amyloidosis with Cardiomyopathy.

Transthyretin (TTR) is a tetrameric protein, synthesized primarily by the liver, that acts as a physiological transport protein for retinol and thyroxine. TTR can misfold into pathogenic amyloid fibrils that deposit in the heart and nerves, causing a life-threatening transthyretin amyloidosis cardiomyopathy (ATTR-CM), and a progressive and debilitating polyneuropathy (ATTR-PN). Recent therapeutic advances have resulted in the development of drugs that reduce TTR production. Patisiran is a small interfering RNA that disrupts the complimentary mRNA and inhibits TTR synthesis, and is the first gene-silencing medication licensed for the treatment of ATTR amyloidosis. After encouraging results following the use of patisiran for the treatment of patients with ATTR-PN, there has been increasing interest in the use of patisiran for the treatment of ATTR-CM. Various studies have demonstrated improvements across a wide range of cardiac biomarkers following treatment with patisiran, and have changed the perception of ATTR-CM from being thought of as a terminal disease process, to now being regarded as a treatable disease. These successes represent a huge milestone and have the potential to revolutionize the landscape of treatment for ATTR-CM. However, the long-term safety of patisiran and how best to monitor cardiac response to treatment remain to be determined.

Liver-directed drugs for transthyretin-mediated amyloidosis.

Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low-density lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

Small interfering RNA: Discovery, pharmacology and clinical development-An introductory review.

Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well-defined short double-stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability toallow successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.

Lipid Nanoparticles: A Novel Gene Delivery Technique for Clinical Application.

Lipid nanoparticles (LNPs) are an emerging vehicle for gene delivery that accommodate both nucleic acid and protein. Based on the experience of therapeutic liposomes, current LNPs have been developed based on the chemistry of lipids and RNA and on the biology of human disease. LNPs have been used for the development of Onpattro, an siRNA drug for transthyretin-mediated amyloidosis, in 2018. The subsequent outbreak of COVID-19 required a vaccine for its suppression. LNP-based vaccine production received much attention for this and resulted in great success. In this review, the essential technology of LNP gene delivery has been described according to the chemistry for LNP production and biology for its clinical application.

Effect of RNAi therapeutics patisiran and vutrisiran on orthostatic hypotension due to dysautonomia in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy

Abstract Background Hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, is a rapidly progressive, multisystem disease. Orthostatic hypotension, due to autonomic neuropathy, is a common yet hard-to-treat disease manifestation in patients with hATTR amyloidosis. Fatigue, muscle weakness, and deterioration in cardiac function further exacerbate orthostatic symptoms. Efficacy of RNAi therapeutics patisiran and vutrisiran was assessed in patients with hATTR amyloidosis with polyneuropathy across the APOLLO (NCT01960348), Global Open-Label Extension (OLE) (NCT02510261), and HELIOS-A (NCT03759379) studies, respectively. Purpose Evaluate the quantitative effect of patisiran and vutrisiran on orthostatic hypotension in patients with hATTR amyloidosis with polyneuropathy. Methods In APOLLO, patients were randomised 2:1 to patisiran 0.3 mg/kg or placebo, IV q3w. Patients who completed APOLLO (APOLLO-placebo, APOLLO-patisiran) were eligible to enrol into the ongoing Global OLE (patisiran 0.3 mg/kg IV q3w). In HELIOS-A, patients were randomised 3:1 to vutrisiran (25 mg SC q3m) or patisiran (0.3 mg/kg IV q3w; reference group). Primary endpoint for APOLLO and HELIOS-A was change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7) vs APOLLO placebo at M18 (APOLLO) and M9 (HELIOS-A). Orthostatic hypotension was evaluated using the postural blood pressure (PBP) component of mNIS+7, calculated as the mean of 2 supine readings of systolic BP [SBP, mmHg] taken 15 min apart minus the lowest SBP upon standing at 1, 3, and 5 min. A smaller reduction in observed SBP between supine and upright readings indicated an improved PBP. Results APOLLO enrolled 225 patients (placebo, n=77; patisiran, n=148), Global OLE 211 and HELIOS-A 164 (vutrisiran, n=122; patisiran, n=42). At baseline, the severity of orthostatic hypotension was similar between within-study treatment arms in APOLLO and HELIOS-A. In APOLLO, patisiran-treated patients showed PBP improvement or stabilization from baseline to M18 (mean [SD] change in SBP: baseline, −17.6 [19.4]; M18, −13.5 [16.8]) and was maintained at Global OLE 36m (−13.4 [15.6]). In contrast, placebo-treated patients in APOLLO had an increased change in PBP over 18m (baseline, −17.5 [16.5]; M18, −20.4 [16.9]); their PBP improved after patisiran initiation (Global OLE 36m, −16.6 [18.1]). In HELIOS-A, stabilization in PBP was observed in the vutrisiran arm (baseline, −11.2 [14.0], M18, −11.7 [14.6]). In the smaller patisiran arm, while the change in PBP increased, the value remained in the normal range (baseline, −11.6 [17.2]; M18, −14.2 [15.5]). Patisiran and vutrisiran have acceptable safety profiles. Conclusions PBP analyses quantify the benefits of RNAi therapeutics patisiran and vutrisiran on autonomic function in patients with hATTR amyloidosis with polyneuropathy. The increase in change in PBP to a symptomatic range without treatment indicates the importance of early intervention. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Alnylam Pharmaceuticals

Impact of baseline polyneuropathy severity on patisiran treatment outcomes in the APOLLO trial

Objective Assess how baseline polyneuropathy severity impacts response to patisiran regarding neurologic impairment and quality of life (QOL) in patients with hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis). Methods This post hoc analysis grouped patients from the Phase 3 APOLLO study (n = 225) by baseline Neuropathy Impairment Score (NIS) into quartiles: 6–<31; 31–<57; 57–<85.5; 85.5–141.6. Neurologic impairment (modified NIS+7 [mNIS+7], NIS total score), disability (Rasch-built Overall Disability Scale [R-ODS]), gait speed (10-meter walk test [10-MWT]), grip strength, and QOL (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN] questionnaire) were assessed. Results Across all baseline NIS quartiles, patisiran improved several clinical markers of disease compared with placebo at 18 months. Patients in lower NIS quartiles, treated with patisiran earlier in the disease course, maintained better scores in mNIS+7, NIS total score, R-ODS, 10-MWT, grip strength, and Norfolk QOL-DN versus those in higher NIS quartiles, while placebo-treated patients experienced worsening of all functional measures after 18 months across all quartiles. Conclusions Patisiran treatment improved neurologic function and QOL across a wide range of baseline polyneuropathy severities versus placebo. Timing of treatment initiation in patients with ATTRv amyloidosis remains critical for the preservation of function. (ClinicalTrials.gov number, NCT01960348)

The Silent Period for Small Fiber Sensory Neuropathy Assessment in a Mixed Cohort of Transthyretin-Mediated Amyloidosis.

Background: Transthyretin-mediated amyloidosis (ATTR) is a rare multisystemic disease involving the peripheral nervous system and heart. Autonomic and small fiber involvement is one of the hallmarks of ATTR, and many tools have been proposed to assess this aspect. Aim: The aim of this study was to investigate cutaneous and mixed nerve silent periods (CSP and MnSP) as instruments for small fiber assessment. Methods: A total of 21 ATTR patients, 20 healthy controls, and 18 asymptomatic carriers underwent a sensory conduction study from the right sural and non-dominant ulnar nerves. A motor conduction study from the right deep peroneal and non-dominant ulnar nerves, with their F waves, CSPs, and MnSPs, was performed. Results: The amplitudes of the sural and ulnar sensory nerves and of the peroneal and ulnar motor nerves were reduced in ATTR patients compared to the other groups. F waves from the ulnar and peroneal nerves showed no differences between the three groups. The CSP and MnSP latency, but not amplitude, were increased in both the ulnar and peroneal nerves of ATTR patients. Conclusions: ATTR patients showed axonal involvement of large sensory and motor nerve fibers and demyelinating features of small sensory fibers.

Therapeutic siRNA: State-of-the-Art and Future Perspectives.

The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application of small interfering RNAs (siRNAs), opens novel avenues towards innovative therapies. Two decades after the discovery of the RNA interference mechanism, the first siRNA drugs received approval for clinical use by the US Food and Drug Administration and the European Medicines Agency between 2018 and 2022. These are mainly based on an siRNA conjugation with a targeting moiety for liver hepatocytes, N-acetylgalactosamine, and cover the treatment of acute hepatic porphyria, transthyretin-mediated amyloidosis, hypercholesterolemia, and primary hyperoxaluria type 1. Still, the development of siRNA therapeutics faces several challenges and issues, including the definition of optimal siRNAs in terms of target, sequence, and chemical modifications, siRNA delivery to its intended site of action, and the absence of unspecific off-target effects. Further siRNA drugs are in clinical studies, based on different delivery systems and covering a wide range of different pathologies including metabolic diseases, hematology, infectious diseases, oncology, ocular diseases, and others. This article reviews the knowledge on siRNA design and chemical modification, as well as issues related to siRNA delivery that may be addressed using different delivery systems. Details on the mode of action and clinical status of the various siRNA therapeutics are provided, before giving an outlook on issues regarding the future of siRNA drugs and on their potential as one emerging standard modality in pharmacotherapy. Notably, this may also cover otherwise un-druggable diseases, the definition of non-coding RNAs as targets, and novel concepts of personalized and combination treatment regimens.

Vutrisiran: First Approval

Vutrisiran (AMVUTTRA™) is a subcutaneously administered transthyretin-directed small interfering ribonucleic acid (siRNA) therapeutic (also called RNA interference, or RNAi therapeutic) being developed by Alnylam Pharmaceuticals, Inc. for the treatment of amyloid transthyretin-mediated (ATTR) amyloidosis, including hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis. Vutrisiran was approved in June 2022 in the USA for the treatment of the polyneuropathy of hATTR amyloidosis in adults and received a positive opinion in the EU in July 2022 for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy. Vutrisiran is also under regulatory review for the treatment of the polyneuropathy of hATTR amyloidosis in adults in Japan and Brazil. This article summarizes the milestones in the development of vutrisiran leading to this first approval in hATTR amyloidosis.

Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis.

Transthyretin-mediated amyloidosis is a progressive and fatal disease caused by the build-up of misfolded transthyretin (TTR) protein. Eplontersen is a triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotide targeting TTR messenger ribonucleic acid (mRNA) to inhibit production of both variant and wild-type TTR. We aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for eplontersen and to evaluate the impact of covariates on exposure and response. Plasma eplontersen and serum TTR concentration data were obtained from two phase 1 studies in healthy volunteers (ClinicalTrials.gov: NCT03728634, NCT04302064). Model development was conducted using a nonlinear mixed-effects approach. Eplontersen PK was well described by a two-compartment model. Evaluation of demographics identified significant covariates of lean body mass on clearance and body weight on intercompartmental clearance and volumes of distribution. Population PK modelling showed the absorption rate was 29.6% greater with injection into the abdomen versus the arm. The typical population terminal elimination half-life was 25.5days. Serum TTR was well described by an indirect response model with inhibition of TTR production by eplontersen. Maximum fractional inhibition (Imax ) was 0.970 (0.549%RSE) and the half maximal inhibitory concentration (IC50 ) was 0.0283 ng/ml (13.3%RSE). Simulations showed subjects with lower weight had higher exposure (AUC, Cmax ), while higher Cmax was observed when comparing site of administration (ratio abdomen/arm = 1.18), but differences in exposure did not significantly impact response at evaluated doses. The exposure-response relationship of eplontersen was well characterised by the PKPD model. Weight and injection site were found to affect systemic exposure, but this effect does not seem to result in clinically relevant variation in response.

Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial.

Hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN) progressively affects patients' functionality and compromises health-related quality of life (HRQL). The aim of this study was to quantify the projected long-term treatment effects of inotersen vs placebo on HRQL measures. The inotersen phase 2/3 randomized, double-blind, placebo-controlled trial NEURO-TTR (NCT01737398, 65 weeks) and its subsequent open-label extension (OLE; NCT02175004, 104 weeks) included 172 (112 inotersen and 60 placebo) patients. Placebo double-blind period and overall inotersen-inotersen (double-blind/OLE) treatment period (170 weeks) data were used to extrapolate the long-term placebo-placebo effect using mixed-effects models with repeated measures. Changes from baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) and 36-Item Short Form Health Survey version 2 (SF-36v2) in hATTR-PN were estimated. Differences in changes were compared between the inotersen-inotersen and extrapolated placebo-placebo arms. Inotersen-inotersen patients maintained their HRQL with an observed change ranging from 10.3% improvement (Norfolk QoL-DN item "Pain kept you awake at night") to 11.6% deterioration (SF-36v2 Activities of Daily Living subdomain). The extrapolated placebo-placebo results suggest greater deterioration over time compared with inotersen-inotersen treatment on Norfolk QoL-DN total score (23.6; 95% confidence interval [CI], 8.9-38.3; P < .01), Activities of Daily Living (4.6; 95% CI, 2.0-7.3; P < .001), and "Pain kept you awake at night" (1.2; 95% CI, 0.4-1.9; P < .01). Similarly, greater deterioration was expected for the SF-36v2 Physical Component Summary (8.0; 95% CI, 3.2-12.8, P < .01), Bodily Pain (7.8; 95% CI, 2.0-13.5; P < .01), and Physical Functioning (10.6; 95% CI, 5.5-15.6; P < .0001). Long-term (>3 years) inotersen treatment was associated with slowing and, in some domains, halting of deterioration in key HRQL outcome measures, particularly physical functioning and pain.

Amyloidogenicity assessment of transthyretin gene variants.

ObjectiveHereditary transthyretin‐mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the transthyretin‐gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineation of these into pathogenic or non‐pathogenic is highly desirable but hampered by low frequency and penetrance. We thus sought to characterize their amylogenic potential by an unbiased in vitro approach.MethodsThioflavin T and turbidity assays were used to compare the potential of mammalian cell expressed wt‐transthyretin and 12 variant proteins (either variants of uncertain significance, benign, pathogenic) to aggregate and produce amyloid fibrils in vitro. As proof of principle, the assays were applied to transthyretin‐Ala65Val, a variant that was newly detected in a family with peripheral neuropathy and amyloid deposits in biopsies. In silico analysis was performed to compare the position of the benign and pathogenic variants.ResultsTransthyretin‐Ala65Val showed a significantly higher amyloidogenic potential than wt‐transthyretin, in both turbidity‐ and Thioflavin T‐assays, comparable to known pathogenic variants. The other eight tested variants did not show an increased amyloidogenic potential. In silico structural analysis further confirmed differences between pathogenic and benign variants in position and interactions.InterpretationWe propose a biochemical approach to assess amyloidogenic potential of transthyretin variants. As exemplified by transthyretin‐Ala65Val, data of three assays together with histopathology clearly demonstrates its amyloidogenicity.

Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

Background The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. Methods HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months. Results HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10−12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. Conclusions Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile. ClinicalTrials.gov NCT03759379

Tafamidis Meglumine (Vyndaqel)

&#x0D; CADTH recommends that Vyndaqel should be reimbursed by public drug plans for the treatment of transthyretin-mediated amyloidosis (ATTR) if certain conditions are met.&#x0D; Vyndaqel should only be covered to treat adult patients who have a documented diagnosis of cardiomyopathy caused by ATTR. The type of ATTR cardiomyopathy could be either hereditary (inherited) or wild type (patients without a family history of the disease). Patients who are eligible for Vyndaqel coverage must also have a New York Heart Association (NYHA) classification of I to III and a history of heart failure. Patients who have received a heart transplant or a cardiac mechanical assist device (CMAD) or who are taking other disease-modifying treatments for ATTR are not eligible for reimbursement of Vyndaqel.&#x0D; Vyndaqel should only be reimbursed for patients with ATTR if they are being cared for by a specialist for the condition and if the price of Vyndaqel is reduced.&#x0D;

Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation

Hereditary transthyretin‐mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long‐standing treatment. However, disease progression continues post‐LT. This Phase 3b, open‐label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post‐LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty‐three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%–92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, −3.7 [2.7]; Norfolk Quality of Life‐Diabetic Neuropathy questionnaire, −6.5 [4.9]; least‐squares mean [SEM], Composite Autonomic Symptom Score‐31, −5.0 [2.6]); and stabilized disability (Rasch‐built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post‐LT (www.clinicaltrials.gov NCT03862807).