Ines M, Costa J. Survival in Familial Amyloid Polyneuropathy: A Review. J Neurol Neuromedicine Neuromed (2019) 4(1): 22-25 www.jneurology.com www.jneurology.com Journal of Neurology && NeuromedicineNeuromedicine

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Survival in Transthyretin Familial Amyloid Polyneuropathy: A Review Monica Ines1, Joao Costa1,2,3* 1Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal 2Laboratório de Farmacologia Clínica e Terapêutica, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal 3Centro de Estudos de Medicina Baseada na Evidência, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

Article Info Abstract

Article Notes Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is a Received: January 22, 2019 neurological disease that affects severely patients and their families and caregivers Accepted: February 14, 2019 over generations. It is a rare, progressive, and if untreated fatal autosomal dominant *Correspondence: hereditary disorder. The disease may affect multiple organ systems and if untreated Dr. João Costa, Faculdade de Medicina, Universidade de Lisboa, progress rapidly to death. TTR-FAP affects nearly 10,000 people worldwide, with Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal; Telephone No: known endemic regions in Portugal, Sweden, and Japan. Until recently only liver +351 217940424; Email: [email protected]. transplantation and tafamidis were treatment options across several world regions. Despite the worldwide use of these disease-modifying treatments to delay disease © 2019 Costa J. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License progression, challenges in clinical assessment and management remain because of disease heterogeneity, phenotypic diversity, small patient populations, incomplete natural history and uncertainty of treatment effect in survival. The two new treatment options ( and patisiran) appear to provide important benefits for patients, based on clinical trials short-term evidence. In this review, we discuss Keywords: the disease natural survival course and currently available treatments impact on Transthyretin Familial Amyloid Polyneuropathy survival. We also discuss the importance of treatment choice (and or sequence Liver Transplantation of treatments) to maximize survival, while preserving the patient’s health-related Tafamidis quality of life. Survival

Introduction Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is an autosomal-dominant, adult‐onset, progressive neurodegenerative 1. TTR- FAP symptoms stem from amyloidosis that results from misfolding of the systemic disease, first identified by Corino de Andrade in Portugal aggregates2-5 thetransthyretin most common (TTR) ofprotein which tetramer, associated leading with toTTR-FAP TTR fibrils is Val30Met and other6. The disease .is More rare; than it affects 120 TTR 8000 gene to 10,000mutations people have worldwide, been described, with the endemic group of patients mainly found in Portugal, Sweden, and Japan7-9. Both sexes are affected, the disease onset occurs mainly in young adulthood (median 33 years age) and if untreated, it progresses rapidly to death, usually within 10 years after symptom onset, depending on the endemic region, genotype, symptoms, and other factors2 causes of death among untreated patients include cachexia, cardiac failure, arrhythmia and secondary infections10,11. The disease .imposes Common a

in physical health, quality of life, reduced productivity and a negative impactsubstantial on the burden mental characterized health of families by high and levels caregivers of patient´s12. impairment

surgical treatment option to halt or ameliorate familial TTR amyloidosis13. Liver transplantation (LTx) was first implemented in 1990 as a 14,15 LTx,Because improved 95% of survival plasma is TTR attained is of hepatic at the expense origin, LTx of long substantially waiting times reduces for the concentration of mutant TTR in the blood . Despite the benefits of

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the transition from assisted to unassisted walking, an early mortality, and postoperative complications which outstanding outcome for patients consistent with the effect canan organ, impact lifelong long-term immunosuppressive health-related therapy,quality significantof life16-19. of the medicine on gait speed32,33. In the present work, we review the TTR-FAP disease (22%), cardiovascular-related deaths (22%), liver-related complicationsCauses of death (14%) after LTx and include intraoperative secondary todeath septicaemia (3%)17. natural course and currently available treatments impact 20 progress after LTx . on survival. We also reflect on treatment choice (and Also, in some cases, polyneuropathy has been reported to and the newly approved medicines. The clinical aim is to sequence of treatments), given the available treatments (NSAID) developed in the 1970s. In Europe, the drug is not including those in more advanced stages, hence decreasing Diflunisal is a non-steroidal anti-inflammatory drug thestabilize/halt disease excess disease mortality. progression in all possible patients, generally available and has occasional authorization use Literature Review doseon a of country 250 mg basis. twice A daily randomized slows the multicentre, progression placebo- of the neuropathycontrolled phase21. However, 3 study the confirmedsafety concerns that with diflunisal long-term at a NSAIDs use may limit its use in real world clinical setting We searched Medline and Embase (Ovid interface), among TTR-FAP patients22. with the search terms “transthyretin*” OR (“amyloid* theAND population [family* OR(transthyretin-associated heredit*]) combined familial with the amyloid terms Tafamidis, an oral, potent and selective TTR kinetic “polyneuropathy” OR “neuropathy*” for the definition of

polyneuropathy [TTR-FAP]). The terms “natural history”, stabiliser that slows tetramer dissociation and amyloid outcomes of interest. To increase sensitivity, search terms “survival”, and “mortality” were used for the definition of the genesis became available as a treatment option at 20 mg language or type of study restrictions. After deduplication, Union)once daily, for thefirst treatment in the context of adult of TTR-FAPclinical trials patients (2007) in stage and awere total used of 455 as both references indexed were and free-textindependently terms, withoutscreened any to 1later to delayas an approveddisease progression drug (November23,24. Tafamidis 2011 in the is Europeancurrently the standard of care25; disease progression delay, quality of life preservation, nutritional status improvement and of TTR-FAP and evaluating the effect of treatment on the naturalidentify historypotential (survival) studies characterizingof the disease. the natural history demonstrated26-30 atafamidis-treated favourable safety patients profile include in long-term urinary tract use infections, has been of TTR-FAP and treatment impact, particularly as it . Most common adverse effects (≥1/10) in relatesLimited to survival number and of studies its determinants. report the naturalIn the historylargest vaginalTwo infections,new treatment upper optionsabdominal were pain, recently and diarrhoea. approved for the treatment of adult patients in stage 1 or stage cohort study published,34 3160 consecutive Portuguese 2 transthyretin amyloid polyneuropathy disease31,32. patient presentation . The natural history of the disease patients with Val30Met were followed up since the first 12 years, with men and patients with late-onset disease Inotersen, a 2′-O-methoxyethyl–modified antisense was characterized by a median overall survival (mOS) of 300mgoligonucleotide, once weekly inhibits improved hepatic the course production of neurologic of if untreated. The median overall survival in the LTx cohort transthyretin. Treatment with subcutaneous inotersen wasfacing 21 significantly years since worsetransplantation prognosis (maximumand a lower follow-up, survival, 25 years). The median overall survival in the tafamidis (includingdisease and glomerulonephritis) quality of life compared are important with placebo. safety concerns,Nevertheless, managed thrombocytopenia with enhanced and renal monitoring dysfunction31. cohort has not been reached, as the maximum follow- Patisiran, an RNA interference therapeutic delivered via the mortality risk was higher among patients with longer up for this cohort was 10 years. In both treated cohorts, of transthyretin. This treatment (0.3 mg per kilogram of intravenous infusion, specifically inhibits hepatic synthesis anddisease onwards) duration and before tafamidis-treated treatment initiation. cohorts were The 85% 10-year and survival rates for the most recent LTx subgroup (year 2007 multiple clinical manifestations of hereditary transthyretin 93%, respectively. In comparison with the untreated cohort body weight, once every 3 weeks) significantly improved neuropathy, quality of life, walking, nutritional status, and survival in stage 1 Val30Met patients with early-onset (<50 amyloidosis including significant improvements in years)of patients, disease, both with LTx 75% and andtafamidis 91% reductionssignificantly in improvedmortality most commonly reported adverse events in patisiran- risk, respectively. Among this population, tafamidis was treatedactivities patients of daily included living asperipheral compared edema with and placebo. infusion- The LTx, a 63% reduction in mortality risk. However, nearly 11% score improved in some (8%) patients which included ofassociated tafamidis-treated with significant patien survivalts have gainsundergone compared posterior with related reactions. Notably, the polyneuropathy disability

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LTx. Some authors argue that early-stage patients should for survival. LTx if their disease progressed while on oral treatment35. patients were independent favourable, significant factors be treated initially with tafamidis, and only undergone Some variants such as Thr60Ala and Ile107Val 17 are associated with a more rapid and severe disease 41 On the other hand, other authors found this treatment progression as compared to Val30Met patients, and have a shorter median survival42. strategysurvival study questionable this treatment because sequence the patient strategy prognosis was studiedwould be and worse it was for found liver transplantation.that previous tafamidis In the Portuguese treatment Conclusion did not worsen the survival prognosis for patients who later underwent LTx as compared with LTx treatment only, alloObservational studies are of exceptional usefulness in the context of rare diseases such as TTR-FAP because they which can be very relevant for medical treatment sequence clinical trials and are of key importance for health policy is not a general treatment option, hence only tafamidis w investigating questions unaddressed by randomized wasdecision. compared For olderwith an late-onset untreated patients cohort. (≥50Among years) patients LTx with late-onset disease tafamidis was associated with a and medical decision making. Our review has found that tafamidisboth LTx is and associated tafamidis with are higher associated patient with survival statistically rates disease, shorter disease duration, and tafamidis treatment significant and clinically relevant survival gains. Notably, significant 82% reduction in mortality risk. Early onset of factors for survival. than LTx; although the follow-up has been relatively were found to be independent favourable and significant novelty,short (as no comparedevidence was with found LTx for follow-up) survival among for definitive patients course of the disease which evaluated the effect of treatment treatedconclusions with to inotersen be drawn. or As patisiran. anticipated Altogether, due to theirthis (LTx)We on found survival. two other The studiesSweden characterizing survival study the included natural evidence shows that the prognosis for patients with TTR- 141 Val30Met patients (LTx, 108; untreated, 33) and has FAP has changed dramatically in the past 25 years, from a progressive, devastating, fatal disease to a more chronic increased survival rate compared with untreated patient. condition with treatment leading to delayed disease shown that patients who underwent LTx had significantly progression and life expectancy gains. Improvements may of 12 years and 10 and 15 year survival rates of 62% and 19%,Untreated respectively. patients Patients had a median who underwent overall survival LTx had (mOS) 10 and early treatment initiation key aspects. However, not all and 15 year survival rates of 83% and 60%, respectively. be made in the prognosis of patients being timely diagnosis The study of 80 consecutive Japanese Val30Met patients (LTx, 37; untreated, 43) found similar outcomes for the treatmentpatients are options eligible which for LTx are or much tafamidis less treatment.invasive than Recent LTx untreated cohort37 outstanding advances have been made in therapeutic years (10-year survival rate of 56%), and LTx-treated Longer follow-up data may facilitate understanding of patients had prolonged. Untreated survival patients compared had with a mOS untreated of 10 howand appearclinical practice to provide can important reach optimal benefits treatment for patients. choice related or unrelated to progressive amyloidosis and patient’s health-related quality of life. reportedpatients. an Notably, outstanding this study 100% classified survival deathsrate at as10 eitheryears and sequence to maximize survival, while preserving the among LTx treated patients (n=37). The different approach Conflicts of Interest followed on this study on how to analyze deaths can lead Mónica Inês is PhD candidate and Outcomes & Evidence isto associatedcompletely with different an early survival excess results.mortality. 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