https://orcid.org/0000-0002-1768-2373
Abstract
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)
Introduction
Hereditary transthyretin (ATTRv) amyloidosis, also known as hereditary transthyretin-mediated (hATTR) amyloidosis, is an underdiagnosed, rapidly progressive, debilitating, and fatal disease that occurs when variants in the transthyretin (TTR) gene cause abnormal TTR proteins to accumulate as amyloid deposits in multiple tissues, including the nerves and heart [Citation1–5]. It is a heterogeneous, multisystem disease, in which the majority of patients develop a mixed phenotype of polyneuropathy and cardiomyopathy [Citation6–9].
Polyneuropathy from ATTRv amyloidosis imparts a substantial burden, encompassing sensory and motor neuropathy and autonomic dysfunction [Citation10–15], which typically renders patients wheelchair-bound or bedridden in late-stage disease, resulting in a median survival of 4.7 years following diagnosis [Citation4,Citation7,Citation10,Citation16]. Patients with ATTRv amyloidosis also experience a decrease in quality of life (QOL), which can be worse than in other conditions associated with high morbidity/mortality, including cancer and diabetes [Citation8,Citation17].
The therapeutic landscape for ATTRv amyloidosis includes liver transplantation, which suppresses the main systemic source of variant TTR, and pharmacotherapies that stabilize the tetrameric form of TTR or suppress whole hepatic wild-type and variant TTR production through gene silencing [Citation18]. Patisiran, an RNA interference therapeutic targeting both the disease-causing variant and the wild-type TTR proteins, is approved in >30 countries for the treatment of hATTR amyloidosis with polyneuropathy [Citation19–24]. Patisiran gained approval based on the results of the Phase 3 APOLLO study, which demonstrated its ability to halt or reverse polyneuropathy progression and improve QOL, among other endpoints [Citation8]. However, there remains a gap in understanding the trajectory of neurologic and QOL deterioration in patients with ATTRv amyloidosis with varying disease severity. The objective of this post hoc analysis was to further elucidate the impact of baseline polyneuropathy severity on disease-relevant outcomes among patients assigned to patisiran treatment in APOLLO.
Materials and methods
The primary research purpose was to evaluate how polyneuropathy severity at baseline impacted the changes in polyneuropathy and overall QOL over 18 months of treatment with patisiran or placebo in the Phase 3 APOLLO study.
The full methodology for APOLLO has been described previously [Citation8,Citation25]; relevant details are summarized below.
Study population
APOLLO (NCT01960348) was a multicenter, international, randomized, double-blind, placebo-controlled, Phase 3 study of patisiran in patients with ATTRv amyloidosis with polyneuropathy. Eligible patients were aged 18–85 years, had a diagnosis of ATTRv amyloidosis with a documented TTR variant, polyneuropathy (Neuropathy Impairment Score [NIS] of 5–130), polyneuropathy disability (PND) score ≤ IIIb (ambulatory, with or without walking aids), a Karnofsky Performance Status (KPS) of ≥60%, and adequate liver and renal function. Patients were randomized 2:1 to receive either patisiran 0.3 mg/kg or placebo intravenously once every 3 weeks for 18 months.
Standard protocol approvals, registrations, and patient consent
APOLLO was conducted according to the guidelines of the International Conference on Harmonization, the World Health Organization Declaration of Helsinki, and the Health Insurance Portability and Accountability Act of 1996. Written informed consent was obtained from all patients. The APOLLO study protocol and all amendments were approved by the local Institutional Review Boards and Ethics Committees.
Measures
Details of the primary, secondary, and exploratory endpoints and safety assessments in APOLLO have been described previously [Citation8,Citation25]. This post hoc analysis evaluated the impact of baseline polyneuropathy severity, as defined by baseline NIS quartiles, on changes in various functional and QOL assessments from baseline to 18 months in patients treated with patisiran or placebo in the APOLLO study.
The modified NIS+7 (mNIS+7) score was designed to evaluate the neurologic impairment in patients affected by ATTRv amyloidosis. mNIS+7 is a 304-point composite measure of polyneuropathy that assesses motor, sensory, and autonomic neuropathy, with a higher score indicating greater impairment [Citation26]. The NIS assessment, from which the mNIS+7 was developed, is a simpler and more widely used 244-point composite score derived from a neurologic assessment of muscle strength, reflexes, and sensation in the upper and lower limbs to evaluate the neurologic impairment in patients affected by ATTRv amyloidosis and other types of polyneuropathy. A higher score indicates greater impairment.
The Rasch-built Overall Disability Scale (R-ODS) is a 24-item, patient-reported scale that measures limitations in normal activities of daily living and social participation, such as doing the dishes or having the ability to run. Scores range from 0 to 48, with lower scores indicating greater disability and lower functional status [Citation27].
The 10-meter walk test (10-MWT) is used to assess gait speed by recording the time it takes a patient to walk 10 meters, while grip strength is assessed using a dynamometer held in the dominant hand while standing. Lower values of both measures indicate poorer motor function.
The Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire is a 35-item questionnaire comprising five domains (physical functioning/large-fiber neuropathy, symptoms, activities of daily living, small-fiber neuropathy, and autonomic neuropathy; total range −4 to 136), with a higher total or component score indicating greater impairment [Citation28]. This tool was initially designed for use in patients with diabetic neuropathy; however, it has also been validated for use in patients with ATTRv amyloidosis with polyneuropathy [Citation28].
In addition to these measures, clinical assessments reported at baseline include PND score (scores of I [no walking disability], II, IIIa, IIIb, and IV [wheelchair-bound or bedridden], with higher scores indicating more limited ambulatory function due to greater neurologic impairment) and KPS (measure of functional impairment, scored in increments of 10% from 0% to 100%, with lower percentage scores indicating worse impairment).
Statistical analysis
Full details of the statistical analyses of APOLLO have been described previously [Citation8,Citation25].
For this post hoc subgroup analysis, patients from the APOLLO study were divided into four quartiles based on increasing baseline NIS: quartile (Q)1: 6–<31 (n = 56), Q2: 31–<57 (n = 56), Q3: 57–<85.5 (n = 56), and Q4: 85.5–141.6 (n = 57). Baseline demographics and disease characteristics were summarized by treatment group for each baseline NIS quartile. Observed assessment scores over 18 months were summarized descriptively by treatment group and baseline NIS quartile.
Data availability
The datasets generated and analyzed during the current study are not publicly available.
Results
Patient demographics, characteristics, and disposition
Baseline characteristics by treatment group and NIS quartile are reported in . Baseline polyneuropathy (as assessed by NIS) ranged from 6.0 to 141.6 points, reflecting the wide distribution of neurologic impairment at baseline in APOLLO. Median age was comparable between the placebo and patisiran arms within each quartile, with patients in Q1 having a lower median age compared with patients in higher quartiles (). The majority of patients were male. The proportion of patients with unassisted ambulation (PND ≤ II) was greater in Q1 (least severe disease) than Q4 (most severe disease) (100% [placebo] and 91.9% [patisiran] of patients at PND ≤ II in Q1, compared with 6.3% [placebo] and 24.4% [patisiran] at PND ≤ II in Q4). Similarly, the proportion of patients with a better functional status, as indicated by higher KPS, was higher in the lower NIS quartiles (89.5% [placebo] and 97.3% [patisiran] of patients had a KPS of 70–100 in Q1) and decreased in the higher NIS quartiles (56.3% [placebo] and 14.6% [patisiran] had a KPS of 70–100 in Q4).
Table 1. Baseline demographics and disease characteristics of patients across the NIS quartiles and the mITT population.
Across all quartiles, a larger proportion of placebo patients discontinued from the study compared with patients on patisiran (Q1: 2.7% [patisiran], 31.6% [placebo]; Q2: 5.9% [patisiran], 36.5% [placebo]; Q3: 8.3% [patisiran], 40.0% [placebo]; Q4: 12.2% [patisiran], 43.8% [placebo]).
Overall clinical picture
Overall, a favorable effect of patisiran treatment compared with placebo was observed for all endpoints across all NIS quartiles. Substantial deterioration was consistently seen across all NIS quartiles in the placebo arm, while those patients treated with patisiran demonstrated improvement or slight deterioration in the endpoints assessed (). The results from each of the endpoints are detailed below.
Table 2. NIS, R-ODS, 10-MWT, grip strength, and Norfolk QOL-DN at baseline and 18 months by baseline NIS quartiles.
mNIS+7 and NIS assessments by baseline NIS quartile
Within each quartile, baseline mNIS+7 scores were comparable between placebo and patisiran arms. In both treatment arms, mean ± standard error of the mean (SEM) baseline mNIS+7 scores were lower in Q1 (34.3 ± 2.1 [patisiran], 32.1 ± 5.7 [placebo]) and increased through the higher NIS quartiles (Q4: 132.1 ± 4.9 [patisiran], 122.3 ± 2.9 [placebo]). By 18 months, patients across all quartiles in the patisiran arm showed an improvement in polyneuropathy, as demonstrated by a negative mean change in mNIS+7 score from baseline, ranging between −6.4 and −1.9 (). In contrast, patients in the placebo arm had continued progression of polyneuropathy, as demonstrated by a positive mean change in mNIS+7, across all quartiles (ranging between 18.4 and 32.5). Despite the improvement in polyneuropathy among patisiran-treated patients, those in higher NIS quartiles (most severe disease at baseline) continued to exhibit more severe polyneuropathy, as demonstrated by higher mean ± SEM mNIS+7 scores, at 18 months than those in the lower NIS quartiles (least severe disease at baseline) (mNIS+7 at 18 months: Q1: 31.3 ± 2.9, Q2: 53.1 ± 3.5, Q3: 89.2 ± 4.2, Q4: 125.7 ± 4.7). Similar findings were observed when evaluating NIS total scores by baseline NIS quartile ().
Figure 1. Mean mNIS+7 (A) and NIS (B) scores at baseline, 9 months, and 18 months according to baseline polyneuropathy group. BL: baseline; mNIS+7: modified Neuropathy Impairment Score+7; m: months; NIS: Neuropathy Impairment Score; Q: quartile; SEM: standard error of the mean.
R-ODS, 10-MWT, and grip strength assessments by baseline NIS quartile
The additional functional measures, as assessed by R-ODS, 10-MWT, and grip strength, showed similar baseline scores between patisiran and placebo arms within each quartile, with the highest values observed in Q1 and the lowest values in Q4 (). Overall, these measures mirrored the pattern of mNIS+7 and NIS measures described above, favoring patisiran treatment across all baseline NIS quartiles at 18 months, compared with a rapid decline in the placebo arm (). Across all quartiles, the mean change from baseline at 18 months in R-ODS scores was consistently worse in the placebo arm than in the patisiran arm, ranging between −2.9 and 1.0 (patisiran) versus −12.9 and −3.8 (placebo). The R-ODS scores showed stabilization or slight improvement compared with baseline in Q1 and Q2 of the patisiran arm and mild worsening in Q3 and Q4, while the placebo arm showed substantial deterioration from baseline in functional status, with greater decline in the higher NIS quartiles (; ).
Figure 2. Mean R-ODS score at baseline and 18 months according to baseline polyneuropathy group. BL: baseline; m: months; NIS: Neuropathy Impairment Score; Q: quartile; R-ODS: Rasch-built Overall Disability Scale; SEM: standard error of the mean.
Figure 3. Mean 10-MWT, in m/s, at baseline and 18 months according to baseline polyneuropathy group. *n = 14. 10-MWT: 10-meter walk test; BL: baseline; m: months; m/s: meters per second; NIS: Neuropathy Impairment Score; Q: quartile; SEM: standard error of the mean.
Figure 4. Mean grip strength, in kg, at baseline and 18 months according to baseline polyneuropathy group. *n = 32; †n = 10. BL: baseline; m: months; NIS: Neuropathy Impairment Score; Q: quartile; SEM: standard error of the mean.
The mean change from baseline to 18 months was also consistently better in the patisiran arm than in the placebo arm in the 10-MWT, ranging between −0.04 and 0.17 m/s (patisiran) versus −0.36 and −0.06 m/s (placebo), and in grip strength, ranging between −2.0 and 0.7 kg (patisiran) versus −10.8 and −6.4 kg (placebo) (; and ). Furthermore, as seen across all measures, patients with higher baseline NIS quartiles did not perform as well on these functional assessments at 18 months as those who initiated treatment at a lower NIS quartile.
Norfolk QOL-DN assessment by baseline NIS quartile
Baseline Norfolk QOL-DN scores were generally comparable between patients in the placebo and patisiran arms within each quartile, with mean ± SEM Norfolk QOL-DN scores being lowest among patients in Q1 (39.7 ± 4.7 [patisiran], 36.4 ± 3.9 [placebo]) and increasing through the higher NIS quartiles (Q4: 81.8 ± 3.0 [patisiran], 72.9 ± 5.2 [placebo]). In Q1 and Q2, patients in the patisiran arm showed improved QOL, as demonstrated by a negative mean change in Norfolk QOL-DN from baseline to 18 months (−8.1 ± 4.0 and −6.1 ± 3.8, respectively). Patisiran-treated patients in Q3 and Q4 had a mean ± SEM change from baseline to 18 months of 0.5 ± 3.4 and 2.8 ± 3.2, respectively (). In contrast, patients in the placebo arm experienced rapid deterioration of their QOL across all NIS quartiles from baseline to 18 months, with the mean change in Norfolk QOL-DN scores ranging between 15.6 and 23.1. Overall, as opposed to the substantial deterioration of Norfolk QOL-DN score observed in the placebo arm, patients who received patisiran showed improvement of QOL in Q1 and Q2, and only slight deterioration of QOL in Q3 and Q4 (; ). Similar patterns were also observed across individual Norfolk QOL-DN domain scores (Supplementary Figures S1–S5). Despite experiencing an improvement in QOL when compared with placebo, patisiran-treated patients in higher NIS quartiles were unable to achieve the same level of QOL at the end of the 18 months compared with patients in the lower NIS quartiles.
Figure 5. Mean Norfolk QOL-DN scores at baseline, 9 months, and 18 months according to baseline polyneuropathy group. BL: baseline; m: months; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy; NIS: Neuropathy Impairment Score; Q: quartile; QOL: quality of life; SEM: standard error of the mean.
Discussion
This post hoc analysis examined the impact of baseline polyneuropathy severity on the trajectory of neurologic function, QOL, and other functional assessments in patients with ATTRv amyloidosis with polyneuropathy who had received patisiran or placebo treatment in the APOLLO study. Across all NIS quartiles, patients in the patisiran arm showed a halting or reversal of polyneuropathy progression by 18 months, as demonstrated by mNIS+7, compared with patients in the placebo arm who experienced rapid polyneuropathy progression across the full range of baseline disease severity.
The pattern of stabilization or improvement in mNIS+7 was also reflected in QOL, whereby patisiran treatment improved or preserved patients’ QOL at 18 months regardless of baseline disease severity, compared with the substantial rapid deterioration of QOL over time in the placebo arm. However, for both polyneuropathy and QOL, the patients in the patisiran arm with more severe disease at baseline continued to have more advanced disease following 18 months of treatment and were not able to recover the same level of function exhibited by those who initiated patisiran treatment earlier in their disease course. Hence, although the benefit of patisiran was noted in each baseline NIS quartile, earlier intervention afforded greater opportunity to maintain or improve neuropathy and QOL in this debilitating and progressive disease.
These results are mirrored by those from additional functional assessments including R-ODS, which measures the level of disability, and the 10-MWT and grip strength, which monitor motor function over time. The complementary patterns shown in these three assessments further illustrate the rapid downward trajectory of functional ability in this patient population over time without treatment and the importance of early diagnosis and treatment initiation. Indeed, it has been reported that neurologic worsening may accelerate with increasing baseline disease burden in the absence of active treatment [Citation29], and that increasing severity of polyneuropathy is correlated with poorer QOL [Citation30]. However, the demonstration of patisiran’s benefit in patients with higher disease severity in this analysis should not be overlooked. This is important in daily practice as many patients still experience a significant diagnostic delay, so treatments that provide potential benefit in later-stage disease represent an important unmet need.
The substantial QOL burden of ATTRv amyloidosis can be further contextualized by comparison with other neuropathies. For example, in a study also utilizing Norfolk QOL-DN, patients with self-reported diabetic neuropathy without ulceration, gangrene, or amputation had a mean score of 34.9, while those with ulceration, gangrene, or amputation had a mean score of 50.4 [Citation31]. The current post hoc analysis demonstrates that patients in the lowest NIS quartile (Q1) had a mean Norfolk QOL-DN score similar to those in patients with diabetic neuropathy without complications at baseline (36.4 [placebo], 39.68 [patisiran]). However, patients in Q2 through Q4 had mean baseline Norfolk QOL-DN scores that were comparable with, and in some cases worse than, those with diabetic neuropathy with complications such as ulceration, gangrene, or amputation (Q2: 50.9 [placebo], 54.8 [patisiran]; Q3: 65.4 [placebo], 59.4 [patisiran]; Q4: 72.9 [placebo], 81.8 [patisiran]), underscoring the significant burden these patients experience as a result of their disease.
The results of the current analysis suggest that earlier treatment with patisiran results in better outcomes for patients, which is also supported by the patisiran Global Open-Label Extension (OLE) study [Citation32]. Patients who entered the patisiran Global OLE from the patisiran Phase 2 OLE study, who had less advanced disease and the longest patisiran treatment duration of the patient groups enrolled in the Global OLE, retained the highest level of neurologic function during an additional 24 months of patisiran treatment [Citation33]. In contrast, patients who received placebo during the APOLLO study had accumulated greater disease burden compared with those who had initiated patisiran earlier, and therefore remained the group with the lowest level of neurologic function despite stabilizing following patisiran treatment. Similar results have also been observed in patients with ATTRv amyloidosis with polyneuropathy who have received other pharmacotherapies (inotersen or tafamidis) as part of other OLE studies [Citation34,Citation35]. These data, in conjunction with the results from the current study, highlight the importance of early intervention (when disease is less advanced) to prevent accumulation of disease burden, and demonstrate that patient function can be preserved with extended treatment.
As a limitation of this post hoc analysis, it should be noted that although the APOLLO study is the largest controlled study in this patient population to date, the sample size by treatment group within each baseline NIS quartile is relatively small and was not powered to detect significant differences between the groups defined in this post hoc analysis. In addition, the sample size in the highest quartile (Q4) was further reduced due to the higher number of treatment discontinuations in this quartile. Study discontinuation occurred in 7/16 (43.8%) patients from the Q4 placebo group and 5/41 (12.2%) from the Q4 patisiran group; the greater proportion of missing data in the placebo group may lead to an underrepresentation of the benefit of patisiran in Q4, as patients in Q4 who discontinued due to progressive disease (0% [patisiran], 12.5% [placebo]) or death (7.3% [patisiran], 18.8% [placebo]) may otherwise have reported high levels of polyneuropathy and QOL impairment that may have further worsened the overall mean placebo scores at 18 months. Despite the relatively small number of patients in each quartile, the results present a consistent pattern of a positive patisiran treatment effect across the disease spectrum in this study population.
Another potential limitation is that this study was not randomized by baseline NIS quartile and thus some small differences between treatment groups and quartiles are present. Although the treatment groups within each quartile were generally well balanced with regard to their baseline covariates (e.g. similar median age and proportion of males) patisiran-treated patients had a slightly better baseline KPS in lower quartiles (KPS 70–100%; Q1: 97.3% [patisiran], 89.4% [placebo]; Q2: 91.2% [patisiran], 86.4% [placebo]), while there was a larger proportion of patients in the placebo arm with unassisted ambulation in the same baseline quartiles (PND ≤ II; Q1: 91.9% [patisiran], 100% [placebo]; Q2: 64.7% [patisiran], 77.3% [placebo]). In addition, the NIS assessment is a general neuropathy assessment tool commonly used across a variety of neurologic diseases, while the mNIS+7 was specifically designed for patients with ATTRv amyloidosis due to the heterogeneity of the disease. Although NIS may be more easily implemented in routine office settings, this may be a less sensitive tool to capture the overall baseline neurologic impairment in these patients compared with the mNIS+7. How the magnitude of change across the different assessments may correlate with clinical signs and symptoms should be explored in further analyses.
In conclusion, while treatment with the RNA interference therapeutic patisiran resulted in improvement of neurologic function and QOL over 18 months when compared with placebo regardless of baseline polyneuropathy severity, patients who initiated treatment with earlier disease experienced the greatest benefit in their level of neurologic function and QOL compared with those who initiated treatment with more advanced disease. As the overall disease burden was lowest in patients who started patisiran treatment earlier in their disease course, these data highlight that early diagnosis and treatment initiation has the potential to maximize the preservation of neurologic function and minimize burden on QOL. The data from this study may also be helpful to physicians in clinical practice for monitoring the progression of ATTRv amyloidosis and anticipating disease trajectory across a range of disease severities. Improved awareness of this disease and its multisystem symptomatology are key to ensuring early diagnosis and initiation of treatment, and thus allowing patients to retain a better QOL while living with ATTRv amyloidosis.
| Abbreviations | ||
| 10-MWT | = | 10-meter walk test |
| ATTRv | = | hereditary transthyretin-mediated (v for variant) |
| BL | = | baseline |
| hATTR | = | hereditary transthyretin-mediated |
| KPS | = | Karnofsky Performance Status |
| m: months; mITT | = | modified intent-to-treat |
| mNIS+7 | = | modified Neuropathy Impairment Score+7 |
| m/s | = | meters per second |
| NIS | = | Neuropathy Impairment Score |
| Norfolk QOL-DN | = | Norfolk Quality of Life-Diabetic Neuropathy |
| OLE | = | open-label extension |
| PND | = | polyneuropathy disability |
| Q | = | quartile |
| QOL | = | quality of life |
| R-ODS | = | Rasch-built Overall Disability Scale |
| SEM | = | standard error of the mean |
| TTR | = | transthyretin |
Supplemental Material
Download MS Word (3.7 MB)Acknowledgments
The authors thank the patients, their families, investigators, study staff, and collaborators involved in the APOLLO study for their valued contribution to this study. They would also like to thank Rebecca Shilling for her contribution to the study and manuscript content.
Disclosure statement
Dianna Quan reports research funding from Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Apellis, Argenx, Cytokinetics, Ionis Pharmaceuticals, Momenta, Pfizer, and Viela, consulting fees from Alnylam Pharmaceuticals, and investigator meeting expenses from Pfizer.
Laura Obici reports support for conducting clinical trials and manuscript preparation funded by Alnylam Pharmaceuticals, and speaker honoraria from Akcea Therapeutics, Alnylam Pharmaceuticals, and Pfizer.
John L. Berk reports support as a study investigator and coordinator from Alnylam Pharmaceuticals and Pfizer, fees for scientific advisory board attendance from Corino Therapeutics and Intellia Therapeutics, fees for participating in ad hoc advisory committees for Akcea Therapeutics and Ionis Pharmaceuticals, and fees for a visiting professor presentation by Alnylam Pharmaceuticals.
Yukio Ando reports speaker honoraria from Pfizer.
Emre Aldinc and Matthew T. White are employees of Alnylam Pharmaceuticals and hold shares in Alnylam Pharmaceuticals.
David Adams reports consulting fees from Alnylam Pharmaceuticals and Pfizer, and support for participation in clinical trials funded by Alnylam Pharmaceuticals and Ionis Pharmaceuticals.
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.
Additional information
Funding
References
- Hanna M. Novel drugs targeting transthyretin amyloidosis. Curr Heart Fail Rep. 2014;11(1):50–57.
- Mohty D, Damy T, Cosnay P, et al. Cardiac amyloidosis: updates in diagnosis and management. Arch Cardiovasc Dis. 2013;106(10):528–540.
- Adams D, Coelho T, Obici L, et al. Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study. Neurology. 2015;85(8):675–682.
- Hawkins PN, Ando Y, Dispenzeri A, et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625–638.
- Damy T, Judge DP, Kristen AV, et al. Cardiac findings and events observed in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis. J Cardiovasc Trans Res. 2015;8(2):117–127.
- Rapezzi C, Quarta CC, Obici L, et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013;34(7):520–528.
- Coelho T, Maurer MS, Suhr OB. THAOS – the Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63–76.
- Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11–21.
- Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22–31.
- Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.
- Gonzalez-Duarte A. Autonomic involvement in hereditary transthyretin amyloidosis (hATTR amyloidosis). Clin Auton Res. 2019;29(2):245–251.
- Shin SC, Robinson-Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79(6):733–748.
- Amyloidosis Research Consortium. The voice of the patient report – amyloidosis. 2016. Available from: https://www.arci.org/wp-content/uploads/2018/05/Voice-of-the-Patient.pdf, accessed July 22, 2022.
- Duncan D. With hope for a cure. 2018. Available from: http://amyloidosis.org/proactive-3/, accessed July 22, 2022.
- Mariani LL, Lozeron P, Theaudin M, French Familial Amyloid Polyneuropathies Network (CORNAMYL) Study Group, et al. Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Ann Neurol. 2015;78(6):901–916.
- Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv Neurol Disord. 2013;6(2):129–139.
- Mitchell PM, Al-Janabi H, Richardson J, et al. The relative impacts of disease on health status and capability wellbeing: a multi-country study. PLoS One. 2015;10(12):e0143590.
- Adams D, Koike H, Slama M, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387–404.
- swissmedic. Abbreviated information for health care professionals for ONPATTRO 10 mg/5 ml, concentrate for solution for infusion (version September 2019). 2022. Available from: www.swissmedicinfo.ch, accessed July 22, 2022.
- European Medicines Agency. Summary of product characteristics: Onpattro 2 mg/mL concentrate for solution for infusion. 2018. Available from: https://www.ema.europa.eu/documents/product-information/onpattro-epar-product-information_en.pdf, accessed July 22, 2022.
- Alnylam announces approval in Brazil of ONPATTRO® for the treatment of hereditary ATTR amyloidosis with polyneuropathy [Internet]. Alnylam Pharmaceuticals Inc. 2020. Available from: https://investors.alnylam.com/press-release?id=24606, accessed July 22, 2022.
- Alnylam announces approval in Japan of ONPATTRO® for the treatment of hereditary ATTR amyloidosis with polyneuropathy [Internet]. Alnylam Pharmaceuticals Inc,; 2019. Available from: https://investors.alnylam.com/press-release?id=23886, accessed July 22, 2022.
- Alnylam Pharmaceuticals Inc. US prescribing information: ONPATTRO (patisiran) lipid complex injection, for intravenous use. 2020. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210922s007lbl.pdf, accessed July 22, 2022.
- CADTH. Patisiran. 2019. Available from: https://www.cadth.ca/patisiran, accessed July 22, 2022.
- Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.
- Suanprasert N, Berk JL, Benson MD, et al. Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials. J Neurol Sci. 2014;344(1-2):121–128.
- van Nes SI, Vanhoutte EK, van Doorn PA, et al. Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies. Neurology. 2011;76(4):337–345.
- Vinik EJ, Vinik AI, Paulson JF, et al. Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2014;19(2):104–114.
- Gundapaneni BK, Sultan MB, Keohane DJ, et al. Tafamidis delays neurological progression comparably across Val30Met and non-Val30Met genotypes in transthyretin familial amyloid polyneuropathy. Eur J Neurol. 2018;25(3):464–468.
- Waddington-Cruz M, Ackermann EJ, Polydefkis M, et al. Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial. Amyloid. 2018;25(3):180–188.
- Veresiu AI, Bondor CI, Florea B, et al. Detection of undisclosed neuropathy and assessment of its impact on quality of life: a survey in 25,000 Romanian patients with diabetes. J Diabetes Complications. 2015;29(5):644–649.
- Adams D, Polydefkis M, González-Duarte A, patisiran Global OLE study group, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol. 2021;20(1):49–59.
- Adams D, Gonzalez Duarte A, Mauricio E, et al. Global open-label extension: 24-month data of patisiran in patients with hATTR amyloidosis. Peripheral Nerve Society (PNS) Congress; June 27–30 2020. Miami, FL, USA.
- Barroso FA, Judge DP, Ebede B, et al. Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years. Amyloid. 2017;24(3):194–204.
- Brannagan TH, Wang AK, Coelho T, NEURO-TTR open-label extension investigators, et al. Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial. Eur J Neurol. 2020;27(8):1374–1381.