Giacomo Urbinati1†
Ilaria Cani2†
Marco Currò Dossi3Simone Longhi4Samuela Carigi5Christian Gagliardi4Elena Biagini4
Nazzareno Galiè4
Pietro Cortelli1,2
Pietro Guaraldi2*- 1Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Alma Mater Studiorum Università di Bologna, Bologna, Italy
- 2IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
- 3Neurology Unit, Ospedale degli Infermi, Rimini, Italy
- 4Cardiology Unit, Cardiac Thoracic and Vascular Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- 5Cardiology Unit, Ospedale degli Infermi, Rimini, Italy
Objectives: Evidence on the activity of patisiran therapy in specific subgroups of patients with hereditary transthyretin amyloidosis variant (ATTRv) is still scarce. This prospective real-world study was designed to provide the first in-depth clinical data on the effectiveness of patisiran in patients with ATTRv reporting the p.Ile88Leu variant, the most widespread variant in the Emilia-Romagna regional area, which has been less represented in previous clinical trials.
Patients and methods: This prospective study evaluated all the patients with genetically proven ATTRv (p.Ile88Leu) and polyneuropathy treated with patisiran in the Emilia-Romagna referral centers for ATTRv (Institute of Neurological Sciences in Bologna and Division of Neurology in Rimini) from March 2021 to April 2023. All subjects underwent clinical and neurological evaluations at baseline and after 9–12 months of treatment.
Results: A total of 22 patients were included in the study; the median age was 73 years (IQR: 9), the age at diagnosis was 72 years (IQR: 10), and the disease duration was 1.6 years (IQR: 2.3). We observed stability of all considered neurological and cardiological parameters at 9–12 months after the beginning of patisiran treatment.
Conclusion: Our findings support the clinical data regarding the effectiveness of patisiran in stabilizing the disease course and extend this activity to the subset of patients with the p.Ile88Leu variant.
Introduction
Hereditary transthyretin amyloidosis (ATTRv) is a rare, autosomal dominant, multisystem disease caused by mutations in the transthyretin (TTR) gene (1). The main features of the disease are progressive sensory-motor and autonomic neuropathy and cardiomyopathy (2, 3).
ATTRv is a rare disease; Portugal and Sweden are considered endemic areas, and Japan, Brazil, Maiorca, and Cyprus have been reported as other foci (4).
Recent progress in the diagnosis points out that more patients with ATTRv are affected worldwide than expected. Specifically, more than 140 missense mutations in the TTR gene have been recognized to date, and significant regional variations in genotype and phenotype distribution have been observed (5, 6). Regarding the Italian scenario, the national prevalence of ATTRv is 4.33/million, with higher rates in southern Italy and in Lazio region (in particular, in this latter area, the prevalence is around 17.2/million) (7); the most common variant in patients and asymptomatic carriers is p.Ile88Leu, which is particularly frequent in Emilia Romagna and Tuscany and Romagna Apennines (8).
Little is known about most ATTR variants (9). Concerning p.Ile88Leu, although it is mainly associated with a cardiac phenotype, frequent neurological symptoms have been reported in affected patients, including carpal tunnel syndrome (reported in 43% of patients), which may precede the diagnosis of amyloidotic cardiomyopathy within 5–7 years, autonomic dysfunction and sensory-motor distal polyneuropathy (10, 11). The natural history of this variant has been explored in a recent study by our group (12) and is characterized by high mortality in the short term (41% at 3 years and 63% at 5 years) (11).
Over the past 15 years, increasing knowledge of the molecular mechanisms of the disease has enabled the progressive development of new specific disease-modifying therapies to slow its progression (13). Among them, patisiran is a small, double-stranded interfering RNA that selectively targets TTR mRNA, reducing both ATTRv and wild-type ATTR production (14, 15). The phase III placebo-controlled APOLLO study evaluated the efficacy and safety of patisiran versus placebo at 18 months in 225 patients (15). Within the APOLLO study, patisiran showed the ability to preserve functional capacity, health status, and quality of life (QoL) in patients with ATTRv and polyneuropathy regardless of the stage of the disease, the associated TTR variant, and the age of onset. In contrast, placebo was associated with steady worsening (15). In detail, improvements compared with placebo were reported in the modified Neuropathy Impairment Score + 7 (mNIS+7, primary endpoint: 56% vs. 4%), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN, 51.4% vs. 10.4%), gait speed (53% vs. 13%) and Composite Autonomic Symptom Scale-31 (COMPASS-31) measure of autonomic symptoms (15). These results were confirmed by the global OLE study, demonstrating that patisiran could maintain long-term efficacy (16). Furthermore, an analysis of several cardiac parameters in a pre-specified cardiac subpopulation of APOLLO study showed a beneficial effect on cardiomyopathy, suggesting that patisiran could halt or reverse the progression of cardiac symptoms of patients with ATTRv (17).
Overall, 39 TTR variants were reported among the patients enrolled in the APOLLO study; however, no patient had the p.Ile88Leu variant (15). Similarly, within the APOLLO-B study, only one patient in the treatment group reported the p.Ile88Leu variant (17). Consequently, evidence on the activity of patisiran therapy in this specific subgroup of patients is still scarce. The study aimed to provide additional knowledge on the effectiveness of patisiran treatment in real-world practice, considering a p.Ile88Leu patient population. In particular, this prospective study analyzed the activity of patisiran in patients from Emilia-Romagna affected from p.Ile88Leu ATTRv and polyneuropathy, monitoring both neurological and cardiological parameters.
Patients and methods
In this study, we prospectively evaluated all the patients with genetically proven ATTRv (p.Ile88Leu) and polyneuropathy treated with patisiran in the Emilia-Romagna referral centers for ATTRv (Institute of Neurological Sciences in Bologna and Division of Neurology in Rimini) from March 2021 to April 2023. Patisiran was administered as an intravenous infusion at 300 μg/kg dose every 3 weeks.
All the subjects underwent clinical and neurological evaluations at baseline (T0) and after 9–12 months of treatment (T1, range varies depending on the latest available clinical assessment), including a Familial Amyloid Polyneuropathy (FAP) scale (with higher scores indicating more impaired walking ability), Neuropathy Impairment Score (NIS) (range, 0–192, with higher scores indicating more impairment), COMPASS-31 scale score (for evaluation of autonomic dysfunction symptoms), a QoL assessment with the Norfolk QOL-DN and Karnofsky Performance Status Scale questionnaires (range − 4–136 and 0–100, respectively, with higher scores indicating worse QoL). Patients also underwent extensive cardiological evaluation at both T0 and T1, including cardiological examination, transthoracic echocardiogram, and blood tests. Statistical analysis was conducted using SPSS software (29.0 version). We focused on indicators readily available in clinical practice that do not need dedicated instruments (i.e., QST). Data were expressed as median (interquartile range [IQR]). T0 and T1 data were compared with the Wilcoxon signed-rank test.
The study was conducted in accordance with the ethical principles of the revised version of the Declaration of Helsinki (52nd WMA General Assembly, Edinburgh, Scotland, October 2000) and with the protocol approved by the Ethics Committee of the Local Health Authority of Bologna (reference number CE21006, P.I. Dr. P. Guaraldi). All patients gave consent to the publication of their clinical data for scientific and educational purposes.
Results
A total of 22 patients were included in the study; the median age was 73 years (IQR: 9), the age at diagnosis was 72 years (IQR: 10), and the duration of disease was 1.6 years (IQR: 2.3). Further clinical features were reported in Table 1. As with previous therapies, three patients (14%) were treated with tafamidis, two patients (9%) had combined heart and liver transplants and one patient had liver transplant alone.
Table 1. Patient baseline characteristics.
Cardiac amyloidosis evaluation with 99mTc-DPD scintigraphy was available for 19 patients; most had a Perugini score of 2 (12 patients, 54.5%); regarding the three patients for whom the scintigraphy was not reported, two of them received combined heart and liver transplantation and were confirmed by biopsy. In the other case, the diagnosis was made considering the high suggestiveness of the ECG and echocardiographic findings, combined with the genetic evidence of the mutation and the absence of other possible compatible causes (particularly the absence of blood dyscrasias).
Neurological evaluation at baseline documented 17 patients (77%) with polyneuropathy FAP stage 1 and five patients (23%) with polyneuropathy FAP stage 2. Overall, the median NIS score was 22 (IQR: 23), and the COMPASS-31 scale score was 18 (IQR: 30). Norfolk QOL-DN median score was 36 (IQR: 40), and the Karnofsky Performance Status Scale median score was 80 (IQR: 10) (Table 1).
Baseline cardiological features were characterized by a median New York Heart Association (NYHA) stage 2 (IQR: 2), mean left ventricle wall thickness of 16.5 mm (IQR: 4.9), left ventricle ejection fraction of 53% (IQR: 18%), left ventricular telediastolic volume of 86 mL (IQR: 40), and N-terminal pro–B-type natriuretic peptide of 1,300 pg./mL (IQR: 2,795).
Follow-up parameters
Neurological and cardiological parameters stability was observed after 9–12 months at T1 compared with T0 values (Figure 1). In detail, a median NIS total scale of 20 (IQR: 26; p = 0.698), Norfolk QOL-DN of 30 (IQR: 34; p = 0.618), and a Karnofsky Performance Status Scale of 90 (IQR: 20; p = 0.527) were reported. The FAP stage at T1 was unchanged (5/22 patients had polyneuropathy stage 2, the others stage 1).
Figure 1. Box plots of neurological and cardiological parameters assessed at T0 and T1. NIS, Neuropathy Impairment Score; NT-ProBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; LV, left ventricle. Source: original.
The cardiological parameters also proved to be stable at T1 (Figure 1): median NYHA class was 2 (IQR: 2; p = 0.999), mean left ventricle wall thickness was 15.3 mm (IQR: 6.9; p = 0.672), left ventricle ejection fraction was 52% (IQR: 22; p = 0.799), and left ventricular telediastolic volume was 96 mL (IQR: 80; p = 0.138). A trend for an increased serum level of N-terminal pro–B-type natriuretic peptide was reported (2,130 pg./mL, IQR, 6,825, p = 0.050, Figure 1).
During the follow-up, two patients were hospitalized: one patient was admitted for a hip fracture following an accidental fall, while a second patient was admitted twice for heart failure and eventually died from voluntary ingestion of drugs.
In our cohort, only one patient experienced adverse reactions to the medication, consisting of an urticarial reaction treated with antihistamines with resolution of the reaction. During subsequent infusions, the patient underwent premedication with antihistamines starting 2 days before, in addition to the standard premedication, with no further adverse reactions.
Discussion
Patisiran is an effective therapy for neurological and cardiac parameters in patients with ATTRv and polyneuropathy stage 1 or 2, as previously demonstrated in the pivot clinical trial APOLLO (15).
Our prospective real-world study provided for the first time in-depth clinical data on the effectiveness of patisiran in patients with ATTRv reporting the p.Ile88Leu variant, the most widespread mutation in our Italian regional area, which has been less represented in previous clinical trials (15, 17). We observed the stability of all the considered neurological and cardiological parameters at 9–12 months after the initiation of the treatment with patisiran. These findings support the clinical data regarding the effectiveness of patisiran in stabilizing the disease course and extend this activity to the subset of patients with the p.Ile88Leu variant.
Among the available disease-modifying therapies, vutrisiran was recently approved. Similar to patisiran, it is an RNA interference therapeutic that reduces the synthesis of variant and wild-type TTR (18). Vutrisiran siRNA–N-Acetylgalactosamine (GalNAc) is characterized by enhanced stabilization chemistry leading to increased potency and high metabolic stability, allowing subcutaneous injection once every 3 months. Consistent with the pharmacodynamic effects observed in the phase I vutrisiran study (18), vutrisiran and patisiran demonstrated comparable effectiveness in treating ATTRv with polyneuropathy at 9 and 18 months within the HELIOS-A study. The patterns of stabilization or improvement across endpoints observed in the APOLLO study were also observed in the HELIOS-A trial (19, 20). Although vutrisiran and patisiran use different siRNA delivery platforms (vutrisiran is conjugated to a triantennary GalNAc ligand that binds the asialoglycoprotein receptor expressed on the surface of hepatocytes), serum TTR reduction was comparable, resulting in consistent clinical benefits. Therefore, we expect similar results in the real-world experience with vutrisiran as with patisiran in the p.Ile88Leu patient cohort.
Our study’s limitations are the small sample size and the short follow-up period due to the rarity of this condition. We did not analyze many biomarkers typically assessed in clinical studies, such as Quantitative Sensory Testing (QST), autonomic parameters, intraepidermal nerve fiber density (IENFD), composite scores like mNIS+7, or scales like the time-up-and-go (TUG) or 6-min walking test (6MWT). These tests are not part of our clinical routine and were not included as they extend beyond the scope of our study’s real-life context. Therefore, further studies with a larger sample and longer follow-ups are warranted to confirm our results.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics statement
The studies involving humans were approved by the Ethics Committee of the Local Health Authority of Bologna (reference number CE21006, P.I. Dr. P. Guaraldi). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
Author contributions
GU: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. IC: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. MCD: Conceptualization, Data curation, Formal analysis, Writing – review & editing. SL: Data curation, Formal analysis, Writing – review & editing. SC: Data curation, Formal analysis, Writing – review & editing. CG: Data curation, Formal analysis, Writing – review & editing. EB: Data curation, Formal analysis, Writing – review & editing. NG: Data curation, Formal analysis, Writing – review & editing. PC: Conceptualization, Data curation, Formal analysis, Writing – review & editing. PG: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing.
Funding
The authors declare that financial support was received for the research, authorship, and/or publication of this article. This work was funded by the Italian Ministry of Health, RC-2022-2773270 project. Funding for editorial assistance was provided by Alnylam. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.
Acknowledgments
Editorial assistance was provided by Simonetta Papa, Valentina Attanasio, and Aashni Shah (Polistudium srl, Milan, Italy).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. Luigetti, M, Romano, A, Di Paolantonio, A, Bisogni, G, and Sabatelli, M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. TCRM. (2020) 16:109–23. doi: 10.2147/TCRM.S219979
2. De Bleecker, JL, Claeys, KG, Delstanche, S, Van Parys, V, Baets, J, Tilleux, S, et al. Retrospective survey of patients with hereditary transthyretin-mediated (hATTR) amyloidosis treated with patisiran in real-world clinical practice in Belgium. Acta Neurol Belg. (2023) 123:1029–37. doi: 10.1007/s13760-023-02188-z
3. Di Stefano, V, Fava, A, Gentile, L, Guaraldi, P, Leonardi, L, Poli, L, et al. Italian real-life experience of patients with hereditary transthyretin amyloidosis treated with patisiran. Pharmgen Pers Med. (2022) 15:499–514. doi: 10.2147/PGPM.S359851
4. Waddington-Cruz, M, Schmidt, H, Botteman, MF, Carter, JA, Stewart, M, Hopps, M, et al. Epidemiological and clinical characteristics of symptomatic hereditary transthyretin amyloid polyneuropathy: a global case series. Orphanet J Rare Dis. (2019) 14:34. doi: 10.1186/s13023-019-1000-1
5. Scirpa, R, Russo, D, Tini, G, Sclafani, M, Tropea, A, Cava, F, et al. Clinical translation of genetic testing in TTR amyloidosis: genotype-phenotype correlations, management of asymptomatic carriers and familial screening. Vessel Plus. (2022) 6:52. doi: 10.20517/2574-1209.2021.74
6. Dispenzieri, A, Coelho, T, Conceição, I, Waddington-Cruz, M, Wixner, J, Kristen, AV, et al. Clinical and genetic profile of patients enrolled in the transthyretin amyloidosis outcomes survey (THAOS): 14-year update. Orphanet J Rare Dis. (2022) 17:236. doi: 10.1186/s13023-022-02359-w
7. Luigetti, M, Guglielmino, V, Antonini, G, Casali, C, Ceccanti, M, Chiappini, MG, et al. ATTRv in Lazio-Italy: a high-prevalence region in a non-endemic country. Genes. (2021) 12:829. doi: 10.3390/genes12060829
8. Russo, M, Obici, L, Bartolomei, I, Cappelli, F, Luigetti, M, Fenu, S, et al. ATTRv amyloidosis Italian registry: clinical and epidemiological data. Amyloid. (2020) 27:259–65. doi: 10.1080/13506129.2020.1794807
9. Gentile, L, Diemberger, I, Plante-Bordeneuve, V, Mazzeo, A, Dori, A, Luigetti, M, et al. Phenotypic characteristics of F64L, I68L, I107V, and S77Y ATTRv genotypes from the transthyretin amyloidosis outcomes survey (THAOS). PLoS One. (2024) 19:e0292435. doi: 10.1371/journal.pone.0292435
10. Guaraldi, P, Rocchi, C, Cani, I, Gagliardi, C, Longhi, S, Baschieri, F, et al. Cardiovascular reflex tests detect autonomic dysfunction in symptomatic and pre-symptomatic subjects with hereditary transthyretin amyloidosis. Clin Auton Res. (2023) 33:15–22. doi: 10.1007/s10286-022-00921-x
11. Gagliardi, C, Perfetto, F, Lorenzini, M, Ferlini, A, Salvi, F, Milandri, A, et al. Phenotypic profile of Ile68Leu transthyretin amyloidosis: an underdiagnosed cause of heart failure. Eur J Heart Fail. (2018) 20:1417–25. doi: 10.1002/ejhf.1285
12. Caponetti, AG, Sguazzotti, M, Accietto, A, Saturi, G, Ponziani, A, Giovannetti, A, et al. Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral centre. Eur J Prev Cardiol. (2024) 31:866–76. doi: 10.1093/eurjpc/zwae011
13. Aimo, A, Castiglione, V, Rapezzi, C, Franzini, M, Panichella, G, Vergaro, G, et al. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat Rev Cardiol. (2022) 19:655–67. doi: 10.1038/s41569-022-00683-z
14. Tsoi, MR, Lin, JH, and Patel, AR. Emerging therapies for transthyretin amyloidosis. Curr Oncol Rep. (2023) 25:549–58. doi: 10.1007/s11912-023-01397-2
15. Adams, D, Gonzalez-Duarte, A, O'Riordan, WD, Yang, CC, Ueda, M, Kristen, AV, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. (2018) 379:11–21. doi: 10.1056/NEJMoa1716153
16. Adams, D, Polydefkis, M, González-Duarte, A, Wixner, J, Kristen, AV, Schmidt, HH, 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) 20:49–59. doi: 10.1016/S1474-4422(20)30368-9
17. Maurer, MS, Kale, P, Fontana, M, Berk, JL, Grogan, M, Gustafsson, F, et al. APOLLO-B trial investigators. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. (2023) 389:1553–65. doi: 10.1056/NEJMoa2300757
18. Habtemariam, BA, Karsten, V, Attarwala, H, Goel, V, Melch, M, Clausen, VA, et al. Single-dose pharmacokinetics and pharmacodynamics of transthyretin targeting N-acetylgalactosamine-small interfering ribonucleic acid conjugate, vutrisiran, in healthy subjects. Clin Pharmacol Ther. (2021) 109:372–82. doi: 10.1002/cpt.1974
19. Adams, D, Tournev, IL, Taylor, MS, Coelho, T, Planté-Bordeneuve, V, Berk, JL, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. (2023) 30:18–26. doi: 10.1080/13506129.2022.2091985
20. Polydefkis, M, Frank, B, Yoshiki, S, Pareyson, D, Cruz, MW, Danese, D, et al., Comparison of efficacy outcomes with vutrisiran vs. patisiran in hattr amyloidosis with polyneuropathy: post-hoc analysis of the HELIOS-A study. Presented at: 74th Annual Meeting of the American Academy of Neurology, Boston (2023).
Keywords: hereditary transthyretin amyloidosis, patisiran, p.Ile88Leu, TTR, familial amyloid polyneuropathy, transthyretin amyloid cardiomyopathy
Citation: Urbinati G, Cani I, Currò Dossi M, Longhi S, Carigi S, Gagliardi C, Biagini E, Galiè N, Cortelli P and Guaraldi P (2024) Patisiran for the treatment of patients with p.Ile88Leu hereditary transthyretin amyloidosis: an Italian real-life experience. Front. Neurol. 15:1415851. doi: 10.3389/fneur.2024.1415851
Edited by:
Antonio Orlacchio, Santa Lucia Foundation (IRCCS), ItalyReviewed by:
Luca Leonardi, Sapienza University of Rome, ItalyGeorgios E. Manousakis, University of Minnesota, United States
Copyright © 2024 Urbinati, Cani, Currò Dossi, Longhi, Carigi, Gagliardi, Biagini, Galiè, Cortelli and Guaraldi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Pietro Guaraldi, p.guaraldi@isnb.it
†These authors share first authorship