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Clinical Trial
. 2025 Mar 1;82(3):228-236.
doi: 10.1001/jamaneurol.2024.4631.

Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy: A Randomized Clinical Trial With Open-Label Extension

David Adams  1 , Jonas Wixner  2 , Michael Polydefkis  3 , John L Berk  4 , Isabel M Conceição  5   6 , Angela Dispenzieri  7 , Amanda Peltier  8 , Mitsuharu Ueda  9 , Shaun Bender  10 , Kelley Capocelli  10 , Patrick Y Jay  10 , Elena Yureneva  10 , Laura Obici  11 ; patisiran Global OLE study group
Collaborators, Affiliations
Clinical Trial

Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy: A Randomized Clinical Trial With Open-Label Extension

David Adams et al. JAMA Neurol. .

Abstract

Importance: There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN.

Objective: To present the long-term efficacy and safety of patisiran in adults with hATTR-PN.

Design, setting, and participants: This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE.

Intervention: Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years.

Main outcomes and measures: Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed.

Results: At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and -3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival.

Conclusions and relevance: In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine.

Trial registration: ClinicalTrials.gov Identifier: NCT02510261.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Adams reported consulting fees from Alnylam Pharmaceuticals, AstraZeneca, and Intellia Therapeutics outside the submitted work. Dr Wixner reported personal fees from Alnylam Pharmaceuticals (paid to institution) during the conduct of the study as well as personal fees (all paid to institution) from Pfizer, Intellia Therapeutics, Ionis Pharmaceuticals, and AstraZeneca outside the submitted work. Dr Polydefkis reported serving as site principal investigator as at Johns Hopkins, which participated in the trial. Dr Berk reported advisory board fees from Alnylam Pharmaceuticals, Alexion, AstraZeneca, Ionis Pharmaceuticals, Eidos/BridgeBio, and Intellia Therapeutics during the conduct of the study and from Alnylam Pharmaceuticals, Alexion, AstraZeneca, Ionis Pharmaceuticals, Eidos/Bridgebio, and Intellia outside the submitted work and has contributed to efforts to license treatment for familial amyloid polyneuropathy. Dr Conceição reported personal fees from AstraZeneca and Alnylam and grants from Pfizer outside the submitted work. Dr Dispenzieri reported personal fees from Pfizer (payment for manuscript writing and research funds to institution during the conduct of the study and outside the submitted work as well as research funds from Alynlam Pharmaceuticals. Dr Peltier reported personal fees from Alnylam Pharmaceuticals (speaker and consultant), AstraZeneca (speaker, consultant), and nonfinancial support from CSL Behring (serving as chairperson for another study and consultant) outside the submitted work. Dr Ueda reported advisory board and speaker fees from Alnylam Pharmaceuticals during the conduct of the study as well as grants from Alnylam Pharmaceuticals and Pfizer and advisory board and speaker fees from Pfizer outside the submitted work. Dr Bender reported employment at Alnylam Pharmaceuticals during the conduct of the study and outside the submitted work as well as former employment at Boehringer Ingelheim outside the submitted work. Dr Capocelli reported stock ownership in and previous employment at Alnylam Pharmaceuticals. Dr Jay reported employment at Alnylam Pharmaceuticals and ownership of Alnylam Pharmaceuticals shares. Dr Yureneva reported stock-eligible employment at Alnylam Pharmaceuticals outside the submitted work. Dr Obici reported personal fees from Alnylam Pharmaceuticals, Pfizer, Novo Nordisk, Intellia Therapeutics, AstraZeneca, and BridgeBio Pharma outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Shift in Polyneuropathy Disability (PND) Score From Global Open-Label Extension (OLE) Baseline
PND scores are as follows: I, preserved walking and sensory disturbances; II, impaired walking without the need for a stick or crutches; IIIA, walking with 1 stick or crutch; IIIB, walking with 2 sticks or crutches; and IV, confined to a wheelchair or bedridden. Green indicates improvement, gray stabilization, and red worsening in PND score. aPatients who received placebo in the APOLLO study, and switched to patisiran in the global OLE. bPatients who received patisiran in the APOLLO study, and continued patisiran in the global OLE. cPatients who received patisiran in the phase 2 OLE and continued patisiran in the global OLE.
Figure 2.
Figure 2.. Change in Scores From Parent Study Baseline up to 5 Years in the Global Open-Label Extension (OLE)
NIS indicates Neuropathy Impairment Score; QOL-DN, Quality of Life–Diabetic Neuropathy; R-ODS, Rasch-Built Overall Disability Scale; SEM, standard error of the mean. aPatients who received placebo in the APOLLO study, and switched to patisiran in the global OLE. bPatients who received patisiran in the APOLLO study, and continued patisiran in the global OLE. cPatients who received patisiran in the phase 2 OLE and continued patisiran in the global OLE. dNorfolk QOL-DN was not assessed in the phase 2 OLE parent study and not required for these patients in the global OLE.
Figure 3.
Figure 3.. Kaplan-Meier Product-Limit Survival Estimates by Parent Study Treatment
Patients were followed up with from the first dose date of treatment (placebo or patisiran) until the last date of follow-up, defined as the earliest of last dose date plus 90 days, database lock, or date of last contact. aPatients who received placebo in the APOLLO study, and switched to patisiran in the global open-label extension (OLE). bPatients who received patisiran in the APOLLO study, and continued patisiran in the global OLE. cPatients who received patisiran in the phase 2 OLE and continued patisiran in the global OLE.
See this image and copyright information in PMC

References

    1. 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. doi:10.1212/WNL.0000000000001870 - DOI - PMC - PubMed
    1. Lane T, Fontana M, Martinez-Naharro A, et al. . Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. 2019;140(1):16-26. doi:10.1161/CIRCULATIONAHA.118.038169 - DOI - PubMed
    1. Adams D, Sekijima Y, Conceição I, et al. . Hereditary transthyretin amyloid neuropathies: advances in pathophysiology, biomarkers, and treatment. Lancet Neurol. 2023;22(11):1061-1074. doi:10.1016/S1474-4422(23)00334-4 - DOI - PubMed
    1. Hanna M. Novel drugs targeting transthyretin amyloidosis. Curr Heart Fail Rep. 2014;11(1):50-57. doi:10.1007/s11897-013-0182-4 - DOI - PubMed
    1. Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-638. doi:10.3109/07853890.2015.1068949 - DOI - PMC - PubMed

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