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31-01-2025 | Hereditary ATTR Amyloidosis | News

Long-term benefits suggested with patisiran for hATTR with polyneuropathy

Author: Matthew Williams

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medwireNews: A 5-year global open-label extension (OLE) study involving patients from the APOLLO trial of patisiran versus placebo and a previous open-label extension (OLE) support the continued use of patisiran for maintaining clinical stability in patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).

The investigators note in JAMA Neurology that patients who received the RNA interference therapeutic patisiran in the current study as well as either the 18-month randomized APOLLO trial or the 24-month OLE, totaling up to 7 years of treatment, “had better outcomes and survival,” than those who were randomly assigned to placebo in the APOLLO trial and switched to patisiran treatment for 5 years in the current study.

This highlights “the importance of initiating early treatment for hATTR,” they say.

David Adams (Université Paris-Saclay, France) and colleagues enrolled 211 patients with hATTR-PN from 43 centers in 19 countries between 2015 and 2017. The participants had completed the phase 2 OLE or the phase 3 APOLLO studies, which had shown “meaningful improvements in [PN] and quality of life (QOL) compared with placebo and stability or improvement of [PN] and cardiomyopathy manifestations compared with baseline,” they report.   

The patients had a median age of 61.3 years and 73.9% were men. In all, 162 patients had previously received partisan (137 from the APOLLO study and 25 from the OLE) and 49 placebo. For the current study, all the patients received 0.3 mg/kg of patisiran intravenously once every 3 weeks for up to 5 years.

Those who received placebo in the APOLLO study had more severe PN at baseline than the patients who had received patisiran in APOLLO or the phase 2 OLE. The proportion of patients with a PN disability (PND) score of I or II (able to walk unaided) was a respective 32.7% versus 49.6% and 92.0%. The Neuropathy Impairment Score (NIS), which measures muscle weakness, reflexes, and sensation on a scale of 0 to 244 points, where a higher score reflects greater neuropathy impairment, was a mean of 81.5 points versus 62.3 points and 35.5 points, respectively.

Among the 138 patients who reached the 5-year follow-up, including 117 who received patisiran in the parent studies, PND scores were sustained in 55.5% of patients and improved in 9.5% compared with baseline.

In total, 47.4% of patients had a PND score of IIIA or IIIB (ie, use of one or two walking aids) at 5 years and 46.0% had a PND score of I–II, while 6.6% had a PND score of IV and were wheelchair users, with four of the nine patients in this latter group wheelchair users at baseline.

For the placebo and patisiran groups separately, the investigators found that a respective 66.7% and 44.0% of patients had a PND score of IIIA or IIIB at the 5-year follow-up, while 23.8% and 50.0% had a PND score of II or below. A PND score of IV was seen in a corresponding 9.5% and 6.0%.

The investigators note that participants who received placebo in the APOLLO parent study “experienced substantial disease progression over 18 months,” which they found was attenuated following 5 years of patisiran treatment.

Specifically, NIS worsened by only a mean of about 7.0 points after 5 years of patisiran treatment, compared with 25.4 points during the APOLLO study, equating to an 87% reduction in worsening on this measure.

Patients who initially received placebo also recovered more than half the modified BMI (BMI x serum albumin) they lost, an indicator of malnutrition and disease progression, when they switched to patisiran for 5 years, with an average worsening of about 50 kg/m2 * g/L over this time compared with 122.1 kg/m2 * g/L during the 18-month APOLLO trial.

Similar findings were also seen for patient-reported assessments of PN, including the Norfolk QOL–DN measure and the Rasch-Built Overall Disability Scale scores.

For the patients who continued to receive patisiran, the improvements seen in the APOLLO and OLE trials for all these measures were largely sustained during the 5-year period, with only “modest quantitative changes,” notes the team. These individuals therefore maintained “better outcomes” than those initially given placebo, although the differences were reduced compared with baseline.

The safety profile of partisan “remained consistent with prior analyses,” say the study authors, “with no new safety signals.” Serious adverse events (AEs) occurred in 63.0% of patients and treatment-related AEs occurred in 37.4%, most commonly infusion-related reactions (16.1%). A total of 22.3% of patients discontinued treatment due to AEs.

In total, 19.4% of participants died over 5 years, none related to patisiran treatment. The exposure-adjusted mortality rate per 100 patient–years was 4.4 overall, 3.3 and 1.8 for those who received patisiran in the APOLLO and OLE parent studies, respectively, and 12.8 for those who were initially given placebo.

The researchers point out that having a low familial amyloid polyneuropathy score at the parent study baseline and receiving patisiran treatment in the parent studies both significantly predicted improved survival at 5 years.

Adams and team say that “the results depict the long-term stability afforded by TTR reduction and the long-term safety of patisiran treatment.”

They add: “The extended follow-up provides compelling evidence for the capacity of patisiran treatment to improve survival.” But they point out that “patients tend not to recover function that is lost before starting treatment, which along with a potential survival benefit, bolsters the importance of diagnosis and early treatment initiation.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA Neurol 2025; doi:10.1001/jamaneurol.2024.4631

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