Science News: Long-Term Safety and Efficacy of Patisiran for Hereditary Transthyretin-Mediated Amyloidosis With Polyneuropathy: 12-Month Results of an Open-Label Extension Study

Submitted by Hristelina Ilieva, MD, PhD
Edited by Niranjan Singh, MD, DM

Adams D, Polydefkis M, González-Duarte A, 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 [published correction appears in Lancet Neurol. 2021 Feb;20(2):e2]. Lancet Neurol. 2021;20(1):49-59. doi:10.1016/S1474-4422(20)30368-9

Summary: This article summarizes the world wide experience of treating patients with HTTR with Patisiran in terms of safety and efficacy. This is a multicenter, open-label extension (OLE) trial that enrolled patients at 43 hospitals or clinical centers in 19 countries. Patisiran is a lipid nanoparticle RNA interference (RNAi) therapeutic that reduces serum TTR concentrations by inhibiting hepatic synthesis of TTR. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (Patisiran and placebo groups) and the phase 2 OLE (Patisiran group) studies enrolled in this global OLE trial and received Patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. This article summarizes the 12 month interim analysis of the data. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-Patisiran, phase 2 OLE Patisiran) based on allocation in the parent trial. 

The authors report that between 2015, and 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-Patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE Patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-Patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE Patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with Patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-Patisiran mean change –4·0, 95 % CI –7·7 to −0·3; phase 2 OLE Patisiran –4·7, –11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment −1·4, 95% CI –6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-Patisiran (48 [35%] of 137) or phase 2 OLE Patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-Patisiran (ten [7%] of 137) and phase 2 OLE Patisiran (0 of 25) groups.

Comments: This is an article that summarizes world wide experience in treating a big number of patients with HTTR, a patient group which unless one is in a amyloidosis center, is not frequently seen in such high numbers by the practicing physiatrist, neurologist and neuromuscular physician. The strengths or the study are the large numbers of patients and relatively long period of following the patients (18 mo for the Apollo, 24 mo for the phase 2 OLE, all patients continuing on a global OLE for 12 months). The treated patients do well and the sooner they are treated the better they do. The drug has side effects that are connected to infusion reactions. Additionally, diarrhea, peripheral edema, UTI are among the common side effects. More severe SE are connected to progression of disease and were more common in the placebo treated group.