Luigetti, Marco

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

Importance Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR ( NCT01737398 ; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group. Interventions Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P < .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration ClinicalTrials.gov Identifier: NCT04136184 ; EU Clinical Trials Register: EudraCT 2019-001698-10

AbstractBackground and purposeThis study was undertaken to assess the long‐term outcome of patients with paraneoplastic and non paraneoplastic autoimmune cerebellar ataxia (ACA) using the Scale for the Assessment and Rating of Ataxia (SARA).MethodsPatients with subacute cerebellar ataxia admitted to our institution between September 2012 and April 2020 were prospectively recruited. Serum and/or cerebrospinal fluid was tested for neural autoantibodies by indirect immunofluorescence on mouse brain, cell‐based assays, and radioimmunoassay. SARA and modified Rankin Scale (mRS) score were employed to assess patients’ outcome.ResultsFifty‐five patients were recruited, of whom 23 (42%) met the criteria for cerebellar ataxia of autoimmune etiology. Neural autoantibodies were detected in 22 of 23 patients (Yo–immunoglobulin G [IgG], n = 6; glutamic acid decarboxylase 65–IgG, n = 3; metabotropic glutamate receptor 1–IgG, n = 2; voltage‐gated calcium channel P/Q type–IgG, n = 2; Hu‐IgG, n = 1; glial fibrillary acidic protein–IgG, n = 1; IgG‐binding unclassified antigens, n = 7). Thirteen patients were diagnosed with paraneoplastic cerebellar syndrome (PCS) and 10 with idiopathic ACA. All patients received immunotherapy. Median SARA score was higher in the PCS group at all time points (p = 0.0002), while it decreased significantly within the ACA group (p = 0.049) after immunotherapy. Patients with good outcome (mRS ≤ 2) had less neurological disability (SARA < 15) at disease nadir (p = 0.039) and presented less frequently with paraneoplastic neurological syndrome (p = 0.0028). The univariate linear regression model revealed a good correlation between mRS and SARA score both at disease onset (p < 0.0001) and at last follow‐up (p < 0.0001). SARA score < 11 identified patients with good outcome.ConclusionsPatients with idiopathic ACA significantly improved after immunotherapy. SARA score accurately reflects patients’ clinical status and may be a suitable outcome measure for patients with ACA.