Conceição, Isabel

Abstract Aims HELIOS-A was a Phase 3, open-label study of vutrisiran, an RNA interference therapeutic, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. This analysis evaluated vutrisiran's impact on exploratory cardiac endpoints in HELIOS-A patients. Methods and results Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months or intravenous patisiran 0.3 mg/kg every 3 weeks (reference group) for 18 months. Exploratory cardiac endpoints included change from baseline in N-terminal prohormone of brain-type natriuretic peptide (NT-proBNP) and echocardiographic parameters versus external placebo (APOLLO study). The modified intent-to-treat (mITT) population comprised randomized patients receiving any study drug (n = 122). A cardiac subpopulation with evidence of cardiac amyloid involvement (n = 40) was prespecified. 99mTc scintigraphy exploratory assessments in a planned vutrisiran-treated cohort at select sites were compared with baseline. At Month 18, vutrisiran demonstrated beneficial effects on NT-proBNP versus external placebo in the mITT and cardiac subpopulations (adjusted geometric mean fold change ratio [95% confidence interval] 0.480 [0.383–0.600], p = 9.606 × 10−10 and 0.491 [0.337–0.716], p = 0.0004, respectively). Benefits or trends towards benefit in echocardiographic parameters versus external placebo were observed for both populations. In 99mTc scintigraphy assessments, 32/47 (68.1%) and 31/48 (64.6%) patients exhibited reduced normalized left ventricular total uptake and heart-to-contralateral lung ratio, respectively. Perugini grade was reduced or unchanged versus baseline in 55/57 (96.5%) evaluable patients. No increase in cardiac adverse events was observed with vutrisiran versus external placebo. Conclusions Vutrisiran demonstrated evidence of potential benefit on cardiac manifestations in patients with ATTRv amyloidosis with polyneuropathy, with an acceptable safety profile.

ABSTRACTIntroductionPolyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.MethodsWe assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis) and its subscores and correlation with disability and health scores.ResultsThe mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests.ConclusionsSpecially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis, broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901–911, 2017