Effect of RNAi therapeutics patisiran and vutrisiran on orthostatic hypotension due to dysautonomia in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy

Abstract Background Hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv is a rapidly progressive, multisystem disease. Orthostatic hypotension, due to autonomic neuropathy, common yet hard-to-treat disease manifestation in patients with hATTR amyloidosis. Fatigue, muscle weakness, and deterioration cardiac function further exacerbate orthostatic symptoms. Efficacy of RNAi therapeutics patisiran vutrisiran was assessed amyloidosis polyneuropathy across the APOLLO (NCT01960348), Global Open-Label Extension (OLE) (NCT02510261), HELIOS-A (NCT03759379) studies, respectively. Purpose Evaluate quantitative effect on hypotension polyneuropathy. Methods In APOLLO, were randomised 2:1 0.3 mg/kg or placebo, IV q3w. Patients who completed (APOLLO-placebo, APOLLO-patisiran) eligible enrol into ongoing OLE (patisiran q3w). HELIOS-A, 3:1 (25 mg SC q3m) (0.3 q3w; reference group). Primary endpoint for change from baseline modified Neuropathy Impairment Score+7 (mNIS+7) vs placebo at M18 (APOLLO) M9 (HELIOS-A). evaluated using postural blood pressure (PBP) component mNIS+7, calculated mean 2 supine readings systolic BP [SBP, mmHg] taken 15 min apart minus lowest SBP upon standing 1, 3, 5 min. A smaller reduction observed between upright indicated an improved PBP. Results enrolled 225 (placebo, n=77; patisiran, n=148), 211 164 (vutrisiran, n=122; n=42). At baseline, severity similar within-study treatment arms HELIOS-A. patisiran-treated showed PBP improvement stabilization (mean [SD] SBP: −17.6 [19.4]; M18, −13.5 [16.8]) maintained 36m (−13.4 [15.6]). contrast, placebo-treated had increased over 18m (baseline, −17.5 [16.5]; −20.4 [16.9]); their after initiation (Global 36m, −16.6 [18.1]). arm −11.2 [14.0], −11.7 [14.6]). arm, while increased, value remained normal range −11.6 [17.2]; −14.2 [15.5]). Patisiran have acceptable safety profiles. Conclusions analyses quantify benefits The increase symptomatic without indicates importance early intervention. Funding Acknowledgement Type funding sources: Private company. Main source(s): Alnylam Pharmaceuticals