Impact of Patisiran, an RNAi Therapeutic, on Orthostatic Intolerance in Patients with Hereditary Transthyretin-Mediated Amyloidosis

Abstract

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease which can impact numerous organs, including peripheral and autonomic nerves and heart. Orthostatic intolerance (OI), caused by amyloid deposition in the autonomic nervous system, is commonly reported in patients with hATTR amyloidosis. OI increases the risk that patients will experience clinically significant events, such as presyncope, syncope, and falls. In the Phase 3 APOLLO study, patisiran demonstrated improvement in OI. This analysis further describes the impact of patisiran on OI symptomatology. APOLLO was an international, randomized (2:1), double-blinded, placebo-controlled study of patisiran 0.3mg/kg or placebo IV q3W in patients with hATTR amyloidosis with polyneuropathy (NCT01960348). COMPASS-31 is a patient-reported autonomic symptoms questionnaire containing 31-items evaluating 6 autonomic domains. In the OI domain, patients were asked, “In the past year, have you ever felt faint, dizzy, ‘goofy’, or had difficulty thinking soon after standing up from a sitting or lying position.” Change in presence and severity of these OI symptoms collected from the OI domain of COMPASS-31 were evaluated descriptively. APOLLO enrolled 225 patients: median age 62 years, 74% male, 43% V30M, FAP Stage 1 (46%) and 2 (53%), 56% in the pre-defined cardiac subpopulation. At baseline, about two-thirds of patients reported mild to severe symptoms of OI in the past year. After 18 months, patisiran-treated patients were 3-fold more likely to report improvement in OI symptoms compared to placebo (30% vs 10%, respectively). Patisiran-treated patients were also less likely to worsen on these symptoms compared to placebo-treated patients after 18 months (14% vs 23%, respectively). Following 18 months of treatment, patients treated with patisiran were three times more likely to improve in their OI symptoms versus their own baseline compared to placebo. These data reinforce the clinical benefit of patisiran in addressing the debilitating autonomic symptoms of hATTR amyloidosis.