Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

Abstract

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, − 7.5; 95% CI: − 11.9, − 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, − 1.1; − 1.8, − 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; − 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, − 0.3; − 0.5, − 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, − 5.3; 95% CI: − 7.9, − 2.7) and individual domains, orthostatic intolerance (− 4.6; − 6.3, − 2.9) and gastrointestinal symptoms (− 0.8; − 1.5, − 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.

Val50Met Hereditary Transthyretin Amyloidosis: Not Just a Medical Problem, but a Psychosocial Burden

“…Some manifestations, such as erectile dysfunction and digestive problems, can severely diminish the quality of life of patients, especially the younger population. This indicates the importance of including autonomic symptoms and quality of life questionnaires in treatment objectives in clinical practice and clinical trials, as already proposed by others (20,21,22). Moreover, the impairment in daily life activities and loss of ambulation abilities worsen the perception of quality of life.…”

Gastrointestinal Manifestations in Hereditary Transthyretin Amyloidosis: a Single-Centre Experience

“…Current therapeutic options increase the survival of patients, slowing the progression of the polyneuropathy and/ or cardiomyopathy [10][11][12][13]. No therapy is approved for the management of GI disturbances, even if some effects of the available drugs have been described [14].…”

Patisiran in hATTR Amyloidosis: Six-Month Latency Period before Efficacy

“…In particular, in the phase 3, randomized, double-blind, placebo-controlled (2:1), 18-month Apollo study, patisiran has been demonstrated effective in substantially reduce TTR concentration [ 23 ], with significant and sustained improvement in polyneuropathy scores [ 26 ], autonomic neuropathy [ 27 ], quality-of-life profile [ 28 ], and some cardiac parameters [ 29 ]. For some parameters, such as the modified Neuropathy Impairment Score + 7 (mNIS + 7) and the Norfolk Quality of Life–Diabetic Neuropathy questionnaire total score (Norfolk QOL-DN), a statistically significant improvement was achieved at 18 months compared with placebo, with effects seen as early as 9 months [ 3 ].…”