Abstract Details

hATTR amyloidosis is a rapidly progressive disease caused by transthyretin gene variants. V122I and T60A variants are associated with cardiomyopathy, yet evidence of a mixed cardiac and neurologic phenotype is emerging. 

Assess the effectiveness of patisiran, an RNAi therapeutic approved for patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, in those with a V122I or T60A variant.

In this multicenter, observational, Phase 4 study of US patients with V122I/T60A variants and polyneuropathy (NCT04201418), the primary endpoint is the proportion of patients with improved/stable polyneuropathy disability (PND) score vs baseline after 12 months of patisiran treatment. Neuropathy- and cardiomyopathy-related quality of life (QOL; Norfolk QOL-Diabetic Neuropathy [QOL-DN], Kansas City Cardiomyopathy Questionnaire [KCCQ]), autonomic symptoms (Composite Autonomic Symptom Score-31 [COMPASS-31]), and severity of cardiac dysfunction (New York Heart Association [NYHA] class) were assessed. PND score change from baseline to 12 months is reported for patients completing the study.

58 patients were included: V122I, n=45; T60A, n=13. At baseline, evaluable patients had impaired QOL (mean [range] QOL-DN, 28.4 [–2 to 78]) and dysautonomia (mean [range] COMPASS-31, 22.4 [0–46]). Patients experienced a wide range of ambulatory dysfunction, with 25 (43.1%) with a PND score of II/IIIA/IIIB. 52 (89.7%) patients had heart failure. At 12 months, out of 45 patients completing the study, 42 (93.3%) demonstrated stabilization or improvement in PND score from baseline. Patients improved in Norfolk QOL-DN (mean change [SE], -7.9 [4.9]), mBMI (+201.8 [139.0]), and COMPASS-31 (-11.0 [4.5]) from baseline. Patisiran treatment in this population demonstrated an acceptable safety profile, consistent with existing data.

Almost 90% of the patients in this study with V122I/T60A variants demonstrated a mixed phenotype, with 10.3% having peripheral neuropathy without heart failure. Regardless of genotype/phenotype, patients demonstrated improved/stabilized PND score and improvement in QOL and autonomic function after 12 months of patisiran.