Results of a 5-year global open-label extension study evaluating the RNA interference therapeutic patisiran for hereditary transthyretin amyloidosis with polyneuropathy found that early treatment with the agent led to better clinical stability and survival compared with delayed initiation.
The trial is the longest evaluation of an RNA interference (RNAi) therapeutic for any disease, according to the study authors. They published their results in JAMA Neurology.
Investigators enrolled 211 patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) across 19 countries who had previously been enrolled in either the phase III APOLLO or phase II OLE trial, with 138 completing the global extension. Patients received intravenous patisiran at 0.3 mg/kg every 3 weeks for up to 5 years.
After 5 years, 65.0% of patients (n = 89) showed stabilization or improvement in their polyneuropathy disability score. Neuropathy Impairment Score increased by a mean of 10.9 (standard deviation [SD] = 14.7), while modified body mass index improved by 46.4 (SD = 120.7), reflecting reduced autonomic dysfunction-related malnutrition. Those who switched from placebo to patisiran exhibited slower disease progression.
Quality-of-life assessments showed a modest increase in Norfolk Quality of Life-Diabetic Neuropathy scores (4.1; SD = 16.7) and a decline in Rasch-Built Overall Disability Scale scores (–3.7; SD = 6.2), suggesting a reduced rate of deterioration.
Over 5 years, 41 patients (19.4%) died, and 47 (22.3%) withdrew due to adverse events. The exposure-adjusted mortality rate was lower in the APOLLO patisiran group (3.3 per 100 patient-years) compared with the APOLLO placebo group (12.8 per 100 patient-years). Infusion-related reactions were the most common adverse event (16.1%).
Kaplan-Meier analysis confirmed a survival advantage for patients who started treatment with patisiran earlier. Multivariate analysis identified familial amyloid polyneuropathy stage and prior treatment as independent predictors of survival (hazard ratio = 5.19; 95% confidence interval = 2.79–9.63, P < .001).
"Patients tend not to recover function that is lost before starting treatment, which, along with a potential survival benefit, bolsters the importance of diagnosis and early treatment initiation," wrote first study author David Adams MD, PhD, of Université Paris-Saclay, and colleagues.
Despite the absence of a placebo control, the findings support the long-term safety and efficacy of RNAi therapeutics in chronic disease management, concluded the investigators.
Full disclosures are available in the published study.