Wainzua(eplontersen)

Wainzua (eplontersen) is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (ATTRv) in adult patients with stage 1 or stage 2 polyneuropathy. It is a New Active Substance (NAS) and was recommended for marketing authorization. Eplontersen demonstrated significant efficacy in reducing transthyretin (TTR) levels. In preclinical studies, eplontersen showed 51-fold more potent hTTR mRNA expression inhibition and 28-fold more potent hTTR mRNA reduction compared to inotersen, with ED50 values of 0.5 mg/kg/week for eplontersen versus 13.9 mg/kg/week for inotersen. TTR protein reduction potency was 15-fold higher for eplontersen, with ED50 values of 1.5 mg/kg/week versus 22.9 mg/kg/week for inotersen. Maximum TTR expression reduction was 85%. In clinical trials, the serum TTR percent change from baseline was -81.2%, with a treatment difference of -66.4%.

Safety findings included a No Observed Adverse Effect Level (NOAEL) of 6 mg/kg/week in a 13-week monkey toxicity study and 25 mg/kg/month in a 39-week monkey toxicity study. Safety margins were 70-fold (AUC-related). The NOAEL for fertility, maternal toxicity, and foetal developmental effects in mice was 75 mg/kg/week. A percentage of patients (41.8%) in the continuous eplontersen group developed treatment-emergent eplontersen anti-drug antibodies (ADA), with a median time to onset of 225 days and a median peak titer of 200. The recommended dose is 45 mg administered monthly.