Abstract Details

hATTR amyloidosis is a rare, progressive, and fatal disease characterized by deposition of non-native transthyretin (TTR) protein aggregates in organs including the heart and peripheral nerves. Preclinically, PRX004 inhibited amyloid fibril formation, neutralized soluble aggregate forms of non-native TTR, and cleared insoluble amyloid fibrils through phagocytosis.

Evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of PRX004 in hereditary amyloid transthyretin (hATTR) amyloidosis.

Phase 1, open-label, dose-escalation (DE) study (dose cohorts: 0.1, 0.3, 1, 3, 10, and 30 mg/kg) with long-term extension (LTE); hATTR patients received PRX004 intravenously once every 28 days for up to 3 infusions in the DE phase and up to 15 infusions in the LTE phase.

All 21 hATTR patients completed DE phase dosing; 17 patients enrolled in the LTE. No drug-related serious adverse events (AEs), drug-related ≥grade 3 events, deaths, or dose-limiting toxicities were reported. Most frequent AEs (≥10%) were fall, anemia, upper respiratory tract infection, back pain, constipation, diarrhea, and insomnia. PRX004 demonstrated a PK profile consistent with IgG1 monoclonal antibodies. Based on PK/pharmacodynamic models, dose levels ≥3 mg/kg were predicted to enable clearance of >90% of amyloid deposits, thus dose cohorts 3, 10, and 30 mg/kg were considered equivalent, and efficacy assessments in these cohorts were pooled. At month 9, all 7 evaluable patient had slower progression versus natural history. (+1.29 vs +9). 3 of 7 patients demonstrated an improvement in Neuropathy Impairment Score (NIS) from baseline (mean change: −3.33). Improvement in global longitudinal strain (GLS) was observed in all 7 patients (mean change: −1.21), and was further enhanced in the 3 patients with NIS improvement (mean change: –1.51).

PRX004 was safe and well tolerated at all doses tested. Patients showed improvement/slower progression in neuropathy versus disease natural history and improvement in GLS, suggesting that amyloid targeting with PRX004 provides therapeutic benefit for patients.