Belcesiran was well-tolerated and reduced serum aat levels in healthy volunteers (phase 1 interim results)

BACKGROUND: In individuals homozygous for SERPINA1 mutant Z‐allele, the alpha‐1 antitrypsin Z protein (Z‐AAT) is prone to misfolding, leading to its aggregation and toxic accumulation in the liver. Belcesiran is a hepatocytetargeted RNAi agent designed to silence the expression of SERPINA1, thereby reducing levels of Z‐AAT accumulation in hepatocytes and serum AAT protein. We report interim results (data as of 05MAY2021) from a Phase 1 study DCRA1AT‐101 in healthy volunteers (HV). METHODS: HVs received a single subcutaneous injection of belcesiran 0.1, 1.0, 3.0, or 6.0 mg/kg or placebo (n=6/cohort, 2:1 randomization). If serum AAT had not returned to ≥ 80% of baseline at Day 57/end of treatment (EOT), HVs had follow up visits until AAT returned to ≥ 80% of baseline. Key inclusion criteria: overtly healthy males or females, 18‐55 years, non‐smoking, serum AAT >100 mg/dL and FEV1 ≥85% of predicted with FEV1/FVC ≥ 0.7. Spirometry and DLCO were performed to monitor pulmonary function. RESULTS: Single doses of belcesiran resulted in robust and dose‐dependent reduction in serum AAT (Figure). At doses 1.0 mg/kg, the mean nadir reduction occurred ~8 weeks post dose (EOT), with % mean reduction from baseline at EOT of approximately 48%, 67%, and 80% for 1.0 (n=4), 3.0 (n=4) and 6.0 mg/kg dose (n=3, one HV has not reached EOT), respectively. Two of the three HVs in the 6 mg/kg group had nadir serum AAT reductions of ~90%. An average serum AAT reduction of >70% was sustained for at least 12 weeks in the 6.0 mg/kg cohort. All doses were safe, and no serious adverse events were reported. All treatment emergent adverse events (TEAEs) were graded as mild except for three TEAEs which were moderate (common cold, gastroenteritis, staphylococcal folliculitis) and not related to the study drug. The most common TEAEs were headache [6 occurring with equal frequency in HVs on belcesiran (4/16) and placebo (2/8)] and AEs related to the injection [11 AEs in HVs on belcesiran (8/16)]. There were 4 injection site reactions reported in 4 HVs on belcesiran. There were no other clinically significant abnormalities in physical exams, vital signs, electrocardiograms, clinical laboratory tests, spirometry and DLCO. CONCLUSION: Belcesiran demonstrated a favorable safety and tolerability profile while inducing a dose‐dependent and durable reduction in serum AAT. Belcesiran is currently being investigated in patients with liver disease associated with alpha‐1 antitrypsin deficiency (NCT04764448).