The investigational RNA interference therapy called belcesiran (DCR-A1AT) for the treatment of alpha-1 antitrypsin (AAT) deficiency (AATD) was found to be well-tolerated and lowered blood serum levels of alpha-1-antitrypsin (AAT) in healthy participants.
The interim trial results were part of a phase 1 clinical trial (NCT04174118) and presented as a poster at The Liver Meeting 2021, hosted by the American Association for the Study of Liver Diseases (AASLD).
“The results from this first-in-human trial showed clear reduction in serum AAT with belcesiran administration,” trial investigator Edward Gane, MD, MBChB, FRACP, MNZ, said.
Compared to baseline, the mean serum AAT levels decreased for each of the 6 ascending doses tested in the trial, with maximum reductions occurring 8 weeks after their dose. The reductions were also largely dose-dependent at levels between 0.1 mg/kg and 12 mg/kg, which yielded decreases of 48% (1.0 mg/kg), 67% (3.0 mg/kg), 77% (6.0 mg/kg), and 78% (12.0 mg/kg).
Two volunteers in the 6 mg/kg group achieved approximately 90% reductions in their AAT levels. No serious treatment-emergent adverse events (TEAEs) were reported in the study, and most mild (39) or moderate (3) TEAEs were determined to be unrelated to treatment with belcesiran. No changes in lung function or laboratory safety tests, including liver function tests, were observed.
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“Belcesiran is designed to reduce the production of abnormal AAT. We are pleased by the results from the first clinical trial of belcesiran, which achieved our goals of demonstrating safety and establishing a dosing regimen for our ESTRELLA phase 2 study of belcesiran, which is underway,” Shreeram Aradhye, MD, executive vice president and chief medical officer at Dicerna said.
“We also look forward to expanding our inclusion criteria for ESTRELLA in the near-term to include patients on augmentation therapy—a key area of interest to us as patients with the liver manifestation can also present with AAT deficiency-associated lung disease.”
The phase 1 trial is a double-blind, placebo-controlled single ascending dose trial of subcutaneous belcesiran in healthy volunteers. A total of 30 participants received either a 0.1, 1.0, 3.0, 6.0, or 12.0 mg/kg dose of belcesiran or placebo, randomized 2:1 with 6 participants in each cohort.
Volunteers were followed for 57 days after treatment or until AAT values had returned to 80% or greater of baseline values. Spirometry and diffusing capacity of the lungs for carbon monoxide were performed to monitor pulmonary function during this time while AAT values were monitored using a validated, standard‐of‐care quantitative nephelometry assay.
Dicerna presents data from phase 1 trial of belcesiran at American Association for the Study of Liver Diseases (AASLD) the liver meeting® 2021. News Release. Dicerna Pharmaceuticals; November 12, 2021.
Gane E, Sjöberg F, Schwabe C, et al. Belcesiran was well tolerated and reduced serum AAT levels in healthy volunteers (phase 1 interim results). Presented at: The Liver Meeting 2021: November 12-15, 2021; Virtual.