Benzinga | Jul 21, 2021 08:04AM EDT

Dicerna Announces Interim Results From Phase 1 Trial Of Belcesiran For Treatment Of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

Interim Results From Phase 1 Study Enabled Initiation and First Patient Dosing in Phase 2 ESTRELLA Study, Which Is Currently Underway --

Dicerna Pharmaceuticals, Inc. (NASDAQ:DRNA) (the "Company" or "Dicerna"), a leading developer of investigational ribonucleic acid interference (RNAi) therapeutics, today announced interim results from the fourcompletedactive-treatment dose cohorts (0.1, 1.0, 3.0 and 6.0 mg/kg) of its Phase 1 double-blind, placebo-controlled, randomized trial of belcesiran, an investigational GalXC(tm) RNAi therapeutic in development for the treatment of alpha-1 antitrypsin deficiency-associated liver disease (AATLD). AATLD is a rare genetic condition that can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Data from this interim analysis showed dose-dependent reductions in serum alpha-1 antitrypsin (AAT) with administration of a single dose of belcesiran. In this analysis, belcesiran was found to have an acceptable safety profile and was generally well tolerated. The primary treatment evaluation period for the final dose cohort (12.0 mg/kg) of belcesiran in the Phase 1 trial is ongoing.

"We are encouraged by the interim results from this first clinical trial of belcesiran, which met our objective, demonstrating an acceptable safety profile and tolerability as well as dose-dependent reductions in AAT levels over the treatment period," said Shreeram Aradhye, M.D., Executive Vice President and Chief Medical Officer at Dicerna. "Given the severity and progressive nature of AATLD, there is a significant need for a therapy that can directly impact the aggregation of mutated AAT protein in the liver. In addition to demonstrating that belcesiran was well tolerated, the results from this study suggest that belcesiran has the potential to meaningfully reduce the production of abnormal AAT protein -- a key objective in developing a pharmacological intervention for people with AATLD."

Serum AAT Reductions, Safety and Tolerability Data

The Phase 1 trial is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a single subcutaneous injection of belcesiran 0.1, 1.0, 3.0, 6.0 or 12.0 mg/kg compared to placebo (n=6 per cohort; 2:1 randomization) in adult healthy volunteers.

* In this interim analysis that included belcesiran doses up to 6.0 mg/kg, mean maximum serum AAT reductions from baseline achieved for doses greater than 0.1 mg/kg were: 50% (1.0 mg/kg), 69% (3.0 mg/kg) and 80% (6.0 mg/kg).

* In the four subjects receiving 6.0 mg/kg, maximum AAT reductions of 91%, 87%, 79% and 62% were observed, with the latter participant experiencing a concomitant skin infection (unrelated to belcesiran) and markedly elevated levels of C-reactive protein (CRP; a measure of inflammation in the body). Both CRP and AAT are known to increase in the presence of infection.1

* There were no serious adverse events reported. All treatment-emergent adverse events (TEAEs) were mild except for three TEAEs, which were moderate and determined to be unrelated to belcesiran.No clinically significant changes in lung function or laboratory tests were reported during the treatment periods for any of the belcesiran dose cohorts included in this analysis.

The final 12.0 mg/kg dose cohort in this trial is ongoing, and data from this cohort were not available for inclusion in this interim analysis. Dicerna plans to present additional results from all Phase 1 dose cohorts at an upcoming medical congress in 2021, subject to abstract acceptance.

About Alpha-1 Antitrypsin Deficiency and Alpha-1 Antitrypsin Deficiency-Associated Liver Disease (AATLD)

Alpha-1 antitrypsin (AAT) deficiency is a rare genetic condition caused by mutations in the SERPINA1 gene that results in disease of the liver and lungs. AAT protein is produced in hepatocytes and circulates in the bloodstream; AAT protects the lungs and other parts of the body by neutralizing neutrophil elastase, an enzyme that fights infection but can also damage healthy tissues if not adequately regulated by AAT. The majority of people with severe AAT deficiency are homozygous for the Z allele (PiZZ genotype).2 In the liver, misfolding of the mutant Z-AAT protein causes the protein to aggregate in liver cells, leading to liver injury, including fibrosis, cirrhosis and hepatocellular carcinoma. An estimated 10% or more of adults with AAT deficiency develop clinically meaningful liver disease.3,4 People with AAT deficiency may also develop lung disease, including emphysema.