Dicerna Presents Data From Phase 1 Trial of Belcesiran at American Association for the Study of Liver Diseases (AASLD) The Liver Meeting® 2021
Nov 12, 2021
– Belcesiran Was Shown to Be Safe and Well Tolerated in Phase 1 Trial and Demonstrated Robust, Dose-Dependent Reductions in Serum Alpha-1 Antitrypsin –
– Enrollment in ESTRELLA Phase 2 Study of Belcesiran Is Ongoing; Global Rollout to Additional Trial Sites Continues –
“In people with AATLD, misfolded AAT aggregates in the liver and causes liver injury that may progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. Liver transplantation is currently the only option for individuals with this rare condition who progress to liver failure, underscoring the need for a safe and effective therapeutic approach that can reduce the production and aggregation of toxic protein in the liver,” said
“The results from this first-in-human trial showed clear reduction in serum AAT with belcesiran administration,” said
“Enrollment in the ESTRELLA trial continues to progress as we bring more clinical trial sites online in multiple countries,”
The Phase 1 trial was designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a single subcutaneous dose of belcesiran 0.1, 1.0, 3.0, 6.0 or 12.0 mg/kg compared to placebo (n=6, 2:1 randomization per cohort) in 30 adult healthy volunteers. A validated, standard‐of‐care quantitative nephelometry assay was used to measure serum AAT levels. Repeat measurements of spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) were performed to monitor pulmonary function. All participants completed their treatment periods (through Day 57). All participants receiving belcesiran and who met certain criteria entered conditional follow-up post Day 57.
Robust, dose-dependent reductions in serum AAT were observed up to 6 mg/kg following a single dose of belcesiran, with the 6 mg/kg and 12 mg/kg cohorts achieving similar AAT reductions. Mean serum AAT reductions from baseline at end of treatment for doses greater than 0.1 mg/kg were 48% (1.0 mg/kg), 67% (3.0 mg/kg), 77% (6.0 mg/kg) and 78% (12.0 mg/kg), with maximum reductions occurring approximately eight weeks post-dose.
- Two participants achieved a maximum serum AAT reduction of approximately 90%; both participants received belcesiran 6 mg/kg.
- No severe or serious treatment-emergent adverse events (TEAEs) were reported. Most TEAEs were mild (39) or moderate (3 in two participants; common cold, gastroenteritis and staphylococcal folliculitis) and were determined to be unrelated to belcesiran treatment. No dose‐dependent increases in frequency or severity of TEAEs, or abnormalities in safety labs, ECGs, physical exams or vital signs were observed.
- Normal lung function was maintained. There were no dose-dependent changes in spirometry measurements, and percent predicted DLCO repeat measurements remained within normal limits.
- No clinically significant changes in laboratory safety tests, including liver function tests, were reported for any belcesiran dose.
These results were presented at AASLD by
About Alpha-1 Antitrypsin (AAT) 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).1 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.2,3 People with AAT deficiency may also develop lung disease, including emphysema.
Belcesiran is a clinical-stage, subcutaneously administered, investigational GalXC™ RNAi therapy targeting alpha-1 antitrypsin (AAT) that is in development for the treatment of AAT deficiency-associated liver disease (AATLD). Belcesiran is designed to target the gene responsible for production of the abnormal AAT protein in order to reduce AAT production in the liver. Dicerna is currently investigating the use of belcesiran for the treatment of AATLD in the SHINE clinical development program.
About the ESTRELLA Trial
ESTRELLA (NCT04764448) is a randomized, multidose, double-blind, placebo-controlled Phase 2 trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of belcesiran in participants with alpha-1 antitrypsin deficiency-associated liver disease (AATLD). The study includes a 24-week cohort and a 48-week cohort to be conducted in participants who have a diagnosis of PiZZ-type AAT deficiency and AATLD. The ESTRELLA clinical trial is part of Dicerna’s SHINE clinical development program to evaluate the safety and efficacy of belcesiran, formerly known as DCR-A1AT, for the treatment of AATLD.
About RNAi and Dicerna’s GalXC™ RNAi Platform
Ribonucleic acid interference, or RNAi, provides a unique advantage to other disease inhibitor technologies, like small-molecule pharmaceuticals or monoclonal antibodies. Instead of targeting proteins after they have been produced and released, RNAi silences the genes themselves via the specific destruction of the messenger RNA (mRNA) made from the gene. Rather than seeking to inhibit a protein, the RNAi approach can prevent a disease-causing protein’s creation, directly impacting disease manifestation.
Dicerna’s proprietary GalXC™ RNAi platform aims to advance the development of next-generation RNAi-based therapies. Investigational therapeutics developed using our flagship GalXC technology utilize a proprietary N-acetyl-D-galactosamine (GalNAc)-mediated structure of double-stranded RNA molecules that are designed to bind specifically to receptors on liver cells, leading to selective hepatocyte internalization and access to the RNAi machinery within the cells. Dicerna is continuously innovating and exploring new applications of RNAi technology beyond GalNAc-mediated delivery to the liver, including alternative RNA structures and fully synthetic ligands that target other tissues and cell types and enable new therapeutic applications, referred to as GalXC-Plus™.
Cautionary Note on Forward-Looking Statements
This press release includes forward-looking statements. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Examples of forward-looking statements include, among others, statements we make regarding: the belcesiran development program, including the results from our clinical trials and the potential impact thereof, the potential of belcesiran as a treatment for alpha-1 antitrypsin deficiency-associated liver disease (AATLD), and the planned progression of our clinical trials, such as for our Phase 2 trial of belcesiran. The process by which investigational therapies could potentially lead to an approved product is long and subject to highly significant risks. Applicable risks and uncertainties include those relating to Dicerna’s clinical research and other risks identified under the heading "Risk Factors" included in the Company’s most recent filings on Forms 10-K and 10-Q and in other future filings with the
GalXC™ and GalXC-Plus™ are trademarks of
1.Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. 2006 Oct 27 [updated 2020 May 21]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews [Internet].
2.Tanash & Piitulainen. J Gastroenterol. 2019 Jun;54(6):541-548. doi: 10.1007/s00535-019-01548-y. Epub 2019 Jan 24.
3.Clark et al. J Hepatol. 2018 Dec;69(6):1357-1364. doi: 10.1016/j.jhep.2018.08.005. Epub 2018 Aug 21.