Dicerna Announces Interim Results From Phase 1 Trial of Belcesiran for Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
Jul 21, 2021
– Interim Results From Phase 1 Study Enabled Initiation and First Patient Dosing in Phase 2 ESTRELLA Study, Which Is Currently Underway –
“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
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.
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 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 timeline or outcomes of trials, the potential of belcesiran as a treatment for alpha-1 antitrypsin deficiency-associated liver disease (AATLD), and the submission, acceptance or delivery of results at conferences. 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.Sanders CL, Ponte A, Kueppers F. The Effects of Inflammation on Alpha 1 Antitrypsin Levels in a National Screening Cohort. COPD. 2018 Feb;15(1):10-16. doi: 10.1080/15412555.2017.1401600.
2.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].
3.Tanash & Piitulainen. J Gastroenterol. 2019 Jun;54(6):541-548. doi: 10.1007/s00535-019-01548-y. Epub 2019 Jan 24.
4.Clark et al. J Hepatol. 2018 Dec;69(6):1357-1364. doi: 10.1016/j.jhep.2018.08.005. Epub 2018 Aug 21.