– 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 –
Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA), a leading
developer of investigational ribonucleic acid interference (RNAi)
therapeutics, today presented results from its Phase 1
double-blind, placebo-controlled, randomized trial of belcesiran,
an investigational GalXC™ RNAi therapeutic in development for the
treatment of alpha-1 antitrypsin (AAT) deficiency-associated liver
disease (AATLD). These data expand upon interim results announced
in July 2021, demonstrating the safety and tolerability of single
ascending doses of belcesiran in healthy volunteers (up to and
including the final 12 mg/kg dose cohort) and further reaffirming
the dosing regimen established for the ESTRELLA Phase 2 study of
belcesiran. In addition, the data demonstrated robust,
dose‐dependent reductions in serum AAT through the 6 mg/kg dose
level, with a maximum individual reduction of 91%. The data were
presented in a poster at The Liver Meeting® 2021, the annual
meeting of the American Association for the Study of Liver Diseases
(AASLD).
“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 Shreeram Aradhye,
M.D., Executive Vice President and Chief Medical Officer at
Dicerna. “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. We are confident in the
dosing regimen that was selected for ESTRELLA and the profile that
we expect it to generate.”
“The results from this first-in-human trial showed clear
reduction in serum AAT with belcesiran administration,” said Edward
Gane, M.D., MBChB, FRACP, MNZ, Auckland City Hospital and
University of Auckland, Auckland, New Zealand, and investigator in
the Phase 1 trial. “The results from this trial support further
evaluation of belcesiran as a potential therapy for AATLD.”
“Enrollment in the ESTRELLA trial continues to progress as we
bring more clinical trial sites online in multiple countries,” Dr.
Aradhye continued. “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 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.
Results
- 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 Dr. Gane as a narrated
poster (Poster #27962) titled, “Belcesiran Was Well Tolerated and
Reduced Serum AAT Levels in Healthy Volunteers.” The poster will be
made available on the Events and Presentations page of Dicerna’s
website.
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.
About Belcesiran
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™.
About Dicerna Pharmaceuticals, Inc.
Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) is a
biopharmaceutical company focused on discovering, developing and
commercializing medicines that are designed to leverage ribonucleic
acid interference (RNAi) to silence selectively genes that cause or
contribute to disease. Using our proprietary GalXC™ and GalXC-Plus™
RNAi technologies, Dicerna is committed to developing RNAi-based
therapies with the potential to treat both rare and more prevalent
diseases. By silencing disease-causing genes, Dicerna’s GalXC
platform has the potential to address conditions that are difficult
to treat with other modalities. Initially focused on
disease-causing genes in the liver, Dicerna has continued to
innovate and is exploring new applications of its RNAi technology
with GalXC-Plus, which expands the functionality and application of
our flagship liver-targeted GalXC technology to tissues and cell
types outside the liver, and has the potential to treat diseases
across multiple therapeutic areas. In addition to our own pipeline
of core discovery and clinical candidates, Dicerna has established
collaborative relationships with some of the world’s leading
pharmaceutical companies, including Novo Nordisk A/S, Roche, Eli
Lilly and Company, Alexion Pharmaceuticals, Inc., Boehringer
Ingelheim International GmbH and Alnylam Pharmaceuticals, Inc.
Between Dicerna and our collaborative partners, we currently have
more than 20 active discovery, preclinical or clinical programs
focused on cardiometabolic, viral, chronic liver and
complement-mediated diseases, as well as neurodegenerative diseases
and pain. At Dicerna, our mission is to interfere – to silence
genes, to fight disease, to restore health. For more information,
visit www.dicerna.com.
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 Securities and Exchange Commission. These
risks and uncertainties include, among others, the cost, timing and
results of preclinical studies and clinical trials and other
development activities by us and our collaborative partners; the
likelihood of Dicerna’s clinical programs being executed on
timelines provided and reliance on the Company’s contract research
organizations and predictability of timely enrollment of subjects
and patients to advance Dicerna’s clinical trials; the reliance of
Dicerna on contract manufacturers to supply its products for
research and development and the risk of supply interruption from a
contract manufacturer; the potential for future data to alter
initial, interim and preliminary results of early-stage clinical
trials; the impact of the ongoing COVID-19 pandemic on our business
operations, including the conduct of our research and development
activities; the unpredictability of the duration and results of the
regulatory review of Investigational New Drug (IND) applications
and Clinical Trial Applications (CTAs) that are necessary to
continue to advance and progress the Company’s clinical programs
and the regulatory review of INDs and CTAs; the timing, plans and
reviews by regulatory authorities of marketing applications such as
New Drug Applications (NDAs) and comparable foreign applications
for one or more of Dicerna’s product candidates; the ability to
secure, maintain and realize the intended benefits of
collaborations with partners; market acceptance for approved
products and innovative therapeutic treatments; competition; the
possible impairment of, inability to obtain and costs to obtain
intellectual property rights; possible safety or efficacy concerns
that could emerge as new data are generated in R&D; and general
business, financial and accounting risks and litigation. The
forward-looking statements contained in this press release reflect
Dicerna's current views with respect to future events, and Dicerna
does not undertake and specifically disclaims any obligation to
update any forward-looking statements.
GalXC™ and GalXC-Plus™ are trademarks of Dicerna
Pharmaceuticals, Inc.
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]. Seattle (WA): University of
Washington, Seattle; 1993–2021. PMID: 20301692.
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.
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version on businesswire.com: https://www.businesswire.com/news/home/20211112005405/en/
Media: Amy Trevvett +1 617-612-6253 atrevvett@dicerna.com
Investors: Kristen K. Sheppard, Esq. +1 617-514-2275
ksheppard@dicerna.com
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