Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the Treatment of Alpha-1 Antitrypsin (AAT) Deficiency
Nov 14, 2012
“In line with our ‘Alnylam 5x15’ product strategy, we are excited about
the potential for RNAi therapeutics for the treatment of AAT deficiency,
a rare, genetic condition that causes lung and liver disease,” said
“Approximately 10,000 people worldwide have been diagnosed with severe
AAT deficiency, a rare genetic disease that results in severe lung and
liver pathology. AAT patients can develop early onset emphysema as well
as liver disease, including hepatitis, cirrhosis, and hepatocellular
carcinoma. While lung disease associated with AAT deficiency has been
addressed with AAT replacement therapy, there are limited treatment
options for patients with liver disease,” said
ALN-AAT is a new RNAi therapeutic program for the treatment of liver disease associated with AAT deficiency. New data presented at the Liver Meeting are based on an AAT-targeting siRNA formulated in a lipid nanoparticle (LNP). The AAT siRNA was administered at doses ranging from 0.03 to 1.0 mg/kg in mice overexpressing a human Z-AAT transgene, resulting in robust, dose-dependent silencing of the target mRNA and protein. Specifically, a single intravenous dose of the drug resulted in 90% knockdown of liver mRNA and a greater than 80% decrease in serum AAT at 48 hours post-dose. Furthermore, a 90% reduction in soluble protein monomers in the liver was observed at 1.0 mg/kg, with an 80% reduction seen at 0.3 mg/kg. In addition, in long-term dosing studies, in which transgenic mice overexpressing Z-AAT were dosed every other week for 12 weeks at 0.3 mg/kg, ALN-AAT resulted in a 45% reduction of pathogenic protein polymers and a significant decrease in the size and number of AAT globules in hepatocytes. Long-term dosing also significantly decreased hepatocyte proliferation and liver collagen levels, known markers of liver dysfunction and fibrosis, respectively. Further, ALN-AAT administration resulted in marked improvements in hepatocyte cellular morphology as assessed by electron microscopy. Finally, 98% suppression of liver mRNA and serum protein was observed 48 hours after a single dose of the drug in transgenic mice that had fibrotic livers, illustrating key pre-clinical proof of concept for RNAi-mediated treatment in diseased livers. Alnylam has also identified a GalNAc-siRNA targeting AAT that enables subcutaneous dose administration for further development.
In addition, in a poster titled “Liposome mediated delivery of siRNA to hepatic stellate cells,” Alnylam scientists presented new data on the systemic delivery of RNAi therapeutics to quiescent and activated hepatic stellate cells (HSCs). HSCs play a key role in the initiation and progression of liver fibrosis, the excessive accumulation of tough, fibrous scar tissue that occurs in most types of chronic liver diseases. These new data show that siRNA formulated in LNPs result in effective silencing of the HSC-specific gene target, collagen 1a1 (col1a1). Specifically, a single intravenous dose of siRNA against col1a1 yielded robust, dose-dependent silencing of target mRNA in activated HSCs at 48 hours, with an approximate ED50 of 0.1 mg/kg. Furthermore, silencing of col1a1 was confirmed to be RNAi-mediated. These data point to a potential strategy for development of RNAi therapeutics for the treatment of liver fibrosis.
About Alpha-1 Antitrypsin (AAT) and AAT Deficiency
Alpha-1
antitrypsin deficiency is an autosomal disorder that results in disease
of the lungs and liver, and afflicts roughly 10,000 patients worldwide.
AAT is a liver-produced serine proteinase inhibitor with the primary
function of protecting the lungs from neutrophil elastase and other
irritants that cause inflammation. In the liver, misfolding of the
mutant Z-AAT protein hinders its normal release into the blood thereby
causing it to aggregate in hepatocytes, leading to liver injury,
fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). A deficient
serum level of the protein can render the lungs susceptible to
emphysema. About 95% of patients with alpha-1 antitrypsin deficiency
carry two copies of the abnormal Z allele (PiZZ patients). Although
about 19 million Americans are carriers (containing one normal form of
the gene and one mutant form), about 100,000 are thought to be
homozygous for the Z allele (PiZZ), and it is estimated that less than
10% of affected patients are currently diagnosed. Treatment for lung
disease associated with AAT deficiency consists of routine emphysema
care and, in some instances, augmentation therapy, whereby purified AAT
from the plasma of healthy donors is administered to patients to
increase circulating and airway levels of AAT and restore its function
in the lungs. The only treatment options presently available for
patients with cirrhosis caused by mutant AAT accumulation in the liver
are supportive care and, in the case of advanced cirrhosis, liver
transplantation. RNAi-mediated inhibition of AAT in AAT-deficient PiZZ
patients represents a promising new way to treat this rare disease.
About RNA Interference (RNAi)
RNAi (RNA interference) is a
revolution in biology, representing a breakthrough in understanding how
genes are turned on and off in cells, and a completely new approach to
drug discovery and development. Its discovery has been heralded as “a
major scientific breakthrough that happens once every decade or so,” and
represents one of the most promising and rapidly advancing frontiers in
biology and drug discovery today which was awarded the 2006 Nobel Prize
for Physiology or Medicine. RNAi is a natural process of gene silencing
that occurs in organisms ranging from plants to mammals. By harnessing
the natural biological process of RNAi occurring in our cells, the
creation of a major new class of medicines, known as RNAi therapeutics,
is on the horizon. Small interfering RNA (siRNA), the molecules that
mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target
the cause of diseases by potently silencing specific mRNAs, thereby
preventing disease-causing proteins from being made. RNAi therapeutics
have the potential to treat disease and help patients in a fundamentally
new way.
About
Alnylam is a biopharmaceutical
company developing novel therapeutics based on RNA interference, or
RNAi. The company is leading the translation of RNAi as a new class of
innovative medicines with a core focus on RNAi therapeutics for the
treatment of genetically defined diseases, including ALN-TTR for the
treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the
treatment of hemophilia, ALN-PCS for the treatment of severe
hypercholesterolemia, ALN-HPN for the treatment of refractory anemia,
and ALN-TMP for the treatment of hemoglobinopathies. As part of its
“Alnylam 5x15TM” strategy, the company expects to have five
RNAi therapeutic products for genetically defined diseases in clinical
development, including programs in advanced stages, on its own or with a
partner by the end of 2015. Alnylam has additional partnered programs in
clinical or development stages, including ALN-RSV01 for the treatment of
respiratory syncytial virus (RSV) infection, ALN-VSP for the treatment
of liver cancers, and ALN-HTT for the treatment of Huntington’s disease.
The company’s leadership position on RNAi therapeutics and intellectual
property have enabled it to form major alliances with leading companies
including Merck,
About LNP Technology
Alnylam has licenses to Tekmira LNP
intellectual property for use in RNAi therapeutic products using LNP
technology.
Alnylam Forward-Looking Statements
Various statements in
this release concerning Alnylam’s future expectations, plans and
prospects, including without limitation, statements regarding Alnylam’s
views with respect to the potential for RNAi therapeutics, including the
potential for ALN-AAT as a treatment for liver disease associated with
AAT deficiency, and Alnylam’s expectations regarding its “Alnylam 5x15”
product strategy, constitute forward-looking statements for the purposes
of the safe harbor provisions under The Private Securities Litigation
Reform Act of 1995. Actual results may differ materially from those
indicated by these forward-looking statements as a result of various
important factors, including, without limitation, Alnylam’s ability to
successfully demonstrate the efficacy and safety of its drug candidates,
the pre-clinical and clinical results for these product candidates,
including ALN-AAT, which may not support further development of such
product candidates, actions of regulatory agencies, which may affect the
initiation, timing and progress of clinical trials for such product
candidates, obtaining, maintaining and protecting intellectual property,
obtaining regulatory approval for products, competition from others
using technology similar to Alnylam’s and others developing products for
similar uses, and Alnylam’s ability to establish and maintain strategic
business alliances and new business initiatives, as well as those risks
more fully discussed in the “Risk Factors” section of its most recent
quarterly report on Form 10-Q on file with the
Source:
Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice
President, Investor Relations and Corporate Communications
or
Spectrum
Amanda
Sellers (Media), 202-955-6222 x2597
For Media Inquiries, please contact:
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