Alnylam and The Alpha-1 Project (TAP) Form Collaboration for Advancement of ALN-AAT, an RNAi Therapeutic in Development for the Treatment of Alpha-1 Antitrypsin (AAT) Deficiency-Associated Liver Disease
Jun 19, 2014
- Alnylam Remains On Track to File Investigational New Drug (IND) Application in Mid-2015 -
"We have assembled what we believe to be the industry's most robust
pre-clinical data package supporting advancement of ALN-AAT - an
‘Enhanced Stabilization Chemistry' or ‘ESC'-GalNAc-siRNA conjugate
targeting AAT - including results in rodent models that demonstrate
knockdown of the disease-causing Z-allele and significant lowering of
the mutant protein (Z-AAT) burden in the liver, with associated
improvements in liver function, as seen by normalization of the
proliferative index, improved liver pathology, attenuated tissue
fibrosis, and decreased incidence of liver tumor formation. In addition,
we believe we have confirmed the activity of ALN-AAT in non-human
primate models and expect our Development Candidate to achieve human
target gene knockdown at doses less than 1 mg/kg with a once-monthly
dose regimen or better. Since our GalNAc-siRNA platform is clinically
validated based on results from other Alnylam RNAi therapeutic programs,
we have a high level of confidence that ALN-AAT can achieve potent
knockdown of the disease-causing Z-allele protein with subcutaneous dose
administration and a favorable safety profile," said
ALN-AAT is one of Alnylam's genetic medicine programs, which are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. Alnylam pioneered the application of RNAi therapeutics toward genetically defined targets expressed in the liver as part of the company's "Alnylam 5x15" product strategy. AAT deficiency-associated liver disease is caused by accumulation of mutant AAT protein ("Z-allele" or "Z-AAT") in liver tissue with subsequent liver injury, fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. It is estimated that approximately 10,000 to 20,000 people with AAT deficiency in the U.S. and E.U. have associated liver pathology.
"I applaud Alnylam for its efforts to develop a therapeutic for Alphas
with liver disease, as there are few options available for them today.
The Alpha-1 community is in desperate need of a treatment to improve the
quality of life for both pediatric and adult liver patients," said
Pre-clinical data from Alnylam's ALN-AAT program were first presented
at the Annual Meeting of the
"TAP is very pleased to collaborate with
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. 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 people with alpha-1 antitrypsin deficiency are homozygous and carry two copies of the abnormal Z allele (PiZZ). There are estimated to be approximately 200,000 people who are PiZZ in the U.S. and major European countries, and of these, at least 10% have an associated liver pathology caused by the misfolded protein encoded by the pathogenic Z-allele. Treatment for lung disease associated with AAT deficiency consists of routine emphysema care and, in some instances, augmentation therapy, which utilizes purified AAT from the plasma of healthy donors to increase circulating and airway levels of AAT to help 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 may represent a promising new way to treat this rare disease.
About
Mission statement:
About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC) GalNAc Conjugates
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC) GalNAc-conjugate technology enables subcutaneous dosing with increased potency, durability, and a wide therapeutic index, and is being employed in several of Alnylam's genetic medicine programs, including programs in clinical development.
About 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 as genetic medicines, including programs as
part of the company's "Alnylam 5x15TM" product strategy.
Alnylam's genetic medicine programs are RNAi therapeutics directed
toward genetically defined targets for the treatment of serious,
life-threatening diseases with limited treatment options for patients
and their caregivers. These include: patisiran (ALN-TTR02), an
intravenously delivered RNAi therapeutic targeting transthyretin (TTR)
for the treatment of TTR-mediated amyloidosis (ATTR) in patients with
familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously
delivered RNAi therapeutic targeting TTR for the treatment of ATTR in
patients with TTR cardiac amyloidosis, including familial amyloidotic
cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an
RNAi therapeutic targeting antithrombin (AT) for the treatment of
hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi
therapeutic targeting complement component C5 for the treatment of
complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting
aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic
porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an
RNAi therapeutic targeting PCSK9 for the treatment of
hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1
antitrypsin (AAT) for the treatment of AAT deficiency-associated liver
disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the
treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an
RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the
treatment of genetic forms of mixed hyperlipidemia and severe
hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting
apolipoprotein C-III (apoCIII) for the treatment of
hypertriglyceridemia; and other programs yet to be disclosed. As part of
its "Alnylam 5x15" strategy, as updated in early 2014, the company
expects to have six to seven genetic medicine product candidates in
clinical development - including at least two programs in Phase 3 and
five to six programs with human proof of concept - by the end of 2015.
Alnylam is also developing ALN-HBV, an RNAi therapeutic targeting the
hepatitis B virus (HBV) genome for the treatment of HBV infection. The
company's demonstrated commitment to RNAi therapeutics has enabled it to
form major alliances with leading companies including Merck, Medtronic,
Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist,
GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme,
a Sanofi company. In
About "Alnylam 5x15™" and Genetic Medicines
The "Alnylam 5x15" strategy, launched in
Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including without limitation,
Alnylam's views with respect to the potential for RNAi therapeutics,
including ALN-AAT for the treatment of AAT deficiency-associated liver
disease, its expectations with respect to timing of regulatory filings
for ALN-AAT, the potential therapeutic opportunities for ALN-AAT, its
expectations regarding its "Alnylam 5x15" product strategy, and its
plans regarding commercialization of RNAi therapeutics, including
ALN-AAT, 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 manage
operating expenses, Alnylam's ability to discover and develop novel drug
candidates and delivery approaches, successfully demonstrate the
efficacy and safety of its drug candidates, the pre-clinical and
clinical results for its product candidates, which may not support
further development of product candidates, actions of regulatory
agencies, which may affect the initiation, timing and progress of
clinical trials, obtaining, maintaining and protecting intellectual
property, Alnylam's ability to enforce its patents against infringers
and defend its patent portfolio against challenges from third parties,
obtaining regulatory approval for products, competition from others
using technology similar to Alnylam's and others developing products for
similar uses, Alnylam's ability to obtain additional funding to support
its business activities and establish and maintain strategic business
alliances and new business initiatives, Alnylam's dependence on third
parties for development, manufacture, marketing, sales and distribution
of products, the outcome of litigation, and unexpected expenditures, as
well as those risks more fully discussed in the "Risk Factors" filed
with Alnylam's most recent Quarterly Report on Form 10-Q filed with the
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Contacts:
Executive Director
jmquach@thealpha-1project.com
or
Vice
President, Investor Relations and
or
Spectrum
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