Alnylam and The Alpha-1 Project (TAP) Form Collaboration for Advancement of ALN-AAT, an RNAi Therapeutic in Development for the

  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

– Alnylam Remains On Track to File Investigational New Drug (IND) Application
                                in Mid-2015 –

Business Wire

CAMBRIDGE, Mass. & MIAMI -- June 19, 2014

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, and The Alpha-1 Project (TAP), the venture philanthropy subsidiary of
the Alpha-1 Foundation, announced today that they have entered into a
collaboration agreement for the continued advancement of ALN-AAT, a
subcutaneously administrated RNAi therapeutic in development for the treatment
of alpha-1 antitrypsin (AAT) deficiency-associated liver disease. TAP’s
mission is to work with patients, academia, pharmaceutical and biotech
companies, and public health organizations in the pursuit of cures and
therapies for chronic obstructive pulmonary disease (COPD) and liver disease
caused by AAT deficiency. TAP is partially funding research activities for
ALN-AAT. Detailed financial terms of the research agreement were not
disclosed. Alnylam remains on track to file an investigational new drug (IND)
application for this program 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 Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and
Chief Medical Officer of Alnylam. “Accordingly, we are fully committed to the
continued advancement of our RNAi therapeutic to patients with AAT deficiency
with associated liver disease. This new recognition from TAP, part of the
leading patient advocacy group for people afflicted with AAT deficiency,
brings our efforts closer to patients in need and to their caregivers. We
continue to expect that we will file our IND or IND equivalent for ALN-AAT in
mid-2015.”

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 John Walsh, CEO and
co-founder of the Alpha-1 Foundation.

Pre-clinical data from Alnylam’s ALN-AAT program were first presented at the
Annual Meeting of the American Association for the Study of Liver Diseases
(AASLD, “The Liver Meeting”) in November 2013 and were most recently updated
at Digestive Disease Week (DDW) in May 2014. Amongst other results presented,
these data in rodent studies showed that administration of ALN-AAT was
associated with a potent and dose-dependent knockdown of serum AAT (a
surrogate for AAT knockdown in the liver) with a single-dose ED[50] of 0.5
mg/kg. In multi-dose rodent experiments, subcutaneous administration at 0.5
mg/kg resulted in approximately 90% knockdown of serum AAT. In addition,
initial single-dose NHP results were performed showing dose-dependent
knockdown of serum AAT with an ED[50] of less than 3 mg/kg; these results are
expected to support a multi-dose ED[50] of less than 0.3 mg/kg. ALN-AAT
employs Alnylam’s ESC-GalNAc-conjugate technology, enabling subcutaneous
administration with a wide therapeutic index. Alnylam’s GalNAc-siRNA conjugate
platform has been clinically validated for both activity and tolerability
through the company’s ALN-TTRsc (an RNAi therapeutic targeting transthyretin
(TTR) for the treatment of TTR cardiac amyloidosis; currently in Phase 2) and
ALN-AT3 (an RNAi therapeutic targeting antithrombin for the treatment of
hemophilia and rare bleeding disorders; currently in Phase 1) programs.

“TAP is very pleased to collaborate with Alnylam Pharmaceuticals. Their
cutting-edge work on a therapy for liver disease brings us closer to finding a
cure for Alpha-1 Antitrypsin Deficiency, thus fulfilling our mission,” said
Jean-Marc Quach, Executive Director for The Alpha-1 Project.

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 The Alpha-1 Project

Mission statement: The Alpha-1 Project will work with patients, academia,
pharmaceutical and biotech companies, and public health organizations in the
relentless pursuit of cures and therapies for COPD and liver disease caused by
Alpha-1 Antitrypsin Deficiency. For more information, visit
www.thealpha-1project.com. The Alpha-1 Project is a wholly-owned for-profit
subsidiary of the Alpha-1 Foundation. For more information on the Foundation,
visit www.alpha-1foundation.org.

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 Pharmaceuticals

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
5x15^TM” 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 March 2014, Alnylam acquired Sirna Therapeutics,
a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity
position in Regulus Therapeutics Inc., a company focused on discovery,
development, and commercialization of microRNA therapeutics. Alnylam
scientists and collaborators have published their research on RNAi
therapeutics in over 200 peer-reviewed papers, including many in the world’s
top scientific journals such as Nature, Nature Medicine, Nature Biotechnology,
Cell, the New England Journal of Medicine, and The Lancet. Founded in 2002,
Alnylam maintains headquarters in Cambridge, Massachusetts. For more
information, please visit www.alnylam.com.

About “Alnylam 5x15™” and Genetic Medicines

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for
development and commercialization of novel RNAi therapeutics as genetic
medicines. Alnylam’s genetic medicine programs are RNAi therapeutics directed
toward genetically defined targets for the treatment of diseases with high
unmet medical need. These programs share several key characteristics
including: a genetically defined target and disease expressed in the liver;
the potential to have a major impact in a high unmet need population; the
ability to leverage the existing Alnylam RNAi platform with clinically proven
delivery to the liver; the opportunity to monitor an early biomarker in Phase
1 clinical trials for human proof of concept; and the existence of clinically
relevant endpoints for the filing of a new drug application (NDA) with a
focused patient database and possible accelerated paths for commercialization.
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. The “Alnylam 5x15” programs include: patisiran (ALN-TTR02),
an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) in
development for the treatment of TTR-mediated amyloidosis (ATTR) in patients
with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously
delivered RNAi therapeutic targeting TTR in development 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) in development for the treatment of
hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic
targeting complement component C5 in development for the treatment of
complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting
aminolevulinic acid synthase-1 (ALAS-1) in development for the treatment of
hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an
RNAi therapeutic targeting PCSK9 in development 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 in development 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, a subcutaneously administered RNAi therapeutic targeting
apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and
other programs yet to be disclosed. In 2014, Alnylam and Genzyme, a Sanofi
company, formed a multi-product geographic alliance on Alnylam's genetic
medicine programs. Specifically, Alnylam will lead development and
commercialization of programs in North America and Europe, while Genzyme will
develop and commercialize products in the rest of world. In addition, Alnylam
and Genzyme will co-develop and co-commercialize ALN-TTRsc in North America
and Europe.

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 Securities and Exchange Commission (SEC) and in other filings that
Alnylam makes with the SEC. In addition, any forward-looking statements
represent Alnylam’s views only as of today and should not be relied upon as
representing its views as of any subsequent date. Alnylam explicitly disclaims
any obligation to update any forward-looking statements.

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Contact:

Contacts:
The Alpha-1 Project
Jean-Marc Quach, 1-888-920-0002
Executive Director
jmquach@thealpha-1project.com
or
Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and
Corporate Communications
or
Spectrum
Liz Bryan (Media), 202-955-6222 x2526
 
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