Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the Treatment of Hemoglobinopathies at 54th American Society of

  Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the
  Treatment of Hemoglobinopathies at 54th American Society of Hematology (ASH)
  Annual Meeting

    – ALN-TMP, an RNAi Therapeutic Targeting Tmprss6 for the Treatment of
Hemoglobinopathies, Shows Disease Modifying Effects in Model of β-Thalassemia
               including Correction of Globin Gene Expression –

              – Results Also Published in the Journal “Blood” –

Business Wire

CAMBRIDGE, Mass. -- December 08, 2012

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has presented new pre-clinical data from its
RNAi therapeutic program for the treatment of hemoglobinopathies at the 54^th
American Society of Hematology Annual Meeting being held December 8-11, 2012
in Atlanta. Alnylam scientists presented data showing that ALN-TMP, an RNAi
therapeutic targeting Tmprss6, leads to disease modifying effects, including a
correction in globin gene expression, in a model of β-thalassemia. These
studies were conducted in collaboration with Boston Children’s Hospital.
Alnylam’s program in hemoglobinopathies comprises part of its ‘Alnylam 5x15™’
product strategy, by which the company aims to advance five programs in
clinical development, including programs in advanced stages, by the end of
2015.

“Our ‘Alnylam 5x15’ strategy is aimed at bringing innovative medicines to
patients, with a focus on RNAi therapeutics toward genetically defined targets
for diseases with very high unmet medical need. ALN-TMP exemplifies this
strategy where we are advancing RNAi therapeutics for the treatment of
hemoglobinopathies,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice
President and Chief Medical Officer of Alnylam. “We are very excited by these
new data with ALN-TMP where we have demonstrated disease modifying effects in
models of β-thalassemia, including amelioration of anemia, iron overload,
extra-medullary hematopoiesis, and ineffective erythropoiesis, in addition to
correction of globin gene expression.”

“Mouse genetic studies have shown that knockdown of Tmprss6 and up-regulation
of the hepcidin pathway can result in disease modifying effects in models of
β-thalassemia, a disease of enormous worldwide burden with limited treatment
options for certain groups of patients. Our studies with ALN-TMP, an RNAi
therapeutic targeting Tmprss6, recapitulate these genetic findings with an
innovative pharmacologic strategy. This work is an example of how rare disease
research that brings in RNA silencing technologies to ‘target the
untargetable’ could rapidly lead to therapies for more common disorders,” said
Mark Fleming, M.D., D.Phil., Pathologist-in-Chief at Boston Children’s
Hospital and S. Burt Wolbach Professor of Pathology at Harvard Medical School,
who collaborated on the work. “Specifically, we have demonstrated that ALN-TMP
administration results in disease modifying effects in a model of
β-thalassemia. Indeed, our studies show that ALN-TMP administration results in
reduced iron overload, decreased extra-medullary hematopoiesis, increased
hemoglobin levels, and a reduction in ineffective erythropoiesis. Further, we
have found that these effects are accompanied by a decrease in
membrane-associated hemoglobin, one of the primary causes of the decreased red
blood cell survival in β-thalassemia. Clearly, these results could be of
significance for the treatment of patients with β-thalassemia and possibly
other hemoglobinopathies.”

In a poster titled “RNAi-Mediated Inhibition of Tmprss6 Ameliorates Anemia and
Secondary Iron Overload in a Mouse Model of β-Thalassemia Intermedia and
Decreases Iron Overload in Hfe^-/- Mice,” (#1018) Alnylam scientists presented
data showing that systemic administration of ALN-TMP, an RNAi therapeutic
targeting Tmprss6, resulted in disease modifying effects in a model of
β-thalassemia. In addition, ALN-TMP demonstrated pre-clinical efficacy in a
model of hereditary hemochromatosis. In the pre-clinical studies, ALN-TMP
administration resulted in a greater than 80% silencing of Tmprss6 mRNA levels
and a greater than two-fold elevation of Hamp1, the gene that encodes for
hepcidin, a liver hormone that negatively regulates iron transport and
absorption. ALN-TMP administration resulted in an approximately 30% decrease
in serum iron and non-heme liver iron, as well as a similar reduction in
transferrin saturation. In a mouse model of β-thalassemia, ALN-TMP reduced the
severity of anemia as evidenced by an approximately 1 g/dL increase in total
hemoglobin. Moreover, treatment with ALN-TMP was found to significantly
attenuate extra-medullary hematopoiesis, including a two-to-three fold
reduction in spleen size. Treatment with ALN-TMP also decreased ineffective
erythropoiesis, with a three-to-four fold decrease in reticulocyte count, an
approximate 30% increase in red blood cell count (RBC), and a normalization of
RBC morphology and lifespan. Finally, ALN-TMP administration was found to
restore the ratio of alpha globin to beta globin, thereby correcting the
genetic defect associated with β-thalassemia with possible implications for
the treatment of other hemoglobinopathies such as sickle cell anemia.

In addition, Alnylam announced today that its research studies on ALN-TMP have
been published in the journal Blood (doi: 10.1182/blood-2012-09-453977).

About ALN-TMP and Hemoglobinopathies

ALN-TMP comprises a systemically delivered RNAi therapeutic targeting
transmembrane protease, serine 6 (Tmprss6) for the treatment of
hemoglobinopathies, including β-thalassemia and sickle cell anemia.
Hemoglobinopathies are associated with chronic anemia, extra-medullary
hematopoiesis, and iron overload. Tmprss6, a genetically validated target
expressed on hepatocytes, functions by cleaving hemojuvelin, resulting in
reduced hepcidin levels and increased iron mobilization. Pre-clinical animal
model studies with ALN-TMP have demonstrated corrective effects on iron
overload in addition to broader disease modifying effects including
improvements in hemoglobin levels, spleen histopathology, and globin gene
expression.

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 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 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
5x15^TM” 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, Medtronic, Novartis, Biogen Idec, Roche, Takeda,
Kyowa Hakko Kirin, Cubist, Ascletis, Monsanto and Genzyme. In addition,
Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on
discovery, development, and commercialization of microRNA therapeutics;
Regulus has formed partnerships with GlaxoSmithKline, Sanofi, AstraZeneca and
Biogen Idec. Alnylam has also formed Alnylam Biotherapeutics, a division of
the company focused on the development of RNAi technologies for applications
in biologics manufacturing, including recombinant proteins and monoclonal
antibodies. Alnylam’s VaxiRNA™ platform applies RNAi technology to improve the
manufacturing processes for vaccines; GlaxoSmithKline is a collaborator in
this effort. Alnylam scientists and collaborators have published their
research on RNAi therapeutics in over 100 peer-reviewed papers, including many
in the world’s top scientific journals such as Nature, Nature Medicine, Nature
Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in
Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About “Alnylam 5x15™”

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for
development and commercialization of novel RNAi therapeutics to address
genetically defined diseases with high unmet medical need. Products arising
from this initiative share several key characteristics including: a
genetically defined target and disease; the potential to have a major impact
in a high unmet need population; the ability to leverage the existing Alnylam
RNAi delivery platform; the opportunity to monitor an early biomarker in Phase
I 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.
By the end of 2015, the company expects to have five such RNAi therapeutic
programs in clinical development, including programs in advanced stages, on
its own or with a partner. The “Alnylam 5x15” programs include 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. Alnylam intends to focus on
developing and commercializing certain programs from this product strategy
itself in the United States and potentially certain other countries; the
company will seek development and commercial alliances for other core programs
both in the United States and in other global territories.

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
ALN-TMP, and 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
discover and develop novel drug candidates, the pre-clinical and clinical
results for these product candidates, including ALN-TMP, 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 Securities and Exchange
Commission. 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 does not assume any obligation to update
any forward-looking statements.

Contact:

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and
Corporate Communications
or
Spectrum
Amanda Sellers (Media), 202-955-6222 x2597
 
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