Alnylam Reports Positive Phase II Data for ALN-TTR02, an RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR

  Alnylam Reports Positive Phase II Data for ALN-TTR02, an RNAi Therapeutic
  Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis
  (ATTR)

   – Interim Results in ATTR Patients Show up to 93% Knockdown of TTR with
               Activity toward Both Wild-Type and Mutant TTR –

     – Multiple Doses of ALN-TTR02 Generally Safe and Well Tolerated with
       Once-Every-Four-Week and Once-Every-Three-Week Dosing Regimens –

Business Wire

CAMBRIDGE, Mass. -- June 30, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today the achievement of positive clinical results from its
Phase II trial of ALN-TTR02, an RNAi therapeutic targeting the transthyretin
(TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The data were
presented today at the 2013 Biennial Meeting of the Peripheral Nerve Society,
held June 29 – July 3 in St. Malo, France. Interim results show that multiple
doses of ALN-TTR02 led to robust and statistically significant (p<0.001)
knockdown of serum TTR protein levels of up to 93%. Knockdown of TTR, the
disease-causing protein in ATTR, was found to be rapid, dose dependent, and
durable, and similar activity was observed toward both wild-type and mutant
protein. In addition, ALN-TTR02 was found to be generally safe and well
tolerated in this study.

“These new ALN-TTR02 results are a major milestone in our TTR program, where –
for the first time in ATTR patients – we have demonstrated robust knockdown of
up to 93% of circulating wild-type and mutant TTR in a multi-dose study. The
clinical relevance of lowering circulating TTR has been demonstrated in ATTR
patients who have benefited from the elimination of mutant TTR through liver
transplantation. In addition, we are very encouraged with the continued safety
profile of ALN-TTR02 which has now been extended with this experience in ATTR
patients and with multi-dose regimens,” said Jared Gollob, M.D., Vice
President, Clinical Research at Alnylam. “This Phase II trial continues in
patients receiving a once-every-three-week dosing regimen and we plan to share
the complete data set at the International Symposium on Familial Amyloidotic
Polyneuropathy in Rio de Janeiro this November.”

“I am very encouraged by these new clinical activity and safety data with
ALN-TTR02, an RNAi therapeutic for the treatment of ATTR. Specifically, I am
impressed with the potent, rapid, and durable knockdown of both mutant and
wild-type TTR, which is important since TTR protein reduction in patients with
ATTR has the potential to delay or even reverse disease progression with
associated clinical benefits,” said Professor David Adams, M.D., Ph.D.,
Neurology Department Head at CHU de Bicetre (APHP), Le Kremlin-Bicetre Cedex,
France. “I very much look forward to the continued advancement of RNAi
therapeutics in clinical trials for the treatment of ATTR, as there are
currently few options for patients suffering from this debilitating,
progressive disease.”

The Phase II trial with ALN-TTR02 is an open-label, multi-center, multi-dose,
dose-escalation trial to evaluate the safety and tolerability of two doses of
ALN-TTR02 and to demonstrate clinical activity based on serial measurement of
circulating serum levels of wild-type and mutant TTR. The study was designed
to treat up to 30 ATTR polyneuropathy patients with ALN-TTR02 administered at
doses of 0.01 to 0.30 mg/kg, using either a once-every-four-week or
once-every-three-week dosing regimen. To date, 25 patients in eight cohorts
have been dosed in the study, and all patients for the final cohort have been
scheduled for dosing. The international study is being conducted at 10 sites
in Portugal, France, Sweden, Germany, Spain, Brazil, and the U.S.

Data from the first 19 patients enrolled and analyzed in this study showed
that multiple doses of ALN-TTR02 resulted in rapid, dose-dependent, and
durable knockdown of serum TTR levels. As compared with the lowest dose group
of 0.01 mg/kg, there was a statistically significant knockdown of serum TTR at
doses of 0.15 mg/kg (p<0.01) and 0.30 mg/kg (p<0.001). At 0.30 mg/kg
administered once every four weeks, mean TTR knockdown at nadir of 82.6% and
84.8% was observed following the first and second doses, respectively, and
maximum TTR knockdown was up to 90.8%. At 0.30 mg/kg administered once every
three weeks, mean TTR knockdown at nadir of 83.1% and 87.4% was observed
following the first and second doses, respectively, and maximum TTR knockdown
was up to 92.8%.

Summary of ALN-TTR02 Clinical Activity Results

                    Dose 1                    Dose 2
Dose                       Max           TTR KD          Max          TTR KD @
Group       N       TTR       @ Nadir     TTR      Nadir
(mg/kg)                    KD            (Mean %         KD           (Mean %
                           (%)           ± SD)           (%)          ± SD)
0.01 q4w    4^+     37.8      20.1 ±      34.4     32.9 ±
                                         13.2                         2.3
0.05 q4w    3       58.0      48.4 ±      58.5     46.9 ±
                                         16.2                         15.0
0.15 q4w    3       81.7      74.5 ±      86.0     77.0 ±
                                         6.8^***                      7.8^**
0.30 q4w    6^^     87.5      82.6 ±      90.8     84.8 ±
                                         5.9^***                      10.5^***
0.30 q3w    3       83.8      83.1 ±      92.8     87.4 ±
                                         1.1^***                      5.9^***

**p < 0.01 vs. 0.01 mg/kg group; p values from ANCOVA models including
baseline TTR as covariate and dose group as factor

***p < 0.001 vs. 0.01 mg/kg group; p values as above

^+ Includes first dose data from additional patient prior to protocol
amendment

^^ Excludes post-day 28 data from patient that experienced drug extravasation
during second infusion

A number of additional analyses were performed in this first-ever study of
ALN-TTR02 in ATTR patients. First, a proprietary mass spectrometry method was
used to measure serum levels of wild-type and mutant V30M proteins. These
results demonstrated an essentially 1:1 knockdown of mutant and wild-type TTR
(r^2=0.95, p<0.001) with superimposable pharmacodynamic effects toward both
protein species. Furthermore, a similar degree of TTR knockdown was observed
in patients on concurrent TTR stabilizer therapy (specifically, tafamidis or
diflunisal) compared to those who received ALN-TTR02 alone. These results
demonstrate the absence of any interference by TTR stabilizer drugs with the
pharmacologic activity of ALN-TTR02. Finally, and as expected, serum TTR
reductions were highly correlated with parallel changes in retinol binding
protein (RBP) (r^2=0.85, p<0.001) and vitamin A levels (r^2=0.84, p<0.001).

Multiple doses of ALN-TTR02 were found to be generally safe and well
tolerated. There were no significant adverse events or discontinuations
associated with drug up through 0.30 mg/kg. There were no abnormalities in
liver function tests, renal function, or hematologic parameters. Adverse
events included a mild infusion-related reaction that occurred in one patient
who was able to complete dosing with slowing of the infusion rate. An episode
of self-limiting cellulitis of the arm, a serious adverse event, occurred as a
result of drug extravasation at the infusion site in a patient with poor
intravenous access. In the ongoing dosing in patients at 0.30 mg/kg once every
three weeks using a reduced and simplified pre-medication regimen, there have
been no reports to date of any infusion-related reactions. The new
pre-medication regimen includes a reduced steroid dose administered prior to
ALN-TTR02 infusion.

Alnylam intends to present the final data from this ALN-TTR02 Phase II study
at the IXth International Symposium on Familial Amyloidotic Polyneuropathy
(ISFAP) to be held in Rio de Janeiro, Brazil, November 10 – 13, 2013. In
addition, the company remains on track to initiate in mid-2013 an open-label
extension (OLE) study of ALN-TTR02 for patients treated in the Phase II study.
The ALN-TTR02 OLE study will include a number of clinical endpoint
measurements, such as neuropathy impairment score, or “NIS,” with initial data
expected to be presented in 2014. In addition, the company intends to start a
Phase III pivotal trial for ALN-TTR02 in familial amyloidotic polyneuropathy
(FAP) patients by the end of 2013.

“We are in the midst of a very exciting time at Alnylam, with a steady flow of
pre-clinical and clinical data that reflect the strong potential of RNAi
therapeutics as innovative medicines. These data points support our ongoing
‘Alnylam 5x15’ product strategy, where we are advancing RNAi therapeutics
toward genetically defined targets for diseases with limited treatment options
for patients and their caregivers,” said Akshay Vaishnaw, M.D., Ph.D.,
Executive Vice President and Chief Medical Officer of Alnylam. “These
ALN-TTR02 data presented today demonstrate robust and durable knockdown of
serum TTR, as well as safety and tolerability in a multi-dose study in ATTR
patients. By all accounts, these data are consistent with our earlier
experience from pre-clinical and Phase I clinical studies showing excellent
translation of RNAi therapeutics, and support our belief that ALN-TTR02 will
be best-in-class for the treatment of ATTR patients with polyneuropathy.
Assuming continued success in the Phase II study, these results position us
well for continued execution on our program, which includes initiation in the
next few months of our open label extension study that will include clinical
endpoint measurements and the start of our Phase III trial by year’s end.”

Alnylam has an exclusive alliance with Genzyme, a Sanofi company, to develop
and commercialize RNAi therapeutics, including ALN-TTR02 and ALN-TTRsc, for
the treatment of ATTR in Japan and the broader Asian-Pacific region. Alnylam
plans to develop and commercialize the ALN-TTR program in North and South
America, Europe, and rest of the world.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively
debilitating, and fatal disease caused by mutations in the TTR gene. TTR
protein is produced primarily in the liver and is normally a carrier for
retinol binding protein. Mutations in TTR cause abnormal amyloid proteins to
accumulate and damage body organs and tissue, such as the peripheral nerves
and heart, resulting in intractable peripheral sensory neuropathy, autonomic
neuropathy, and/or cardiomyopathy. ATTR represents a major unmet medical need
with significant morbidity and mortality; familial amyloidotic polyneuropathy
(FAP) affects approximately 10,000 people worldwide and familial amyloidotic
cardiomyopathy (FAC) affects at least 40,000 people worldwide. FAP patients
have a life expectancy of five to 15 years from symptom onset, and the only
treatment options for early stage disease are liver transplantation and
tafamidis (approved in Europe). The mean survival for FAC patients is
approximately 2.5 years, and there are no approved therapies. There is a
significant need for novel therapeutics to treat patients who have inherited
mutations in the TTR gene.

About LNP Technology

Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi
therapeutic products using LNP technology.

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
toward genetically defined targets for the treatment of serious,
life-threatening diseases with limited treatment options for patients and
their caregivers. These include: 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 familial amyloidotic cardiomyopathy (FAC);
ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of
hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic
targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of acute
intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for
the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting
TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders;
ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the
treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi therapeutic
targeting the C5 component of the complement pathway for the treatment of
complement-mediated diseases, amongst other programs. 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 and
ALN-VSP for the treatment of liver cancers. 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, Genzyme,
and The Medicines Company. In addition, Alnylam holds an equity position in
Regulus Therapeutics Inc., a company focused on discovery, development, and
commercialization of microRNA therapeutics. 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 toward
genetically defined targets for the treatment of 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-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 familial amyloidotic cardiomyopathy (FAC);
ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of
hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic
targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of acute
intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for
the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting
TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders;
ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the
treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi therapeutic
targeting the C5 component of the complement pathway for the treatment of
complement-mediated diseases, amongst other programs. Alnylam intends to focus
on developing and commercializing certain programs from this product strategy
itself in North and South America, Europe, and other parts of the world; these
include ALN-TTR, ALN-AT3, and ALN-AS1; the company will seek global
development and commercial alliances for other programs.

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam’s future expectations,
plans and prospects, including without limitation, Alnylam’s expectations
regarding its “Alnylam 5x15” product strategy, Alnylam’s views with respect to
the potential for RNAi therapeutics, including ALN-TTR02, its expectations
regarding the reporting of data from its ALN-TTR02 clinical trials, its
expectations with respect to the timing and success of its clinical trials for
ALN-TTR02, and its expectations regarding the potential market opportunity for
ALN-TTR02, 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 and delivery approaches, successfully demonstrate the efficacy
and safety of its drug candidates, including ALN-TTR02, 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 current report on Form 10-Q filed with the
Securities and Exchange Commission (SEC) on May 7, 2013 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.

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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