Alnylam and Collaborators Publish Clinical Trial Results with RNAi Therapeutics Targeting Transthyretin (TTR) for the Treatment

  Alnylam and Collaborators Publish Clinical Trial Results with RNAi
  Therapeutics Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated
  Amyloidosis (ATTR) in the New England Journal of Medicine

 – Represents the Journal’s First Ever Publication of Clinical Trial Results
                          with an RNAi Therapeutic –

 – Results from Phase I Trials of ALN-TTR01 and ALN-TTR02 Demonstrate Rapid,
 Dose-Dependent, Durable, and Specific Knockdown of TTR, the Disease-Causing
                              Protein in ATTR –

Business Wire

CAMBRIDGE, Mass. -- August 28, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today the publication of complete study results from Phase
I trials with ALN-TTR01 and ALN-TTR02 in the New England Journal of Medicine.
The paper, titled “Safety and Efficacy of RNAi Therapy for Transthyretin
Amyloidosis” (Coelho et al., N Engl J Med 2013;369:819-29), shows that RNAi
therapeutics targeting transthyretin (TTR) achieved rapid, dose-dependent,
durable, and specific knockdown of TTR, the disease-causing protein in
TTR-mediated amyloidosis (ATTR). These results document the most robust proof
of concept for RNAi therapy in man to date, including knockdown of serum TTR
protein levels of up to 94% after just a single dose of drug.

“Our ATTR program is the lead effort in our ‘Alnylam 5x15’ product development
and commercialization strategy, which is focused on advancing innovative RNAi
therapeutics toward genetically defined targets for the treatment of diseases
with high unmet medical need. Our overall clinical trial experience with RNAi
therapeutics for the treatment of ATTR now includes a Phase I trial with
ALN-TTR01, Phase I and II trials with ALN-TTR02, and a Phase I trial with
ALN-TTRsc, a subcutaneously administered RNAi therapeutic utilizing our
proprietary GalNAc conjugate delivery platform,” said Akshay Vaishnaw, M.D.,
Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “The
Phase I studies of ALN-TTR01 and ALN-TTR02 demonstrate key human proof of
concept for RNAi therapeutics targeting TTR but also for liver-expressed
target genes in general, and we are thrilled to be publishing these landmark
data in the New England Journal of Medicine. Notably, this is the first time
that clinical results with an RNAi therapeutic have been published in the
Journal, and we are proud to be associated with this milestone as we lead the
clinical translation of RNAi therapeutics as a whole new class of innovative
medicines.”

“This new paper describes our clinical trial experience with ALN-TTR01 and
ALN-TTR02, which utilize first- and second-generation lipid nanoparticle
formulations, respectively. Relative to ALN-TTR01, the results for ALN-TTR02
showed exceptional improvement in potency, without any apparent loss in
tolerability, thus documenting the important advances made by Alnylam
scientists and collaborators on systemic delivery of RNAi therapeutics.
Indeed, with ALN-TTR02 we achieved very robust effects, including up to 94%
reduction of serum TTR and a nearly 80% level of suppression sustained at one
month with just a single dose. Further, ALN-TTR02 was also found to be
generally safe and well tolerated,” said Jared Gollob, M.D., Vice President,
Clinical Research at Alnylam. “Knockdown of circulating TTR is expected to
result in improved clinical outcomes for patients with ATTR based on data from
patients receiving liver transplants. Further, evidence from other systemic
amyloidotic diseases shows that as little as a 50% reduction of the
disease-causing protein can result in disease improvement or stabilization.
Accordingly, we believe the findings published today in the New England
Journal of Medicine suggest that the robust, sustained knockdown of TTR levels
observed in our clinical trials with ALN-TTR02 may ameliorate the course of
disease in patients with ATTR.”

ALN-TTR01 and ALN-TTR02 are systemically delivered RNAi therapeutics using
first- and second-generation lipid nanoparticle (LNP) formulations,
respectively, that encapsulate an identical siRNA targeting both wild-type and
mutant TTR mRNA. The ALN-TTR01 Phase I trial enrolled participants from July
2010 through September 2011, and the ALN-TTR02 Phase I trial enrolled
participants from March through May 2012. Both trials were designed as
multi-center, randomized, single-blind, placebo-controlled, dose-ranging
studies in patients with ATTR (n=32) – in the case of ALN-TTR01, or in healthy
adult volunteers (n=17) – in the case of ALN-TTR02. The primary objective of
each study was to evaluate the safety and tolerability of a single dose of
ALN-TTR01 or ALN-TTR02. In addition, preliminary clinical activity of each
drug was evaluated based on measurements of serum TTR protein levels.

Results of the ALN-TTR01 Phase I study demonstrated a dose-dependent reduction
in serum TTR levels with a statistically significant mean reduction of 38% at
approximately day 7 to 10 in the 1.0 mg/kg group (p<0.05). In addition,
analysis of serum samples by a liquid chromatography-mass spectrometry method
revealed that both mutant and wild-type TTR were similarly affected. ALN-TTR01
was found to be generally safe and well tolerated in ATTR patients.
Mild-to-moderate acute infusion reactions were observed in 20.8% of patients
receiving ALN-TTR01 as a 15 minute infusion and were readily managed by
slowing of the infusion rate where necessary. There were no significant
increases in liver function test parameters.

Results of the ALN-TTR02 Phase I study demonstrated substantial knockdown of
serum TTR in all participants receiving doses of 0.15 to 0.50 mg/kg. Knockdown
was rapid, potent, and durable, with highly significant changes, as compared
to placebo (p<0.001), and minimal variability among participants in both the
kinetics of the response and maximal levels of TTR suppression. At doses as
low as 0.15 mg/kg, substantial serum TTR suppression was achieved, with a mean
81.9% knockdown at nadir. At a dose of 0.30 mg/kg, an 86.8% mean knockdown was
achieved at nadir, with a mean 66.7% reduction still observed 28 days
post-dose. In the one subject treated at 0.50 mg/kg, knockdown of 93.8% was
observed at nadir, with 76.8% reduction maintained at day 28. In addition,
serum TTR reductions were highly correlated with parallel changes in retinol
binding protein (RBP) (r^2=0.83) and vitamin A levels (r^2=0.86). Furthermore,
a single 0.4 mg/kg dose of an siRNA targeting PCSK9 in the identical LNP
formulation showed no effect on serum TTR levels in a separate Phase I trial
in healthy volunteers, showing that the effect of ALN-TTR02 on TTR suppression
was specific to the TTR siRNA. To confirm the RNAi mechanism of action for TTR
knockdown, a 5’ RACE (rapid amplification of cDNA ends) assay was performed on
blood samples – processed to isolate liver-derived exosomes – obtained from
participants in the 0.3 mg/kg group. The predicted TTR mRNA cleavage product
was absent in the pre-dose samples and present in each of the post-dose
samples, consistent with the RNAi mechanism. ALN-TTR02 administered as a
60-minute infusion was found to be generally safe and well tolerated, with no
serious adverse events or discontinuations in the study related to ALN-TTR02
and no significant adverse events associated with drug up through 0.30 mg/kg.
A moderate acute infusion reaction was observed in one subject receiving
ALN-TTR02 at 0.50 mg/kg (overall incidence of 7.7%) who was able to complete
dosing with slowing of the infusion rate. There were no changes in liver
function tests or other laboratory parameters including C-reactive protein and
cytokines.

In addition to the clinical results described above, the new paper describes a
number of important pre-clinical findings in non-human primates. First, the
interrelationship of TTR knockdown in non-human primates and in humans was
evaluated, and revealed a closely correlated, essentially superimposable
pharmacodynamic effect in the two species at the same mg/kg dose. These
results demonstrate that the non-human primate is a predictive species for
RNAi therapeutic clinical activity. Also, the results of extended dosing in
the non-human primate were described, and showed a sustained pharmacodynamic
effect – with no evidence of tachyphylaxis – toward TTR knockdown with
increasing nadir effects upon repeat dose administration.

“RNAi therapeutics represent a novel and exciting approach for ATTR patients
and have great potential to make a meaningful impact in the treatment of this
devastating disease. The ability of RNAi therapeutics to suppress production
of hepatic TTR and to reduce circulating levels of both mutant and non-mutant
TTR has the potential to delay or even reverse disease progression with
associated clinical benefits in patients with ATTR,” said Teresa Coelho, M.D.,
Director, Unidade Clinica de Paramiloidose, and lead author on the paper. “I
am very encouraged with these published data and other more recent data with
ALN-TTR02. I 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 progressive and debilitating genetic
disease.”

Alnylam is currently advancing ALN-TTR02 in a Phase II study which is designed
as 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. Interim results, presented at the 2013 Biennial Meeting of the
Peripheral Nerve Society, held June 29 – July 3, 2013 in St. Malo, France,
showed 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 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. The Phase II study has nearly completed enrollment, and Alnylam intends
to present the final data from this 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 OLE study will include a number of
clinical endpoint measures including Neuropathy Impairment Score, or “NIS,”
and initial data are expected to be presented in 2014. Furthermore, the
company intends to start a Phase III pivotal trial for ALN-TTR02 in FAP
patients by the end of 2013.

Alnylam is also advancing ALN-TTRsc, a subcutaneously administered RNAi
therapeutic targeting TTR for the treatment of ATTR. The company recently
announced top-line results from a Phase I study in healthy adult volunteers,
in which ALN-TTRsc achieved robust and statistically significant (p<0.01)
knockdown of serum TTR protein levels of greater than 80% in healthy volunteer
subjects, in line with results previously reported in non-human primates. In
addition, ALN-TTRsc was found to be generally safe and well tolerated. These
top-line human study results are the first to be reported for Alnylam’s
proprietary GalNAc-siRNA conjugate delivery platform, enabling subcutaneous
dosing of RNAi therapeutics with a wide therapeutic index. Full results from
the Phase I study will be presented at the Annual Scientific Meeting of the
Heart Failure Society of America (HFSA), being held September 22 – 25, 2013 in
Orlando, Fla. In addition, Alnylam expects to initiate a Phase II study of
ALN-TTRsc in ATTR patients with familial amyloidotic cardiomyopathy (FAC) in
late 2013 and, if successful, a Phase III study in FAC patients in 2014.

In 2012, Alnylam entered into 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 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. Research findings
demonstrate potent and durable target gene silencing, as well as a wide
therapeutic index, with subcutaneously administered GalNAc-siRNAs from
multiple “Alnylam 5x15” programs.

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 porphyria
including 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 complement component C5 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, Cell, and the New England Journal of Medicine. 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 porphyria
including 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 complement component C5 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, ALN-AS1, and ALN-CC5.

Alnylam Forward-Looking Statements

Various statements in this press 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-TTR01,
ALN-TTR02, and ALN-TTRsc, its views regarding the predictive nature of
non-human primate data with RNAi therapeutics towards human data, its
expectations regarding the reporting of data from its ALN-TTR02 and ALN-TTRsc
clinical trials, its expectations with respect to the timing and success of
its clinical trials for ALN-TTR02 and ALN-TTRsc, and its expectations
regarding the potential market opportunity for ALN-TTR02 and ALN-TTRsc,
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 and ALN-TTRsc, 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 Quarterly Report on Form 10-Q filed with the
Securities and Exchange Commission (SEC) on August 9, 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