Alnylam and Collaborators Publish Results from Phase I Clinical Trial and Extension Study with ALN-VSP, an RNAi Therapeutic for

  Alnylam and Collaborators Publish Results from Phase I Clinical Trial and
  Extension Study with ALN-VSP, an RNAi Therapeutic for the Treatment of Liver

  - Results Published in Cancer Discovery Document Most Comprehensive Human
 Experience To Date for RNAi Therapeutics Delivered with Lipid Nanoparticles
                                   (LNPs) -

Business Wire

CAMBRIDGE, Mass. -- January 30, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, and collaborators announced today the publication of complete study
results from a Phase I trial with ALN-VSP, a systemically delivered RNAi
therapeutic for the treatment of advanced solid tumors with liver involvement.
The paper, titled “First-in-Man Trial of an RNA Interference Therapeutic
Targeting VEGF and KSP in Cancer Patients with Liver Involvement” appears as
an OnlineFirst publication in the journal Cancer Discovery (Tabernero et al.,
Cancer Discovery CD-12-0429; Published OnlineFirst January 2013). The study
results document anti-tumor activity for ALN-VSP in a heavily pre-treated and
advanced patient population, including a complete response in an endometrial
cancer patient who had multiple hepatic metastases. In addition, this study
provided proof of RNAi mechanism in man based on molecular analysis of biopsy
samples from patients. Finally, in this study – the most comprehensive study
of a systemically administered RNAi therapeutic to date – chronic dosing of
ALN-VSP for up to 26 months was found to be generally safe and well tolerated.

“Our ALN-VSP Phase I clinical trial defines the most comprehensive human
experience for RNAi therapeutics delivered with lipid nanoparticle
formulations. Results from this study highlight safety and tolerability of
multiple doses of ALN-VSP, proof of RNAi activity in man, and evidence for
anti-tumor activity in a very advanced, heavily pre-treated cancer patient
population,” said Jared Gollob, M.D., Vice President, Clinical Research at
Alnylam. “We are encouraged by the anti-tumor activity observed in this study
in multiple patients who achieved stable disease or better; this includes a
patient with endometrial cancer metastatic to the liver who achieved a
complete response. Results from the extension study also give us increased
confidence in long-term chronic dosing for RNAi therapeutics delivered with
lipid nanoparticle formulations, as patients received an average of over 11
months of treatment overall, including one patient who received treatment for
over two full years.”

ALN-VSP is a systemically delivered RNAi therapeutic using first-generation
lipid nanoparticle (LNP) or “SNALP” delivery technology that comprises two
siRNAs targeting two genes critical for the growth and development of cancer
cells: vascular endothelial growth factor (VEGF) and kinesin spindle protein
(KSP). The ALN-VSP Phase I trial was designed as a multi-center, open-label,
dose-escalation study in patients with advanced solid tumors with liver
involvement who failed to respond to or had progressed after standard
treatment. A total of 41 patients were enrolled. The primary objective was to
evaluate the safety, tolerability, and pharmacokinetics of intravenously
administered ALN-VSP given every two weeks. Other secondary and exploratory
objectives included: assessment of tumor response using Response Evaluation
Criteria for Solid Tumors (RECIST); quantitation of change in tumor blood flow
and vascular permeability as measured by dynamic contrast-enhanced magnetic
resonance imaging (DCE-MRI); and, analysis of pharmacodynamic effects of
ALN-VSP on tumors as measured in patients electing to proceed with voluntary
pre- and post-treatment biopsies.

Results of the Phase I study in 41 patients were previously presented at the
American Society of Clinical Oncology (ASCO) Annual Meeting in 2011 and
demonstrated proof of RNAi mechanism based on liver biopsy samples and disease
control (stable disease or better after first two months) in 13/31 (42%)
patients treated at doses greater than or equal to 0.4 mg/kg. ALN-VSP was
generally safe and well tolerated up to a dose of 1.0 mg/kg. The most common
adverse events were grade 1-2 fatigue (24% of patients), nausea (17% of
patients) and fever (17% of patients), with no clear dose relationship. There
were also no dose-dependent changes in liver function tests. Grade 2
infusion-related reactions were observed in 15% of patients, or 3% of total
doses administered; these reactions responded to slowing of the infusion of
drug, and no patients discontinued therapy because of an infusion reaction.
Dose-limiting toxicities included: liver failure and death in one patient with
extensive hepatic metastases involving greater than 70% of liver mass and
prior splenectomy/partial hepatectomy at 0.7 mg/kg; transient grade 3
thrombocytopenia in two patients at 1.25 mg/kg; and grade 3 hypokalemia in one
patient at 1.5 mg/kg.

The ALN-VSP extension study was designed to enable continued dosing with
ALN-VSP in patients who had achieved stable disease or better after completing
four months of treatment on the Phase I trial. Patients enrolled onto the
extension study were permitted to receive bi-weekly ALN-VSP at the same dose
level that they had been safely treated with in the Phase I study until
disease progression or unacceptable toxicity; a total of seven patients were
enrolled. The primary objective was to collect long-term safety data. The
secondary objective was to assess tumor response.

Results from the extension study were previously presented at the American
Society of Clinical Oncology (ASCO) Annual Meeting in 2012 and demonstrated
that chronic dosing with ALN-VSP up to 1.0 mg/kg was generally safe and well
tolerated in this setting. On average, patients received bi-weekly treatments
for 11.3 months. An endometrial cancer patient achieved a complete response
(CR) after 20 months of treatment at 0.7 mg/kg and remained in remission upon
completion of 26 months of therapy. A patient with pancreatic neuroendocrine
tumor (PNET) treated at 1.0 mg/kg remained on study with stable disease (SD)
for 18 months, and two patients with renal cell carcinoma (RCC) treated at 1.0
mg/kg remained on study with SD for approximately 8-12 months. No new
toxicities were reported among the patients enrolled onto the extension study.
A PNET patient and an RCC patient who achieved SD at 1.0 mg/kg came off the
study after 5.5 and 8.5 months, respectively, for adverse events that included
grade 3 elevated alkaline phosphatase or grade 2 fatigue deemed possibly
related to study drug. A decrease in spleen volume, likely an on-target
anti-KSP effect and not associated with any adverse events, occurred to a
greater degree on the extension study than in the Phase I trial and was most
pronounced in patients receiving 12 or more doses.

“Both primary liver cancer and metastatic disease of the liver are associated
with poor prognosis for patients, and new therapies are clearly needed,” said
Josep Tabernero, M.D., Chairman of the Medical Oncology Department and Phase I
Program at Vall d’Hebron University Hospital in Barcelona, Spain. “This Phase
I trial and extension study with ALN-VSP represents, to our knowledge, the
most comprehensive clinical trial of a systemically delivered RNAi therapeutic
and also the most extensive experience with RNAi therapeutics in cancer. The
safety data and anti-tumor activity with ALN-VSP, including a complete
response in a patient with multiple liver metastases who had failed multiple
prior therapies, are very encouraging and I look forward to the further
development of this promising agent.”

In 2012, Alnylam and Ascletis Pharmaceuticals (Hangzhou) Co., Ltd., a
privately held U.S.-China joint venture pharmaceutical company, formed a
strategic collaboration for the development of ALN-VSP in China. Alnylam will
retain all rights in the rest of the world, and is eligible to receive
milestones and royalties from Ascletis based on product sales.

About Liver Cancers

Cancer affecting the liver, known as either primary or secondary liver cancer,
is associated with one of the poorest survival rates in oncology and
represents a major unmet medical need affecting a large number of patients
worldwide. Primary liver cancer, or hepatocellular carcinoma (HCC), is one of
the most common cancers worldwide, with more than 630,000 people diagnosed
each year including approximately 350,000 in China. Secondary liver cancer,
also known as metastatic liver cancer, is cancer that spreads to the liver
from another part of the body due to other common cancers like colon, lung, or
breast cancer. Worldwide, more than 500,000 people are diagnosed with
secondary liver cancer each year.

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 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 and rare bleeding disorders (RBD), ALN-AS1 for the
treatment of acute intermittent porphyria, ALN-PCS for the treatment of
hypercholesterolemia, 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 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, and Genzyme. In addition, Alnylam holds a significant
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

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
the potential for ALN-VSP, and Alnylam’s expectations regarding 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 successfully demonstrate
the efficacy and safety of its drug candidates and the pre-clinical and
clinical results for these product candidates, including ALN-VSP, which may
not support further development of such product candidates, both our and
Ascletis’ ability to successfully advance ALN-VSP resulting in the potential
payment of milestones and royalties to us, 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, including its collaboration with Ascletis, and new
business initiatives, as well as those risks more fully discussed in the “Risk
Factors” filed with Alnylam’s current report on Form 8-K filed with the
Securities and Exchange Commission (SEC) on January 14, 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 does not
assume any obligation to update any forward-looking statements.


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