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Alnylam and Collaborators Demonstrate Regression of Pathogenic Transthyretin (TTR) Amyloid Deposits Following Treatment with an RNAi Therapeutic in an Animal Model of TTR-Mediated Amyloidosis (ATTR)
- New Pre-Clinical Data Presented with ALN-TTR01, an RNAi Therapeutic for Treatment of ATTR, in the Human V30M TTR Transgenic Mouse Model -
- ALN-TTR01 on Track to Enter Phase I Clinical Trial in ATTR Patients in First Half of 2010 -

CAMBRIDGE, Mass., Apr 20, 2010 (BUSINESS WIRE) --Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, presented new pre-clinical data from its ALN-TTR program at the XII International Symposium on Amyloidosis in Rome on April 18 - 21, 2010. ALN-TTR01 is a systemically delivered RNAi therapeutic being developed for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR), including familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC). These new pre-clinical data demonstrate - for the first time - that treatment with an RNAi therapeutic can result in regression of pre-existing pathogenic TTR deposits in peripheral tissues. Additional pre-clinical data presented at the meeting demonstrated the potential application of TTR-specific siRNA for the treatment of ocular disease in ATTR.

ATTR is caused by mutations in the TTR gene, which is expressed predominantly in the liver, that result in the accumulation of pathogenic deposits of mutant and wild-type TTR protein in several tissues, including nerves, heart, and the gastrointestinal tract. There are more than 100 mutations that have been identified in the TTR gene. ALN-TTR targets a conserved region of the TTR gene in wild-type and all known mutant forms of TTR, and therefore, has potential as a therapeutic for all patients with FAP and FAC. TTR is also expressed in the eye by retinal pigment epithelial (RPE) cells, and mutations in TTR can lead to ocular complications in ATTR patients including blindness.

"We are very encouraged by these important new pre-clinical data from our ALN-TTR program which we believe point to the breakthrough potential of an RNAi therapeutic strategy in ATTR. Importantly, we have demonstrated for the first time the ability of achieving regression of pathogenic TTR deposits in tissues when ALN-TTR01 is administered in a treatment paradigm," said Rene Alvarez, Ph.D., Associate Director of Research at Alnylam. "These new data significantly extend our previous results showing that ALN-TTR01 can prevent TTR deposition when administered in a prophylactic regimen. We are also encouraged by our initial pre-clinical data using siRNAs targeting TTR for the treatment of ocular amyloidosis. Expression of mutant TTR in retinal cells can lead to blindness in ATTR patients, and an intraocular injection approach with our TTR-specific siRNA could be advanced as a Direct RNAi therapeutic strategy."

The new pre-clinical studies, performed in collaboration with Dr. Maria Saraiva at the Institute for Molecular and Cellular Biology in Portugal, used a transgenic mouse model where the mutant human V30M TTR gene is over-expressed. Specifically, the new data demonstrated that administration of ALN-TTR01 in mature transgenic mice resulted in the regression of existing pathogenic mutant human V30M TTR deposits in tissues, including: dorsal root ganglia, sciatic nerve, stomach, and intestines. These effects in diseased tissues were mediated through silencing of the mutant human TTR expressed in the liver, resulting in regression of established peripheral TTR deposits. ALN-TTR01 administration resulted in a greater than 90% regression of measurable TTR deposits as compared with control-treated animals.

"It is quite encouraging to see these types of results with a novel RNAi therapeutic for the treatment of ATTR, as there are currently very limited options for patients suffering from this devastating disease," said Maria Joao Saraiva, Ph.D., Professor of Biochemistry, Molecular Neurobiology Group, Institute for Molecular and Cellular Biology in Portugal. "Indeed, the ability to see regression of TTR deposits in a transgenic mouse model suggests that treatment with ALN-TTR01 in patients could potentially reverse complications of established disease. Accordingly, I am excited about the translation of this promising new agent into clinical trials."

In addition, new pre-clinical studies were performed with TTR-specific siRNA in a rat model of ocular amyloidosis in collaboration with Dr. Yukio Ando at Kumamoto University in Japan. As compared with control siRNA, intraocular administration of TTR-specific siRNA was found to silence endogenous rat TTR expression by greater than 50%. In a transgenic human V30M TTR rat model, intraocular administration of TTR-specific siRNA resulted in a similar reduction in expression of the human V30M mutant protein. In aggregate, these studies validate the potential application of RNAi therapeutics for the treatment of ocular amyloidosis in ATTR patients.

"The potential for ALN-TTR01 to effect regression of TTR amyloid deposits is an important pre-clinical finding as it relates to the clinical development plan for this RNAi therapeutic, including the nature of clinical endpoints in later-stage studies," said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President, Clinical Research at Alnylam. "Further, the new data in a model of ocular amyloidosis reveal additional potential clinical indications in our overall ALN-TTR program. As we obtain final regulatory and ethics committee approvals, we look forward to initiating our Phase I study with ALN-TTR01 in ATTR patients, which remains on track to start in the next few months."

Previous pre-clinical studies reported by Alnylam have demonstrated the ability of TTR-specific RNAi therapeutics to mediate potent and durable silencing of both wild-type and mutant forms of the TTR gene in rodents and non-human primates. In the first half of 2010, Alnylam expects to initiate a Phase I clinical trial with ALN-TTR01 in patients with ATTR. ALN-TTR01 is being advanced using stable nucleic acid-lipid particles (SNALP) delivery technology developed in collaboration with Tekmira Pharmaceuticals Corporation. In parallel, Alnylam is also advancing ALN-TTR02 utilizing second generation lipid nanoparticles.

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 RNAs (siRNAs), 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 applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world's top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics; its most advanced program is in Phase II human clinical trials for the treatment of respiratory syncytial virus (RSV) infection. In addition, the company is developing RNAi therapeutics for the treatment of a wide range of disease areas, including liver cancers, TTR-mediated amyloidosis (ATTR), hypercholesterolemia, and Huntington's disease. The company's leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. Alnylam and Isis are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA-based therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

Alnylam Forward-Looking Statement

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-TTR01, its expectations with respect to the timing and success of its clinical and pre-clinical trials, and its plan to initiate clinical trials for ALN-TTR01, 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 the company's ability to discover and develop novel drug candidates, and successfully demonstrate efficacy and safety of its drug candidates in human clinical trials, as well as those risks more fully discussed in the "Risk Factors" section of its most recent annual report on Form 10-K 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.

SOURCE: Alnylam Pharmaceuticals, Inc.

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton (Investors), 617-551-8207
Amanda Sellers (Media), 202-955-6222 x2597
"Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release regarding Alnylam Pharmaceuticals's business which are not historical facts are "forward-looking statements" that involve risks and uncertainties. For a discussion of such risks and uncertainties, which could cause actual results to differ from those contained in the forward-looking statements, see "Risk Factors" in the Company's Annual Report or Form 10-K for the most recently ended fiscal year.