Regulus Therapeutics and Collaborators Discover Role of a microRNA in Tumor Angiogenesis

Regulus Therapeutics LLC, a joint venture between Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) and Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) formed to discover, develop, and commercialize microRNA-based therapeutics, announced today the publication of new research findings in the journal Cancer Cell demonstrating a key role of microRNAs in regulating angiogenesis pathways in cancer, specifically in malignant brain tumors. Angiogenesis is a physiological process required for the growth and spread of many cancers and the new findings demonstrated that miR-296 is a significant regulator of this pathway. Further, targeting miR-296 with anti-miR-296 antisense oligonucleotides (also called "antagomirs”) blocked angiogenesis in tumor xenograft models in mice. This new research was led by Thomas Würdinger affiliated with Xandra O. Breakefield’s laboratory at Massachusetts General Hospital and VU Medical Center in Amsterdam, working in collaboration with researchers from Regulus, Anna M. Krichevsky’s laboratory at Brigham and Women’s Hospital, and Ludwig-Maximilians-University in Munich.

"This new research adds to a rapidly growing body of evidence suggesting that microRNAs control important biological pathways and that inhibiting the function of a single microRNA could have a profound effect on disease pathophysiology,” said Peter Linsley, Ph.D., Chief Scientific Officer of Regulus Therapeutics. "The current study shows that miR-296 is a significant regulator of tumor induced angiogenesis, and that anti-miR-296 may thus represent a novel anti-cancer strategy.”

The new paper (Würdinger et al., Cancer Cell 14, 382-393) describes the role of endothelial cell-expressed miR-296 in regulating the formation of new blood vessels. During neovascularization, increased expression of miR-296 represses hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), which in turn regulates additional growth factor receptors, VEGFR and PDGFR. By inhibiting miR-296 with an anti-miR, levels of the growth factor receptors were decreased resulting in decreased growth of blood vessels. The induction of miR-296 expression was observed in tumor blood vessels isolated from human glioblastoma tumors, suggesting an important role for miR-296 in tumor progression and metastatic potential. The data showed that the regulation of miR-296 in human endothelial cells directly resulted in the modulation of angiogenesis in vitro. Additionally, the specific inhibition of miR-296 in an in vivo tumor xenograft model resulted in decreased neovascularization of tumors.

About microRNAs

microRNAs are a recently discovered class of genetically encoded small RNAs, approximately 20 nucleotides in length, and are believed to regulate the expression of a large number of human genes. microRNA-based therapeutics represent a new approach for the treatment of a wide range of human diseases. The inappropriate absence or presence of specific microRNAs in various cells has been shown to be associated with specific human diseases including cancer, viral infection, metabolic disorders and inflammatory disease. Targeting microRNAs with novel therapeutic agents could result in novel and broadly acting treatments for human diseases.

About Regulus

Regulus Therapeutics LLC is a biopharmaceutical company formed to discover, develop, and commercialize microRNA-based therapeutics. Regulus aspires to translate one of the most important new discoveries in biology into a novel new approach for innovative medicine and to build the leading microRNA company. Created as a joint venture by Alnylam Pharmaceuticals and Isis Pharmaceuticals, Regulus benefits from oligonucleotide drug discovery expertise, an established technology, and a broad intellectual property estate created and consolidated by its parent companies for the development and commercialization of microRNA-based therapeutics. Regulus’ patent estate includes over 600 patents and more than 300 pending patent applications, pertaining primarily to chemical modifications of oligonucleotides targeting microRNA for therapeutic applications. In addition, Regulus has collaborations with academic researchers to build on the company’s understanding of more than 60 microRNAs. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to explore microRNA therapeutics for inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Regulus, founded in September 2007, maintains facilities in Carlsbad, California. For more information, visit www.regulusrx.com.

About Isis Pharmaceuticals, Inc.

Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 19 drugs in development. Isis’ drug development programs are focused on treating cardiovascular and metabolic diseases. Isis’ partners are developing antisense drugs invented by Isis to treat a wide variety of diseases. Ibis Biosciences, Inc., Isis’ majority-owned subsidiary, is developing and commercializing the Ibis T5000™ Biosensor System, a revolutionary system to identify infectious organisms. Isis is a joint owner of Regulus Therapeutics LLC, a joint venture focused on the discovery, development and commercialization of microRNA therapeutics. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of over 1,500 issued patents worldwide. Additional information about Isis is available at http://www.isispharm.com.

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, hypercholesterolemia, Huntington’s disease, and TTR amyloidosis. 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, and Kyowa Hakko Kogyo. To reflect its outlook for key scientific, clinical, and business initiatives, Alnylam has established "RNAi 2010” which includes the company’s plan to significantly expand the scope of delivery solutions for RNAi therapeutics, have four or more programs in clinical development, and to form four or more new major business collaborations, all by the end of 2010. Alnylam is a joint owner of Regulus Therapeutics LLC, a joint venture focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, visit http://www.alnylam.com.

Forward-Looking Statement

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Isis’, Alnylam’s and Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus. Any statement describing Isis’, Alnylam’s or Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement, including those statements that are described as such parties’ goals. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such parties’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause their results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of the management of each such party, these statements are based only on facts and factors currently known by Isis, Alnylam or Regulus, as the case may be. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis’, Alnylam’s and Regulus’ programs are described in additional detail in Isis’ annual report on Form 10-K for the year ended December 31, 2007, and its quarterly report on Form 10-Q for the quarter ended June 30, 2008 and in Alnylam’s annual report on Form 10-K for the year ended December 31, 2007, and its quarterly report on Form 10-Q for the quarter ended June 30, 2008, which are on file with the SEC. Copies of these and other documents are available from Isis or Alnylam.