- New findings published in the journal Nature demonstrate therapeutic benefit of
anti-microRNA-21 in an animal model of heart failure
- Companies to host conference call Monday, December 1, 2008 at 8:30 a.m. ET
to discuss results
CAMBRIDGE, Mass. and CARLSBAD, Calif., November 30, 2008 – 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 in the journal Nature on the role of a microRNA, known as miR-21, in heart failure(1). The new findings demonstrated that miR-21 is over-expressed in the failing human heart and contributes to heart failure through its regulation of a stress-response signaling pathway associated with changes in heart muscle structure and function. The study went on to demonstrate that targeting miR-21 with an anti-miR-21, antisense oligonucleotide (also called an “antagomir”) prevented heart failure in mouse models. Furthermore, administration of anti-miR-21 after established heart failure resulted in a significant treatment benefit in the animal model.
“We view this new study as a landmark event in the advancement of microRNA therapeutics as a new class of innovative medicines. Indeed, we believe that this is the first study to clearly demonstrate therapeutic efficacy for targeting microRNAs in an animal model of human disease,” said Kleanthis G. Xanthopoulos, Ph.D., President and Chief Executive Officer of Regulus Therapeutics. “Moreover, these exciting data highlight microRNA-based therapeutics specifically targeting miR-21 as a promising approach for the treatment of heart failure, extending the scope of disease opportunities for Regulus.”
“Heart failure remains a major cause of morbidity and mortality across the world. Despite decades of clinical research, and some important advances in pharmacologic and device therapy, future development of new high-impact medicines can only emerge with a better understanding of molecular mechanisms in the cause or pathway of this disease,” said Eugene Braunwald, M.D., Distinguished Hersey Professor of Medicine at Harvard Medical School, and Chairman, TIMI Study Group at Brigham and Women’s Hospital. “This exciting research defines an entirely new potential strategy for intervention, where antagonism of a single microRNA could result in correction of the disease pathways of heart failure.”
Heart failure, also known as congestive heart failure (CHF), is a condition where the heart is unable to supply adequate flow of blood to the body’s organs and is caused by significant or prolonged stress to the heart. CHF can occur following a heart attack, certain infections, hypertension, and through genetic causes, and affects approximately five million patients in the U.S.; CHF accounts for substantial morbidity and mortality with approximately 600,000 deaths annually.
microRNAs have been described previously as being involved in the regulation of gene expression as part of heart physiology and development,(2,3) but their exact role in disease and their validity as targets for intervention have remained undetermined. In this new study, miR-21 was discovered to be expressed in fibroblast cells of the heart, with increased levels in mouse models of heart failure and also in human disease tissue. Increased expression of miR-21 was shown to regulate a previously unrecognized stress-response pathway in fibroblasts involving the gene sprouty-1 and the MAP-kinase signaling pathway. In turn, increased MAP-kinase signaling promoted enhanced fibroblast survival, increased secretion of certain factors (e.g., fibroblast growth factor) leading to tissue scarring (fibrosis), and cardiac dysfunction including cellular hypertrophy; all hallmark features of the failing human heart.
Treatment with an anti-miR-21 in a mouse model of heart failure was performed using both prevention and treatment protocols. Administration of the anti-miR oligonucleotide resulted in efficient delivery to the heart as measured by fluorescence staining. In a mouse transaortic constriction model of human heart failure, anti-miR-21 treatment silenced increased expression of miR-21 and corrected downstream changes in sprouty-1 and MAP-kinase signaling. Further, treatment with the anti-miR blocked the development of tissue scarring as measured histologically and also reversed the hypertrophy of cardiomyocytes and increased heart weight associated with both the disease model and human disease. Finally, administration of anti-miR-21 corrected defects in the failing heart including left ventricular dilatation and fractional shortening, echocardiographic measurements of heart function. Importantly, anti-miR-21 demonstrated statistically significant improvements in the heart failure animal model when administered prior to, and as long as three weeks after induction of the experimental heart failure.
“This study has revealed a key role for miR-21 in regulating a major stress-response pathway in the failing heart. Administration of anti-miR-21 led to a striking effect in preventing and treating cellular, morphologic, and functional features of heart failure in a well-established animal model,” said Peter Linsley, Ph.D., Chief Scientific Officer of Regulus Therapeutics. “Most importantly, these new in vivo data point to the significant potential for targeting microRNAs, where therapeutic impact can be achieved by interrupting entire pathways of disease, not just single disease targets.”
The new research was led by the group of Dr. Thomas Thum, affiliated with Dr. Johan Bauersachs’ laboratory in the Department for Internal Medicine at the University of Wuerzburg and Carina Gross in the lab of Dr. Stefan Engelhardt at the Virchow Center at the University of Wuerzburg, working in collaboration with scientists at Regulus, Alnylam, University of California, San Francisco, King’s College London, Heidelberg University, Northwestern University, and The Rockefeller University.
(1) Thomas Thum, Carina Gross, Jan Fiedler, Thomas Fischer, Stephan Kissler, Markus Bussen, Paolo Galuppo, Steffen Just, Wolfgang Rottbauer, Stefan Frantz, Mirco Castoldi, Juergen Soutschek, Victor Koteliansky, Andreas Rosenwald, M. Albert Basson, Jonathan D. Licht, John T. R. Pena, Sara H. Rouhauifard, Martina U. Muckenthaler, Thomas Tuschl, Gail R. Martin, Johann Bauersachs, & Stefan Engelhardt. microRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature advance online publication, 30 November 2008 (10.1038/nature07511).
(2) Divakaran V, Mann, DL. The emerging role of microRNAs in cardiac remodeling and heart failure. Circulation Research. 2008;103:1072-1083.
(3) Callis, TE, Wang, D. Taking microRNAs to heart. Trends in Molecular Medicine. 2008:14(6) 254-260.
Conference Call Information
The call may be accessed by dialing 866-356-4281 (domestic) or 617-597-5395 (international) five minutes prior to the start time, and providing the passcode 24963936. A replay of the call will be available from approximately 10:00 a.m. ET December 1, 2008 until December 8, 2008. To access the replay, please dial 888-286-8010 (domestic) or 617-801-6888 (international), and provide the passcode 98563031. A live audio webcast of the call will also be available on the “Investors” section of the company’s website, www.alnylam.com. An archived webcast will be available on the Alnylam website approximately two hours after the event, and will be archived for 14 days thereafter.
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.
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. To reflect its outlook for key scientific, clinical, and business initiatives, Alnylam established “RNAi 2010” in January 2008 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.
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 September 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 September 30, 2008, which are on file with the SEC. Copies of these and other documents are available from Isis or Alnylam.
Amy Blackley, Ph.D. (Media)
Cynthia Clayton (Investors)