microrna-21 contributes to kinase signalling in fibroblasts Thum et al (2008), Nature AOP December 1, 2008

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1 microrna-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts Thum et al (2008), Nature AOP December 1, 2008

2 Safe Harbor Statement This presentation 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 forwardlooking 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 most recent quarterly report on Form 10-Q, and in Alnylam s annual report on Form 10-K for the year ended December 31, 2007, and its most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from Isis or Alnylam.

3 micrornas are Deregulated in Cardiac Disease Divakaran and Mann (2008), CirculationRes 103,

4 Thum et al. Nature Publication Major collaborative study Thomas Thum and Carina Gross, lead scientists Numerous academic institutions, including: University of Wuerzberg UCSF Stanford Rockefeller Heidelberg University Northwestern King s College Regulus and Alnylam scientists -2 -

5 mir-21 as a Disease Target mir-21 is over-expressed in the human failing heart. It is expressed in interstitial fibroblasts and represses Sprouty1 and de-represses the ERK-MAP Kinase pathway. Failing human heart Failing human heart Increased mir-21 expression Increased ERK-Signaling by repressed SPY1 Thum et al. (2008) Nature, AOP -3 -

6 In Vivo Delivery of anti-mir-21 to Heart Mouse Model mir-21 is also over-expressed in the murine heart following TAC. Anti-miR- 21 achieves delivery to heart. Significant delivery of Cy3 labeled anti-mir ( antagomir ) to cardiac tissue Effective delivery of anti-mir-21 to cardiac tissue Thum et al. (2008) Nature, AOP -4 -

7 In Vivo Activity of Anti-miR-21 Mouse Model Anti-miR treatment restores levels of Sprouty1, restores ERK-MAPKinase suppression, and eliminates interstitial fibrosis in a mouse model of heart failure. Anti-miR-21 restores Sprouty1 and leads to ERK-MAPKinase repression Anti-miR-21 eliminates interstitial fibrosis following TAC Thum et al. (2008) Nature, AOP -5 -

8 In Vivo Efficacy of Anti-miR-21 Mouse Model Anti-miR-21 demonstrates clear efficacy in a murine model of heart failure in a prevention paradigm Anti-miR-21 demonstrates prophylactic efficacy in TAC model Decreased hypertophy and heart tissue weight Decreased dilatation and improved fractional shortnening Thum et al. (2008) Nature, AOP -6 -

9 Therapeutic Efficacy of Anti-miR-21 Mouse Model Anti-miR-21 demonstrates clear therapeutic efficacy in a murine model of heart failure in a treatment paradigm Anti-miR-21 demonstrates therapeutic efficacy in TAC model Reversal of fibrosis, hypertrophy, and increased heart weight Improved dilatation and fractional shortnening Thum et al. (2008) Nature, AOP -7 -

10 Model for Anti-miR-21 Efficacy Anti-miR-21 represents a novel therapeutic strategy for heart failure. Cardiac stress Therapeutic Intervention Anti-miR-21 Fibrosis, remodeling, cardiac dysfunction Normal state Phenotype recovery Thum et al. (2008) Nature, AOP -8 -