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Global Need for Innovative Medicines

Global Need for Innovative Medicines. 2020: Global population projected to rise to 7.6B (from 6.5B) 9.4% of population will be over 65 In the U.S., someone turns 60 every seven seconds 80% over age of 75 take at least one medication. Success in biotech . People. Financing. Idea. SIRT

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Global Need for Innovative Medicines

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  1. Global Need for Innovative Medicines • 2020: Global population projected to rise to 7.6B (from 6.5B) • 9.4% of population will be over 65 • In the U.S., someone turns 60 every seven seconds • 80% over age of 75 take at least one medication

  2. Success in biotech People Financing Idea SIRT ALNY MNTA Acceleron Concert MagenAlnara

  3. 2005 Botero: Una Familia Sirtris The Idea: Diseases of aging 1985 Source: CDC No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

  4. Sirtris The Idea: Sirtuins control aging

  5. Sirtris The Idea: Sirtuins control aging

  6. 1.0 0.8 0.6 Proportion Surviving 0.4 Standard diet High calorie High calorie + resveratrol 0.2 0.0 50 60 70 80 90 100 110 Time (weeks) SirtrisThe Idea: Calorie Restriction Extends Lifespan via SIRT1 activation 100 Calorie restriction (40% fewer calories) 80 60 Control Percentage Surviving 40 20 0 0 500 1,000 1500 Age (Days) McCay et al., J of Nutrition 1935 Baur et al., Nature 2006

  7. SirtrisThe Idea: Link Between Sirtuins and Diseases of Aging Diseases of Aging Calorie Restriction • Calorie Restriction • Extends lifespan and lowers incidence of diseases of aging • Activates SIRT1, lowers glucose, and improves insulin sensitivity • Sirtuin Activation • Exhibits similar beneficial effects of calorie restriction • Sirtris small molecules activate SIRT1 • SIRT1 activators lower glucose, improve insulin sensitivity Sirtuins/Aging Genes

  8. SirtrisThe Idea: SIRT1 Activators for Diseases of Aging/Type 2 Diabetes References Proof Pre-Clinical Therapeutic Human Physiological Human Genetic Human Therapeutic • Nature. 2007 Nov 29;450(7170):712-6. • Nature. 2006 Nov 16;444(7117):337-42. • Cell. 2006 Dec 15;127(6):1109-22. • PLoS Med. 2007 Mar 6;4(3). • JAMA. 2006 Apr 5;295(13):1539-48. • Cell. 2006 Dec 15;127(6):1109-22. • Phase 1a and 1b data in 200 subjects • Statistical significance in OGTT at 2 hrs • Strong trend on lowering fasting glucose

  9. 100 90 80 70 60 SirtrisThe Idea: NCEs - Lower Glucose and Insulin in DIO Model Fasted Blood Glucose(3 weeks of dosing) Fed Blood Insulin(4 weeks of dosing) 100 90 * 80 70 * 60 * * % of DIO + Vehicle % of DIO + Vehicle 50 40 30 20 10 DIO + Veh DIO + Veh DIO + NCE-1 DIO + NCE-1 Control + Veh Control + Veh DIO + Rosiglitazone DIO + Rosiglitazone Nature 450, 712-6 (2007) n=10 for all; *p< 0.05 vs. DIO + vehicle

  10. Sirtris The Idea: SIRT1 activation improves metabolism Resveratrol Treated Untreated

  11. Sirtris The Idea: SIRT1 activation improves metabolism Muscle Fibers Citrate Synthase (CS) Activity in Mouse Skeletal Muscle DIO + SRT501 DIO + vehicle 600 * 500 400 CS/mg protein activity 300 Treadmill Test : Treated mice ran twice distance 200 100 0 DIO + Veh DIO + SRT501 • Increased metabolic rate as shown by: • Reduced plasma glucose • Improved insulin sensitivity • Increased O2 consumption • Improved response to cold challenge Cell 127, 1-14 (2006) n=5 for all; *p< 0.05 vs. DIO+vehicle

  12. Sirtris The People: David Sinclair

  13. Sirtris The People: Boston biotech

  14. The Financing • Financing since inception • $103 million in private equity • $69 million in initial public offering • Nasdaq: SIRT • Cash balance 12/31/07: $118 million • June 6, 2008 acquisition by GSK $720M; ~85% premium • Current infrastructure • ~55 full-time employees in Cambridge • ~40 contractors in China (chemists and biologists)

  15. Sirtris in the News nature

  16. Alnylam (NASDAQ: ALNY) The Idea: RNA Interference (RNAi) Potential for a novel class of drugs • Harnessing natural pathway • Therapeutic gene silencing • Upstream of today’s medicines • Any gene in the genome Natural process for gene silencing • Catalytic mechanism • Potent and selective • Mediated by small interfering RNAs or “siRNAs” • Current Targets: Respiratory Syncytial Virus; Hypercholesterolemia; Liver Cancers; Huntington’s Disease; Hepatitis C; Progressive Multifocal Leukoencphalopathy; Pandemic Flu 2006 Nobel Prize awarded for RNAi discovery

  17. Alnylam (NASDAQ: ALNY) The People: 1. Philip Sharp - Nobel Laureate, National Academy, Biogen, Sirtris2. Tom Tuschl - Max Planck3. Paul Schimmel - National Academy, Sirtris4. Christoph Westphal - Alnylam, Momenta, Sirtris, Acceleron, Concert, Magen

  18. Momenta (NASDAQ: MNTA) The Idea: Glycobiology • Potential for a novel class of drugs • Sugars play a role in normal biological processes and disease • Understanding Malfunction in this pathway • Sugar production malfunctions play a role in many diseases: cancer, cardiovascular disease, Alzheimer’s disease, inflammatory disease and viral infection • Pathway for drug development • By manipulating complex sugars, one can modify disease pathways e.g. generic anticoagulants

  19. Momenta (NASDAQ: MNTA) The People: 1. Bob Langer and Ram Sasisekharan - National Academy, Institute of Medicine, AIR, Momenta, Sirtris2. Christoph Westphal - Alnylam, Momenta, Sirtris, Acceleron, Concert, Magen

  20. Success in biotech People • scientists, clinicians, academic centers • angels, venture capitalists, mutual funds, hedge funds • bankers, analysts, lawyers, accountants, consultants • media • real estate • service providers Financing Idea SIRT ALNY MNTA Acceleron Concert Magen

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