Early Clinical Development #1 REGN727: anti-pcsk9 July 15, 2010 Neil Stahl, Ph.D. Senior Vice President Research and Development Sciences 1
Safe Harbor Statement Except for historical information, the matters contained in this presentation may constitute forward-looking statements that involve risks and uncertainties, including uncertainties related to product development and clinical trials, unforeseen safety issues resulting from the administration of products in patients, uncertainties related to the need for regulatory and other government approvals, risks related to third party patents and proprietary technology, the need for additional capital, uncertainty of market acceptance of Regeneron s product candidates, the receipt of future payments, the continuation of business partnerships, and additional risks detailed from time to time in Regeneron s filings with the Securities and Exchange Commission (SEC). Please refer to Regeneron s recent Forms 10-K, 10-Q, and 8-K for additional information on the uncertainties and risk factors related to our business. Because forward-looking statements involve risks and uncertainties, actual results may differ materially from current results expected by Regeneron. Regeneron is providing this information as of the original date of this presentation and expressly disclaims any duty to update any information contained in these materials. 2
Statins Have Meaningful Impact on LDL Levels and CV Risk High Dose Statins Lower LDL by 30-60%; Lower LDL Lowers CV Risk Current therapy does not eliminate CV events, as many patients do not reach treatment goals Continuous risk reduction with lower LDL Target LDL levels repeatedly adjusted downward as new clinical data has emerged Cardiovascular Event Rates Event rates for HPS, CARE, and Lipid are for death from CHD and nonfatal myocardial infarction. Event rates for 4S and the TNT Study also include resuscitation after cardiac arrest. To convert values for LDL cholesterol to millimoles per liter, multiply by 0.02586. HPS: Heart Protection Study; CARE: Cholesterol and Recurrent Events Trial; LIPID: Long-term Intervention with Pravastatin in Ischaemic Disease; 4S: Scandinavian Simvastatin Survival Study. Source: LaRosa, J, Grundy, S, Waters, D, et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. New England Journal of Medicine 2005; 352:1425. Copyright 2005 Massachusetts Medical Society. 3
Despite Statins, Unmet Medical Need Remains High Cardiovascular Disease Remains Leading Cause of Morbidity and Mortality Deaths from Cardiovascular Disease Estimated Costs ($B) of CV Disease and Stroke Deaths in Thousands Coronary Heart Disease Stroke Hypertensive Disease Heart Failure (United States: 1900 2006). Source: NCHS and NHLBI. (United States: 2010). Source: NHLBI. 4
Many Patients with Elevated LDL-Cholesterol High Numbers Untreated; More than 10M Treated, but Not at Goal 30 million untreated 8 M 1 o prevention 3 M 2 o prevention 11 million not at goal; 1.4 million statin refractory/intolerant Hyperlipidemia Elevated LDL Elevated LDL Treated Statin Refractory/Intolerant Uncontrolled As guidelines lower LDL goals, more patients will not reach desired levels with statins NHANES: National Health and Nutrition Examination Survey, CDC, 2005-2006; Decision Resources, 2008 5
PCSK9: A Novel Genetically Validated Target for CV Disease Landmark Publication Shows Lower PCKS9 Leads to Lower LDL and CV Risk ARIC study revealed that heterozygous mutation reducing PCSK9 activity associated with decreased CHD hazard ratio = 0.11 Volume 354:1264-1272 March 23, 2006 Distribution of Plasma LDL Cholesterol Levels (Panel A) and Incidence of Coronary Heart Disease (Panel B) among Black Subjects, According to the Presence or Absence of a PCSK9142X or PCSK9679X Allele 6
Background: LDL Receptors are the Key Regulators of LDL LDLR Binds to LDL, Internalizes, and Leads to LDL Degradation LDL LDLR returned to cell surface LDLR Hepatocyte LDL degradation 7
Background: PCSK9 Regulates the Concentration of LDLR Increased PCSK9 Leads to Lower LDLR Binds and Leads to Degradation LDL LDLR PCSK9 LDLR degradation 8
Background: Statins Lower LDL by Increasing LDLR However, Statins Cause an Increase in PCSK9, Potentially Offsetting Benefit LDL LDLR LDL LDLR PCSK9 Statins PCSK9 Statins α-pcsk9 Statins + αpcsk9 9
REGN727: Binds to PCSK9 Leading to Increase in LDLR Like Statins, REGN727 Lowers LDL by Increasing Concentration of LDLR PCSK9 antibody LDLR LDL LDLR PCSK9 Statins α-pcsk9 Statins + αpcsk9 10
REGN727: Potential Synergy with Statins Addition of REGN727 Could Neutralize Increase in PCSK9 PCSK9 antibody LDLR LDL LDLR PCSK9 Statins PCSK9 Statins α-pcsk9 Statins + αpcsk9 11
Following Landmark PCSK9 Publications Race Was On Using VelocImmune, Time from Immunization to Clinic Only 19 Months Fully human antibody derived from VelocImmune technology Binds catalytic domain and prevents interaction of PCSK9 with LDLR 19 months from immunization to IND filing Month 2008 2009 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 Immunized Mice Time: 0 IND Enabling Studies Time: 12-months IND Filed Time: 19-months 12-months 7-months REGN727 selected as anti-pcsk9 clinical candidate 12
Preliminary Animal Data with REGN727 Very Encouraging Single Infusion in Monkeys Led to Dramatic Decreases in LDL n=3 per cohort, SD error bars shown 13
Key Questions Could Be Answered in Early Development LDL Levels Allow an Early, Clinically Meaningful, Readout Could REGN727 lower LDL at a meaningful magnitude? Statins lower LDL by 40-60% Ezetemibe lowers LDL by 10-25% in monotherapy or in combination with statins Could REGN727 deliver meaningful LDL reduction by subcutaneous injection? Could REGN727 deliver meaningful LDL reduction at a commercially viable frequency of injection? Would safety issues emerge from Phase 1? Would REGN727 be effective on-top of statins? Dose intensification from moderate to high dose of statins gains ~10% of incremental LDL lowering (e.g., 40 mg to 80 mg of atorvastatin) Statins increase PCSK9 levels, adding uncertainty 14
REGN727: Lowered LDL by 60% in Healthy Volunteers Effect Lasted >1 Month; Dose Dependent Example 1 Baseline LDL - 109 mg/dl Minimum LDL- 44 mg/dl Example 2 Baseline LDL - 186 mg/dl Minimum LDL 65 mg/dl Note: 6 volunteers treated in each dosing group 15
REGN727: Lowered LDL by 60% in Healthy Volunteers Subcutaneous Dosing Every 2 Weeks, or Less Frequently, Feasible Note: 6 volunteers treated in each dosing cohort; Dose group 3 not a full cohort 16
No Safety Issues To Date From Preliminary Phase 1 Data No Elevations in LFTs Greater than 3X Normal Current studies are small and most cohorts are ongoing To date: No SAEs No discontinuations due to AE No LFT elevations of greater than 3X normal One subject at lowest dose had transient asymptomatic increase of CPK (after heavy exercise) 17
Early Phase 1 Data Readout is Encouraging We Look Forward to Multi-dose and Longer-Term Safety and Efficacy Could REGN727 lower LDL at a meaningful magnitude? >60% LDL reduction following single dose Could REGN727 deliver meaningful LDL reduction by subcutaneous injection? Similar LDL reduction with single dose delivered SC Could REGN727 deliver meaningful LDL reduction at a commercially viable frequency of injection? Duration of effect at SC dosing suggests at least q2week dosing Would safety issues emerge from Phase 1? No SAEs to date, but longer and larger studies required Would REGN727 be able to substantially lower LDL when added to stable doses of statins? Going from normal to high dose of statins gains 10-15% of incremental LDL lowering (e.g., 40 mg to 80 mg of atorvastatin) Statins increase PCSK9 levels, adding uncertainty 18
Current Add-on Therapy Offers Modest Benefit over Statins Doubling Statin Dose Typically Lowers LDL by Incremental ~10% 60% Doubling statin dose lowers LDL by ~10% Adding ezetimibe to statin adds 10-25% incremental LDL lowering Monotherapy Added to Statin Mean Change in LDL from Baseline 50% 40% 30% 20% 10% 0% Rosuvastatin Atorvastatin Simvastatin Pravastatin 10mg 20mg 40mg 80mg Statin Dose Source: Jones, et al. STELLAR study. JACC 92, 2003 Placebo Ezetimibe Ongoing Statins Full prescribing information for ezetimibe Note: Comparison of the percent reduction in serum low density lipoprotein (LDL)-cholesterol with various statin drugs 19
REGN727: Preliminary Phase 1 Data With Statins Encouraging Similar LDL Decrease in Monotherapy or Combination with Statins % Change in LDL from baseline 0% -10% -20% -30% -40% -50% -60% 0 2 4 6 8 10 12 14 Dose G Dose H Dose I Statin + Dose G -70% Days Data are early but VERY encouraging Note: N = 11 in statin + Dose G; N =6 in Dose G alone 20
Early Phase 1 Data Readout is Encouraging We Look Forward to Multi-dose and Longer-Term Safety and Efficacy Data Could REGN727 lower LDL at a meaningful magnitude? >60% LDL reduction following single dose Could REGN727 deliver meaningful LDL reduction by subcutaneous injection? Similar LDL reduction with single dose delivered SC Could REGN727 deliver meaningful LDL reduction at a commercially viable frequency of injection? Duration of effect at SC dosing suggests at least q2week dosing Would safety issues emerge from Phase 1? No SAEs to date, but longer and larger studies required Would REGN727 be effective on-top of statins? Preliminary data suggest similar magnitude of LDL reduction when added to statins in Familial Hypercholesterolemia (FH) and non-fh subjects High level of enthusiasm at Regeneron and sanofi-aventis 21