Slide 1: Inhibition of PCSK9 with Monoclonal Antibody
Inhibition of PCSK9 with Monoclonal Antibody REGN727/SAR236553 Effectively Reduces LDL-C as Mono or Add-on Therapy in Heterozygous Familial and Non-Familial Hypercholesterolemia. Gary Swergold' MD, PhD, William Smith? MD, Scott Mellis', MD, PhD, Douglas Logan? MD, Cheryle Webb‘ MD, Richard Wu! PhD,
Slide 2: PCSK9-mediated LDLR degradation and inhibition
SANOFI PProske —> | eas — } ues protein Pcsko > LOLR => Jove protein 727 inhibition of PCSK9 mediated LDLR degradation LDLR recycling PCSK9 mediated LDLR degradation REGENERON
Slide 3: REGN727/SAR236553: A Fully-Human mAb to PCSK9
REGN727/SAR236553: A Fully-Human mAb to PCSK9 REGN727 binds hPCSK9 with subnanomolar affinity ¢ Produced using Regeneron’s Velocimmune technology ¢ Precise humanization of 6 megabases of mouse immune loci rn Nereis Ds Js mouse constants and control regions human kappa chain Vs Js mouse constant and
Slide 4: Single dose studies
¢ Single dose studies — IV N=4o — SC N= 32t ¢ Sustained LDL-C lowering — exceeded 60% and lasted for at least 30 days in higher dose cohort ¢ Safety and tolerability supported decision to initiate studies in patients ‘Study 0902: 6 Swergold, etal. Cire 2010;122(10021): A2325; G Swergold, et al. J Cl
Slide 5: Phase Ib: Multidose Study
Phase Ib: Multidose Study Double-Blind, Randomized, Placebo-Controlled NCTO1161082 Sequential Cohorts SC 50mg or Placebo Eomanyenceon incidence and severity of TEAES 21-day screening period SC 100mg or Placebo Follow up 105 days after last dose HeFH and nonFH Exploratory Endpoint SC 150mg or Placebo
Slide 6: Dose Groups
Dose Groups a) HeFH +Atorva b) nonFH +Artorva c) nonFH Mono-Rx REGN727 Total # Pts HeFH Screening Dose Group Status LDL-C (mg/dL) 1 7 (6:2) HeFH >100 10-40 mg QD 50mg 2 10(8:2) Non-FH >100 10-40 mg QD 3 7 (6:2) HeFH >100 10-40 mg QD 100mg 4 10(8:2) Non-FH >100 10-40 mg QD 5 7 (6:2) HeFH >100 10-40 m
Slide 7: Inclusion Criteria
Inclusion Criteria — Men and women 18 - 65 yrs — HeFH by clinical diagnosis or non-FH » LDL-C > 100 mg/dL * Stable dose of atorvastatin (10-40 mg/day) + 50, 100, 150 mg dose levels — Non-FH with higher LDL-C » LDL-C > 130 mg/dL * Diet alone, no atorvastatin co-therapy + 150 mg dose level only ¢ Excl
Slide 8: Demographics
Demographics Non-FH Atorva Rx Placebo (N=6) | R727 (N=24) | Placebo(N=2) | R727 (N=8) Age 2 a 50 53 5 5 male 2% 20% orm es 100% 20% BM (kg) 28 28 24 24 ne 25 Concomitant ATORVASTATIN. ‘tora 10mg ° 20% 67% erm ° ° ‘torva 20mg 50% 21% 33% 29% ° ° ‘Atorva 40mg 50% Eo ° % ° ° Baseline Lipids Total chole
Slide 9: Demographics
Demographics Non-FH Diet alone R727 (n=24) | Placebo (n=2) | R727 (N=8) Age 29 at 20 53 6 a) emote 23% 20% 67% 54% 100% 20% BMI (kg) 28 28 24 24 ne 205 Concomitant ATORVASTATIN. ‘Atorva 10mg ° 20% 67% 67% ° ° ‘Atorva 20mg 50% 21% 33% 29% ° ° ‘Atorva 40mg 50% 53% ° % ° ° Baseline Lipids Total cholest
Slide 10: Demographics
Demographics Non-FH Atorva Rx Pracebo Ns) |_R727 N=28) | Placebo W=2) [_R7Z7(N8) ae 2 4 0 = 6 os Male = 0% 7m a 100% a i gin 258 7a wa 7a na 25 Concomitant ATORVASTATIN Atorva 10mg ° 20% orm or ° ° ‘tora m9 ES 2% ES 29% ° ° ‘tora dOme =a 5% o * ° ° Baseline Lipids Total cholesterol (mova) 189 200 12
Slide 11: Demographics
Demographics Ace 38 a 0 8 6 a ae ae ae ore ae 100% we mm 258 78 ea wa wae 7288 ‘Concomitant ATORVASTATIN Atora 10mg ° 20% om ome ° ° Aton 2m 0% ES ae 2% ° ° Aton dome ae me Q ° ° Baseline Lipids Total cholesterol (gl 188 200 126 108 28 251 LDL (mail 725 Ee eer 110 182 17 HOLE (moat) ® a u @ me mo Ti
Slide 12: Demographics
Demographics Ace 38 a 0 8 6 a ae ae ae ore ae 100% we mm 258 78 ea wa wae 7288 ‘Concomitant ATORVASTATIN Atora 10mg ° 20% om ome ° ° Aton 2m 0% ES ae 2% ° ° Aton dome ae me Q ° ° Baseline Lipids Total cholesterol (gl 188 200 126 108 28 251 LDL (mail 725 Ee eer 10 tee 7 HOLE (moat) ® a u @ se 0 Tiiye
Slide 13: Treatment Emergent AEs by Treatment Group
Treatment Emergent AEs by Treatment Group Placebo R27 HeFH & Non-FH Non-FH +Atorva (N=14),% —Atorva(N=15),% — Atorva (N=24),% Diet Only (N=8), % Serious TEAE ° ° ° ° DIC due to TEAE 0 0 ° ° ‘Any TEAE 41285) 71887) a7 (708) 6175.0) ‘Any teatmentrelated Tz) 1167) 3128) (600) TEAE TEAE by preferred ter
Slide 14: Treatment Emergent AEs by Treatment Group
Treatment Emergent AEs by Treatment Group R27 Non-FH Diet Only (N-8), % Serious TEAE ° ° ° ° DIC due to TEAE ° ° ° ° ‘Any TEAE 41288) 71887) 17 (70.8) 6 (75.0) ‘Any teatmentrelated 17) 1167) 3128) (600) TEAE TEAE by preferred term that oceurred in >1 patient/group Headache 0 0 é 2 ‘Nasopharyngitis °
Slide 15: Treatment Emergent AEs by Treatment Group
Treatment Emergent AEs by Treatment Group Placebo R727 HeFH & Non-FH Non-FH % Diet Only (N=8), % Serious TEAE ° ° ° ° DIC due to TEAE ° 0 ° ° ‘Any TEAE 4288) 71487) 17 (70.8) 6 (750) ‘Any weatmentrelated 17) 1167) 3125) 41600) TEAE TEAE by preferred term that occurred in >1 patientigroup Headache 0
Slide 16: Treatment Emergent AEs by Treatment Group
Treatment Emergent AEs by Treatment Group Placebo RZ HeFH & Non-FH Non-FH + Atorva (N=14), % Diet Only (N-8), % Serious TEAE ° ° ° ° DIC due to TEAE ° ° ° ° ‘Any TEAE 4288) 787) 708) 6750) ‘Any treatment-related 17) 1167) 3128) 4 (600) TEAE TEAE by preferred term that occurred in >1 patient/group He
Slide 17: Treatment Emergent AEs by Treatment Group
Treatment Emergent AEs by Treatment Group Placebo RIZ7 RIZT HeFH & Non-FH HeFH Non-FH 4 Atorva (N=14),% —Atorva(N=15),% — Atorva (N=24), % Serious TEAE ° o ° ° DIC due to TEAE ° ° ° o ‘Any TEAE 41286) 7187) 17708) 61750) ‘Any teatment-ralated 174) 1167) 31125) 4160.0) TEAE ‘TEAE by preferred term th
Slide 18: Treatment Emergent AEs by Treatment Group
Treatment Emergent AEs by Treatment Group Placebo R727 RIZ7 RIT HeFH & Non-FH HeFH Non-FH Non-FH + Atorva (N=14),% Atorva(N=15),% — Atorva(N=24),% Diet Only (N-8), % Serious TEAE ° ° ° ° DIC dus to TEAE 0 0 0 ° ‘Any TEAE 41286) 718.7) 17708) (750) ‘Any teatment-related 17) 1167) 31125) 4160.0) TEAE
Slide 19: LDL-C Dose Response
LDL-C Dose Response Atorvastatin Combo-Rx, heFH & Non-FH Combined Mean % Change from Baseline in Cale LDL (%) & Mean Percent Change from Baseline 50 70 t § 00 Ph -.se administered “P=Placedo — -#+50mg ——A100mg_— 150mg 12 SANOFI .> REGENERON
Slide 20: ApoB & LDL-C Response
ApoB & LDL-C Response Mean % Change from Baseline, Day 57 LDL-c Apo B 10 0 Ce 40 % 20 30 - * * 40 . z * 50 * x * 60 ot Placebo 50mg 100 mg 150 mg. Placebo 50mg 100 mg 150mg @FH GnonFH GnonFH, no Atorva * P<0,0001 vs. Placebo + P<0.01 vs. Placebo SANOFI \> REGENERON
Slide 21: Placebo 60mg 100mg 160mg Placebo 60mg 100mg 160mg
Placebo 60mg 100mg 160mg Placebo 60mg 100mg 160mg * P< 0,05. Placebo GHeFH [il non-FH SANOFI .> REGENERON
Slide 22: Triglycerides & Lp(a) Response
Triglycerides & Lp(a) Response Median % Change from Baseline, Day 57 TG Lp(a) 10 0 “10 % 20 -30 40 Placebo 60mg 100mg 60mg Placebo 60mg 100mg 160mg * P< 0.05 vs. Placebo [HeFH ll non-FH SANOFI \> REGENERON
Slide 23: Conclusions
Conclusions REGN727/SAR236553 was generally safe and well-tolerated No SAE No discontinuations for TEAE or any reason No apparent hepatotoxicity Numerically more TEAEs in REGN 727 treated vs placebo treated patients Lipid Changes LDL-C: 50-60% mean reduction from baseline on top of atorvastatin or a
Slide 24: Planned Phase II trials
¢ Phase II dose ranging trial in HeFH ¢ Phase II trial in primary hypercholesterolemia with high dose atorvastatin ¢ Phase II dose ranging trial in primary hypercholesterolmia Full details to be presented at future medical conference SANOFI REGENERON
Slide 25: SANOFI
2 SANOFI.)