Efficacy, Safety and Tolerability of 150 mg Q2W Dose of the PCSK9 mab REGN727/SAR236553: Data from Three Phase 2 Studies

Size: px

Start display at page:

Download "Efficacy, Safety and Tolerability of 150 mg Q2W Dose of the PCSK9 mab REGN727/SAR236553: Data from Three Phase 2 Studies"

Helen Powers
5 years ago
Views:

1 Efficacy, Safety and Tolerability of 150 mg Q2W Dose of the PCSK9 mab REGN727/SAR236553: Data from Three Phase 2 Studies Michael J. Koren, 1 Evan A. Stein, 2 Eli M. Roth, 3 James M. McKenney, 4 Dan Gipe, 5 Corinne Hanotin, 6 Anne-Catherine Ferrand, 6 Richard Wu, 5 Robert Dufour 7 1 Jacksonville Center for Clinical Research, Jacksonville, FL, USA; 2 Metabolic and Atherosclerotic Research Center, Cincinnati, OH, USA; 3 Sterling Research Group, Cincinnati, OH, USA; 4 Virginia Commonwealth University and National Clinical Research, Inc., Richmond, VA, USA; 5 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 6 Sanofi, Paris, France; 7 Institut de Recherches Cliniques de Montréal, Montreal, Canada. 1

2 Industry Relationships and Institutional Affiliations 2 Michael J. Koren Author Disclosure Eli M. Roth James M. McKenney Evan A. Stein Dan Gipe Richard Wu Corinne Hanotin Anne-Catherine Ferrand Robert Dufour Employee of a research company that received research funding from Regeneron and/or Sanofi. Received consulting fees from Amgen, Adnexus Therapeutics, and Sanofi related to PCSK9 inhibitors. Employee of a research company that received research funding directly related to PCSK9 clinical trials and/or laboratory analysis from Alnylam, Amgen, BMS, Genentech, Sanofi, and Regeneron. Employee of Regeneron Employee of Sanofi Has received consultancy fees from Sanofi.

3 Background and Rationale Proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease plays a pivotal role in LDL receptor (LDLR) degradation. Human gain-of-function PCSK9 mutations result in hypercholesterolemia; loss-of-function mutations lead to low LDL-cholesterol (LDL-C) and reduced coronary heart disease risk. REGN727/SAR is a highly specific, fully human monoclonal antibody (mab) to PCSK9 currently in evaluation for the treatment of hypercholesterolemia. 3

4 Summary of Dosing REGN727/SAR Program (Phases 1 & 2) Placebo Phase 1 Single-Dose Studies 902 Placebo 0.3 mg/kg 1.0 mg/kg 3.0 mg/kg 6.0 mg/kg 12.0 mg/kg 904 Placebo 50 mg 100 mg 150 mg 250 mg Multiple-Dose 1001 Placebo 50 mg 100 mg 150 mg Phase 2 Q4W Dosing Q2W Dosing 150 mg 200 mg 300 mg 50 mg 100 mg 150 mg 1003 X X X X X X X X X X X X* X* 4 *Placebo and one REGN727/SAR treatment arm included up-titration of atorvastatin 10 mg to atorvastatin 80 mg.

5 Free/Total PCSK9 Conc. (ng/ml) Total REGN727 (ng/ml) X 0.01 LDL--C mean % change REGN727/SAR236553: Dynamic Relationship Between mab, PCSK9, and LDL-C Levels Free PCSK9, Total REGN727/SAR Concentration and Mean % Change LDL-C vs Time Time (hours) Total REGN727/SAR free PCSK9 LDL-c 904: NCT

6 REGN727/SAR Reduced LDL-C Up to 58% in Proof-of-Concept Proof-of-concept trial* in familial and nonfamilial hypercholesterolemia: 36% to 58% dosedependent reduction LDL-C with or without atorvastatin, respectively No serious AEs Small number of mild injection-site reactions with SC administration Headache most common TEAE % LDL-C * * * * Placebo 50 mg 100 mg 150 mg FH non-fh non-fh, monotherapy *P< vs Placebo. P <0.01 vs Placebo. 1001: NCT * * 6 *Stein EA, Mellis S, Yancopoulos GD, et al. N Eng J Med. 2012;366:

7 Summary of Dosing REGN727/SAR Program (Phases 1 & 2) Placebo Phase 1 Single Dose Studies 902 Placebo 0.3 mg/kg 1.0 mg/kg 3.0 mg/kg 6.0 mg/kg 12.0 mg/kg 904 Placebo 50 mg 100 mg 150 mg 250 mg Multiple Dose 1001 Placebo 50 mg 100 mg 150 mg Phase 2 Q4W Dosing Q2W Dosing 150 mg 200 mg 300 mg 50 mg 100 mg 150 mg 1003 X X X X X X X X X X X X* X* 7 *Placebo and one REGN727/SAR treatment arm included up-titration of atorvastatin 10 mg to atorvastatin 80 mg.

8 Pooling Cohorts & Rationale for Data Analyses Efficacy Population N=352 Primary hypercholesterolemia (FH or non-fh) and LDL-C 100 mg/dl on background lipid-lowering therapies including a statin 12-week LDL-C endpoints PBO + statins 150 mg Q2W + statins 8-week LDL-C endpoint with atorva 80 mg PBO + A10 A mg Q2W + A10 A mg Q2W + A10 Safety Population N=77 Placebo (N=31) (N=31) 1003 (N=15) N= mg Q2W (N=31) (N=61) 1003 (N=16) mg Q2W dose common to all 3 studies

9 Pooled Demographics and Patient Characteristics at Baseline (Randomized Population) Characteristic Placebo (n=77) 150 mg Q2W (n=108) Age (mean yrs [SD]) 53.8 [9.4] 58.2 [10.1] Sex (Male) 49.4% 43.5% Race (%) White Black or African American Asian Other Ethnicity Hispanic or Latino 84.4% 88.9% 13.0% 11.1% 1.3% 0% 1.3% 0% 28.6% 22.2% BMI (mean kg/m 2 [SD]) 28.9 [4.7] 29.2 [4.6] 9

10 Pooled Lipid Parameters at Baseline (Randomized Population) Lipid Parameter Mean, mg/dl (mmol/l) Placebo (n=77) 150 mg Q2W (n=108) LDL-C (3.4) (3.3) TC (5.4) (5.4) HDL-C 51.8 (1.3) 53.8 (1.4) Non HDL-C (4.1) (4.0) TGs* (1.4) (1.4) Lp(a)* 19.0 (0.7 mol/l ) 28.0 (1.0 mol/l ) Apo B (1.1 g/l) (1.1 g/l) Apo A (1.5 g/l) (1.6 g/l) 10 LDL-C = low-density lipoprotein-cholesterol; HDL-C = high-density lipoprotein-cholesterol; TC = total cholesterol; TG = triglyceride; Apo B = apolipoprotein B; Apo A1 = apolipoprotein A1; Lp (a) = lipoprotein (a); *median.

11 LS Mean % Change in LDL-C Level at Week 8/12 LOCF Results: Mean % Change in LDL-C at Week 8/12 LOCF in Patients Treated with REGN727/SAR mg Q2W Placebo N= mg Q2W N= mg Q2W + A 10 mg N= mg Q2W + A 80 mg N=30 Placebo + A 80 mg N= , , * -66,2-73.2* *P< vs Placebo/Placebo + A80 mg 11

12 % Patients Achieving Prespecified LDL-C Level at Week 8/12 LOCF Results: Attainment of Prespecified LDL-C Levels at Week 8/12 LOCF 120 LDL-C<2.5 mmol/l (100 mg/dl) LDL-C<1.8 mmol/l (70 mg/dl) , ,3 96, , ,2 17, / /

LS Mean % Change in Lipid Fraction at Week 8/12 LOCF Mean % Reductions in Other Apo B-Containing Lipoprotein Fractions at Week 8/12 LOCF 5 11565/1003 11566 11565/1003 11566 11565/1003 11566

13 LS Mean % Change in Lipid Fraction at Week 8/12 LOCF Mean % Reductions in Other Apo B-Containing Lipoprotein Fractions at Week 8/12 LOCF / / / / ,8-0,3-4,7 0-2, ,9-10,3-15, ,6 * -34, ,4 * -40,1-44,6 ** ,4 * ,3 ** TC Apo B non HDL-C Lp(a) Pooled Placebo Pooled REGN727/SAR mg Q2W #REF! #REF! REGN727/SAR mg Q2W + A 80mg -60,3 * -55,6-64,3 ** 13 * P< vs pooled placebo; **P<0.001 vs placebo + A 80 mg; P= vs placebo + A 80 mg; Percent change from baseline median data are reported

14 % Patients Achieving Non HDL-C and Apo B Guideline Levels at Week 8/12 LOCF Attainment of Non HDL-C and Apo B Guideline Levels at Week 8/12 LOCF 120 non HDL-C<3.3 mmol/l (130mg/dL) non HDL-C<2.6 mmol/l (100 mg/dl) apo B<80 mg/dl , ,3 93,1 93,3 93, , , ,7 27,6 10,9 34, / / /

15 LS Mean % Change in Lipid Fraction at Week 8/12 LOCF Mean % Reductions in Other Lipoprotein Fractions at Week 8/12 LOCF / /1003 8, /1003 a 5,2 5, ,3 1,4 0, ,6-1,8-2,3-5, ,2 * -20,6-11,9 ** *P= vs pooled placebo. ** P<0.05 vs placebo + A 80 mg. P=0.004 vs pooled placebo. P= vs placebo + A 80 mg. a P=0.005 vs pooled placebo. b Percent change from baseline median data are reported. -25 b TGs HDL-C Apo A1 15

16 LDL-C Mean (+/- 95% CI) % Change from Baseline to Week 12 vs. Placebo Results: Background Lipid-Lowering Therapies Do Not Alter % LDL-C Lowering with REGN727/SAR REGN727/SAR mg Q2W Atorvastatin 10 mg (N=11) Atorvastatin 20 mg (N=10) Atorvastatin 40 mg (N=40) Atorvastatin 10 mg (N=29) Rosuvastatin ezetimibe (N=9) All other statins ezetimibe (N=7) All statins + ezetimibe 10 mg (N=11) 16 LS mean (±95% CI) percentage change in calculated LDL-C from baseline to week 12 in the modified intent-to-treat (MITT) population, by treatment group and stratified atorvastatin dose. Week 12 estimation using LOCF method.

17 Pooling Cohorts & Rationale for Data Analyses N=352 Primary hypercholesterolemia (FH or non-fh) and LDL-C 100 mg/dl on background lipid-lowering therapies including a statin Efficacy Population 12-week LDL-C endpoints PBO + statins 150 mg Q2W + statins 8-week LDL-C endpoint with atorva 80 mg PBO + A10 A mg Q2W + A10 A mg Q2W + A10 Safety Population N=77 Placebo (N=31) (N=31) 1003 (N=15) N= mg Q2W (N=31) (N=61) 1003 (N=16) mg Q2W dose common to all 3 studies

18 Pooled TEAEs Safety population Placebo (n=77) Overview of All TEAEs: Number (%) of Patients 150 mg Q2W (n=108) Any TEAE 42 (54.5) 63 (58.3) Any treatment-emergent SAE 2 (2.6) 1 (0.9) Any TEAE leading to death 0 0 Any TEAE or treatment-emergent SAE leading to permanent treatment d/c 4 (5.2) 2 (1.9) Parameters of Special Interest : Number (%) of Patients ALT >3X ULN 0 0 AST > 3X ULN 0 1 (0.9) Alk Phos > 1.5X ULN 0 2 (1.9) Total Bili >1.5X ULN 0 2 (1.9) CK >3X ULN 3 (3.9) 2 (1.9) 18 Data in placebo arm also includes N=31 with up-titration of atorvastatin 10 mg to atorvastatin 80 mg. TEAE: Treatment emergent adverse event, SAE: Serious adverse event.

19 Pooled TEAEs, continued Safety population Placebo (n=77) 150 mg Q2W (n=108) Any class, n (%) 42 (54.5) 63 (58.3) Infections and infestations, n (%) 11 (14.3) 13 (12.0) Nervous system disorders, n (%) 6 (7.8) 12 (11.1) Vascular disorders, n (%) 2 (2.6) 4 (3.7) Respiratory disorders, n (%) 3 (3.9) 7 (6.5) Gastrointestinal disorders, n (%) 12 (15.6) 13 (12.0) Skin disorders, n (%) 0 7 (6.5) Musculoskeletal disorders, n (%) 13 (16.9) 13 (12.0) Renal disorders, n (%) 0 1 (0.9) Injection-site reactions, n (%) 4 (5.2) 12 (11.1) 19 Data in placebo arm also includes N=31 with up-titration of atorvastatin 10 mg to atorvastatin 80 mg. TEAE: Treatment emergent adverse event, SAE: Serious adverse event.

20 Conclusions In phase 2 studies, use of 150 mg Q2W of REGN727/SAR236553, a fully human monoclonal antibody against PCSK9, resulted in Robust in LDL-C and other apo B-containing lipid parameters High attainment rate of clinical goals for LDL-C, non HDL-C, and apo B Modest in HDL-C, along with in TGs and Lp(a) Consistent effects with various background doses of statins, ezetimibe Overall, REGN727/SAR phase 2 treated patients (N=274) The most common TEAE was mild injection-site reaction No persistent/prevalent liver or skeletal muscle safety signals Seven SAEs: 4 treatment-related, 2 placebo, 1 non-treatment-related Further evaluation of REGN727/SAR in larger, more diverse patient populations underway in a phase 3 program 20

Overview of ODYSSEY Phase 3 clinical trial program 11 Global Phase 3 trials Including 22,942 patients across more than 2000 study centers HeFH population HC at high CV risk population Additional

21 Overview of ODYSSEY Phase 3 clinical trial program 11 Global Phase 3 trials Including 22,942 patients across more than 2000 study centers HeFH population HC at high CV risk population Additional populations/studies Add-on to max tolerated statin (± other LMT) Add-on to max tolerated statin (±other LMT) ODYSSEY FH I (EFC12492) N=471 LDL-C 70 mg/dl OR LDL-C 100mg/dL 18 months ODYSSEY COMBO I (EFC11568) N=306 LDL-C 70 mg/dl OR LDL-C 100 mg/dl 12 months ODYSSEY MONO (EFC11716) N=100 Patients on no background LLTs LDL-C 100 mg/dl 6 months ODYSSEY FH II (CL1112) N=250 LDL-C 70 mg/dl OR LDL-C 100mg/dL 18 months ODYSSEY COMBO II (EFC11569) N=660 LDL-C 70 mg/dl 24 months ODYSSEY ALTERNATIVE (CL1119) N=250 Patients with defined statin intolerance LDL-C 70 mg/dl OR LDL-C 100 mg/dl 6 months ODYSSEY HIGH FH (EFC12732) N=105 LDL-C 160 mg/dl 18 months ODYSSEY LONG TERM (LTS11717) N=2,100 LDL-C 100 mg/dl 18 months ODYSSEY OUTCOMES (EFC11570) N=18,000 LDL-C 70 mg/dl ODYSSEY OPTIONS I (CL1110) N=350 Patients not at goal on moderate dose atorvastatin LDL-C 70 mg/dl OR LDL-C 100 mg/dl 6 months ODYSSEY OPTIONS II (CL1118) N=300 Patients not at goal on moderate dose rosuvastatin LDL-C 70 mg/dl OR LDL-C 100 mg/dl 6 months

23 LDL-C Mean ( SE) % Change from Baseline Change in Calculated LDL-C at 2-Week Intervals from Baseline to Week BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK % % % % Placebo SAR mg Q2W SAR mg Q2W SAR mg Q4W SAR mg Q4W SAR mg Q2W % % Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12 in the modified intent-to-treat (mitt) population, by treatment group. Week 12 estimation using LOCF method. 23 McKenney JM, Koren MJ, Kereiakes DJ, et al. JACC. 2012;59(25): : NCT

24 Safety Summary from Phase 2 Studies Safety population Placebo (n=31) All Treatment Groups (n=151) Placebo + Atorvastatin 80 mg (n=31) All Treatment Groups (n=61) Placebo (n=15) All Treatment Groups (n=62) Overview of All TEAEs: Number (%) of Patients Any TEAE 14 (45.2) 91 (60.3) 19 (61.3) 32 (52.5) 9 (60.0) 50 (80.6) Any treatment-emergent SAE 1 (3.2) 3 (2.0) 0 1 (1.6) 1 (6.7) 0 Any TEAE leading to death Any TEAE or treatment-emergent SAE leading to permanent treatment d/c 0 6 (4.0) 4 (12.9) 1 (1.6) 0 1 (1.6) Most common TEAE was mild injection-site reactions No persistent or prevalent liver or skeletal muscle safety signals noted 5 SAEs in 4 patients in active treatment arms;1 patient had 2 SAEs (leukocytoclastic vasculitis, subsequent humerus fracture) 24 TEAE: Treatment emergent adverse event, SAE: Serious adverse event.

Alirocumab Treatment Effect Did Not Differ Between Patients With and Without Low HDL-C or High Triglyceride Levels in Phase 3 trials

Alirocumab Treatment Effect Did Not Differ Between Patients With and Without Low HDL-C or High Triglyceride Levels in Phase 3 trials G. Kees Hovingh, 1 Richard Ceska, 2 Michael Louie, 3 Pascal Minini,