ALN-PCSsc, an RNAi Investigational Agent That Inhibits PCSK9 Synthesis With the Potential for Effective Bi-Annual Dosing: Interim Results Kevin Fitzgerald, PhD Co-authors: Amy Simon 1, Suellen White 1, Anna Borodovsky 1, Nirav Patel 1, Brian Bettencourt 1, Valerie Clausen 1, Jay Horton 3, Peter Wijngaard 2, Robert Kauffman 1, David Kallend 2 1 Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142 USA 2 The Medicines Company, 8 Sylvan Way, Parsippany, NJ 07054 USA 3 University of Texas South Western, 5323 Harry Hines Blvd, Dallas, TX 75390 USA Declaration of Interest: Employees of Alnylam Pharmaceuticals 1 Employees of The Medicines Company 2 1
RNAi Therapeutics A New Class of Innovative Medicines Harness natural pathway Catalytic mechanism Mediated by small interfering RNA or sirna Therapeutic gene silencing Any gene in genome Distinct mechanism of action vs. other drug classes Unique opportunities for innovative medicines Clinically validated platform Human POC in multiple programs Papers in NEJM and Lancet 2
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Coronary Heart Disease (%) Frequency (%) PCSK9 and ALN-PCSsc Program Unmet need in hypercholesterolemia Elevated LDL-C validated risk factor for CVD 34 million Americans have hypercholesterolemia (> 240 mg/dl) Recent clinical studies Many patients on statins do not meet LDL-C goal Lower LDL-C is better 30 20 10 0 30 20 10 0 WT PCSK9 LOF PCSK9 50 100 150 200 250 300 Multiple genetically defined patient subgroups Plasma LDL Cholesterol (mg/dl) PCSK9 is a genetically validated target 12 CHD Risk GOF mutations associated with hypercholesterolemia and premature CHD 8 LOF mutations associated with hypocholesterolemia and decreased CHD risk 4 0 WT LOF 4 Pearson et al., L-TAP Study, Arch Intern Med; 160:459-67 (2005), Blazing et al Am. Heart J; 168:205 (2014) Cohen et al., N. Engl. J. Med.; 354:1264-1272 (2006)
PCSK9 Therapeutic Hypothesis LDLR LDL Endosome Lysosomal degradation Anti-PCSK9 Mabs Transiently block PCSK9 binding To LDL receptor (LDLR) LDLR synthesis PCSK9 Synthesis Inhibitors Durably block PCSK9 synthesis and all intracellular and extracellular PCSK9 functions ALN-PCS PCSK9 synthesis PCSK9 mrna Nucleus PCSK9 5
% PCSK9 Knockdown (relative to pre-bleed) % LDL-C Lowering (relative to pre-bleed) Potent PCSK9 Knockdown and LDL-C Lowering Single Dose Data in NHP Highly durable PCSK9 knockdown and LDL-C reduction with single dose Single SC dose 1-10 mg/kg Up to 96% PCSK9 knockdown, up to 77% LDL-C lowering; absence of statins Highly durable effects, supports once-monthly or possibly once-quarterly dosing >5 LDL-C lowering maintained for over 3 months in 10 mg/kg group PCSK9 LDL-C -20 1.0 3.0 6.0 10.0-20 1.0 3.0 6.0 10.0 0 0 20 20 40 40 60 60 80 80 100 0 20 40 60 80 100 ALN-PCSsc Days (mg/kg) 100 0 20 40 60 80 100 120 ALN-PCSsc Days (mg/kg) 6 Fitzgerald, AHA, Nov 2014
ALN-PCSsc Phase 1 Study Healthy Subjects with LDL-C >100mg/dl, On or Off Statins Primary objectives Safety, tolerability Secondary objectives PK, PCSK9, and LDL-C reduction Part A: Single Dose (SAD) Randomized 3:1, Single blind, Placebo controlled 25 mg x 1 SC 100 mg x 1 SC 300 mg x 1 SC 500 mg x 1 SC 800 mg x 1 SC N=3 N=3 N=3 N=3 N=6 Baseline Mean PCSK9 276.3 (13.9) Mean LDL-C 157.6 (6.6) 7 Part B: Multi-dose (MD) Randomized 3:1, Single blind, Placebo controlled = dose 125mg qw x 4 SC 250mg q2w x 2 SC 300mg qm x 2 SC 500 mg qm x2 SC +/- Statin +/- Statin N=6 N=6 N=6/4 N=6/5 Baseline Mean PCSK9 347.9 (15.6) Mean LDL-C 139.4 (4.89)
Initial ALN-PCSsc Phase 1 Study Results Baseline Values for PCSK9 and LDL-C SAD phase Treatment (N) Placebo (6) 25mg (3) 100 mg (3) 300 mg (3) 500 mg (3) 800 mg (6) Overall (24) Mean (SEM) PCSK9 (ng/ml) 278.9 (40.6) 342.7 (39.2) 233.8 (22.6) 253.8 (12.9) 263.2 (14.4) 279.6 (27.3) 276.3 (13.9) Mean (SEM) LDL-C (mg/dl) 142.2 (11.4) 184.0 (27.0) 161.7 (16.1) 173.2 (29.5) 135.0 (3.3) 161.3 (10.3) 157.6 (6.6) MD phase Treatment (N) Placebo (12) 125 mg qwx4 (6) 250 mg q2wx2 (6) 300 mg qm x2 (6) 300 mg qm x2 S^ (4) 500 mg qm x2 (6) 500 mg qm x2 S^ (5) Overall (45) Mean (SEM) PCSK9 (ng/ml) 333.3 (29.0) 380.0 (20.7) 288.7 (21.9) 308.0 (25.6) 474.7 (86.7) 288.1 (28.2) 433.4 (48.0) 347.9 (16.0) Mean (SEM) LDL-C (mg/dl) 137.0 (11.1) 150.2 (7.6) 129.2 (10.2) 145.4 (12.9) 158.1 (15.6) 131.7 (20.2) 131.3 (11.2) 139.4 (4.9) 8 S ^ = On a stable statin dose Data in database as of 04 August 2015
Initial ALN-PCSsc Phase 1 Study Results SAD Cohort Demographics and Baseline Characteristics 24 SAD subjects dosed with ALN-PCSsc or placebo (3:1) Placebo N = 6 25 mg N=3 100 mg N=3 300 mg N=3 500 mg N=3 800 mg N=6 Total (excluding placebo) N = 18 Age (years), Mean (Min, Max) 47.5 (20, 59) 47.3 (31, 56) 48.0 (41, 53) 48.3 (34, 58) 39.3 (25, 53) 48.7 (37, 56) 46.7 (25,58) Gender: Male (%) 33.3% 10 10 10 10 83.3% 94.4% BMI (kg/m 2 ), Mean 25.0 27.6 25.7 26.8 23.4 25.8 25.8 Race (%) -Asian -Black African or African American -Caucasian -Other 33.3% 66.7% 33.3% 66.7% 10 33.3% 33.3% 33.3% 10 16.7% 5 33.3% 11.1% 11.1% 66.7% 11.1% 9 Data in database as of 04 August 2015
Initial ALN-PCSsc Phase 1 Study Results MD Cohort Demographics and Baseline Characteristics 45 MD subjects dosed with ALN-PCSsc or placebo (3:1) Placebo N=12 125mg qw x4 N = 6 250mg q2w x2 N=6 300 mg qm x2 N=6 300 mg qm x2 S^ N=4 500 mg qm x2 N=6 500 mg qm x2 S^ N=5 Total (excluding placebo) N = 33 Age (years), Mean (Min, Max) 53.3 (25,71) 54.7 (42,67) 60.5 (54,70) 47.3 (37,58) 51.8 (20,68) 42.2 (25,59) 56.4 (38,69) 52.0 (20,70) Gender: Male (%) 66.7% 66.7% 66.7% 10 50. 50. 40. 63.6% BMI (kg/m 2 ), Mean 26.6 26.2 27.1 25.4 27.2 23.0 25.6 25.6 Race (%) -Asian -Black African or African American -Caucasian -Other 91.7% 8.3% 16.7% 83.3% 16.7% 50. 33.3% 10 25. 75. 16.7% 83.3% 20. 20. 60. 12.1% 6.1% 75.8% 6.1% 10 S ^ = On a stable statin dose Data in database as of 04 August 2015
Initial ALN-PCSsc Phase 1 Study Results Safety Summary ALN-PCSsc generally well tolerated following single and multiple subcutaneous doses: No SAE s and no discontinuations due to AE s Most common AE s (>1 or more of ALN-PCSsc subjects) Single dose (N=18): cough, musculoskeletal pain, nasopharyngitis Multiple dose (N=33): headache, back pain, diarrhea, nausea All AE s mild or moderate in severity AE profile generally similar with or without concomitant statins At higher drug exposures, 4 subjects experienced mild, localized, injection site reactions One subject developed clinically significant changes in LFT s ALT ~4x ULN without rise in bilirubin Attributed to concomitant statin therapy; resolved on D/C of statin, recurred on statin rechallenge 11 Data reported are from database transfer Sept.24th 2015
Mean (+/- SEM) PCSK9 Knockdown Relative to Baseline Initial ALN-PCSsc Phase 1 Study Results SAD PCSK9 Knockdown Relative to Baseline -60 Treatment -40 Placebo 25 mg 100 mg 300 mg 500 mg 800 mg -20 0 20 40 60 80 100 0 1 2 3 4 5 6 Day/Treatment combinations where N=1 not displayed Months 12 Max PCSK9 knockdown of 88.7% with mean max of 82.3 ± 2. Data reported are from database transfer Sept.24th 2015
Mean (+/- SEM) PCSK9 Knockdown Relative to Baseline Initial ALN-PCSsc Phase 1 Study Results MD PCSK9 Knockdown Relative to Baseline -60-40 -20 Treatment Placebo 125 mg qwx4 250 mg q2wx2 300 mg qmx2 300 mg S ^ qmx2 500 mg qmx2 500 mg S ^ qmx2 0 20 40 60 80 13 100 0 1 2 3 4 5 6 7 qw, q2w, or qm Months S ^ =On stable dose of statin Two MD subjects excluded: One placebo subject elected to discontinue; One subject in 300 mg statin group was incarcerated on Day 14 Max PCSK9 knockdown of 94.4% with mean max of 88.5 ± 1.6% Data reported are from database transfer Sept.24th 2015
Mean (+/- SEM) LDL-C Reduction Relative to Baseline Initial ALN-PCSsc Phase 1 Study Results SAD LDL-C Lowering Relative to Baseline -20 Treatment Placebo 25 mg 100 mg 300 mg 500 mg 800 mg 0 20 40 60 80 0 1 2 3 4 5 6 Day/Treatment combinations where N=1 not displayed Months Max LDL-C reduction of 78.1% with mean max of 59.3 ± 5. 14 Data reported are from database transfer Sept.24th 2015
Mean (+/- SEM) LDL-C Reduction Relative to Baseline Initial ALN-PCSsc Phase 1 Study Results MD LDL-C Lowering Relative to Baseline -20 Treatment 0 Placebo 125 mg qwx4 250 mg q2wx2 300 mg qmx2 300 mg S ^ qmx2 500 mg qmx2 500 mg S ^ qmx2 20 40 60 80 15 0 1 2 3 Months 4 5 6 7 qw, q2w, or qm S ^ =On a stable dose of statins Two MD subjects excluded: One placebo subject elected to discontinue; One subject in 300 mg statin group was incarcerated on Day 14 Max LDL-C reduction of 83. with mean max of 64.4 ± 5.4% Data reported are from database transfer Sept.24th 2015
Initial ALN-PCSsc Phase 1 Study Results Least Square Mean %Change in LDL-C by Beta Quantification SAD LSM % change at group nadir (N) LSM % change day 84 (N) S = On stable dose of statin *, P < 0.05; **, P < 0.01; ***, P < 0.001 (pairwise comparisons vs. Placebo ) 16 LSMs and P values from baseline-adjusted ANCOVA model Placebo subjects completed prior to day 140 LSM % change day 140 (N) LSM % change day 180 (N) 300mg -50.0 (3) -50.0 (3) ** -43.1 (3) -47.0 (3) 500mg -59.0 (3) -50.5 (3) ** -38.8 (2) -36.3 (2) 800mg -52.8 (6) -43.3 (5) ** -49.3 (4) ongoing MD LSM % change at group nadir (N) LSM % change day 84 (N) Max LDL-C day 180; 53% LSM % change day 140 (N) LSM % Change day 208 (N) 300mg -59.5 (6) -59.5 (6) *** -50.8 (6) -44.4 (5) 300mg S -53.4 (3) -46.6 (3) * -39.2 (3) ongoing 500mg -53.5 (6) -51.9 (6) *** -53.8 (6) ongoing 500mg S -59.9 (4) -53.2 (5) *** -53.0 (3) ongoing Data reported are from database transfer Sept.24th 2015
Initial ALN-PCSsc Phase 1 Study Results Least Square Mean % Change of Other Lipid Parameters at Day 84 SAD Group (N) LP(a) Total Chol ApoB Non-HDL HDL-C Placebo (5) + 2.2-4.7-15.0-10.6 +12.7 25mg (2) + 2.2-16.8-16.5-23.5 + 8.0 100mg (3) -20.2-17.8-26.9-28.3 +18.6 300mg (3) -44.7-30.8** -47.3** -48.9*** +39.5 500mg (3) -34.7-26.1-39.2-36.3 + 6.9 800mg (6) -24.5-28.8** -37.5-37.0* + 0.6 Data reported are from database transfer Sept.24th 2015 Max. reductions: LP(a) (-77%); Total-C (-48%); ApoB (-72%); Non-HDL (-68%) *, P < 0.05; **, P < 0.01; ***, P < 0.001 (pairwise comparisons vs. Placebo) LSMs and P values from baseline-adjusted ANCOVA model 17
Initial ALN-PCSsc Phase 1 Study Results Least Square Mean % Change of Other Lipid Parameters at Day 84 MD Group (N) S = On stable dose of statin *, P < 0.05; **, P < 0.01; ***, P < 0.001 (pairwise comparisons vs. Placebo) LSMs and P values from baseline-adjusted ANCOVA models # Day 91 18 LP(a) Total Chol ApoB Non-HDL-C HDL-C Placebo (10) - 3.2-5.5-12.1-7.1-0.8 125mg qwx4 (6) # -22.7-23.6-33.3-36.8 +13.5 250mg q2wx4 (6) -27.1-34.5*** -46.4*** -45.3*** + 3.9 300mg (6) -21.3-40.4*** -52.5*** -56.9*** +11.2 300mg S (3) -26.6-25.9-36.8-36.7* + 9.1 500mg (6) -28.4-27.1** -46.4*** -45.3*** +13.2 500mg S (5) -39.5* -30.5*** -41.7** -46.4*** + 5.8 Max. reductions: LP(a) (-76%); Total-C (-55%); ApoB (-68%); Non-HDL (-73%) Data reported are from database transfer Sept.24th 2015
ORION-1 Phase 2 Clinical Study 480 ASCVD subjects with elevated LDL-C on maximal lipid lowering therapy Primary objectives LDL-C levels at day 180 Secondary objectives Safety and tolerability, PCSK9 and LDL-C reduction and duration of effect qq vs Bi-annual, proportion of patients reaching global lipid guidelines, changes in other lipoprotein levels Randomized 3:1, Double blind, Placebo controlled Placebo x 1 SC N=60 200 mg x 1 SC 300 mg x 1 SC 500 mg x 1 SC open label extension N=60 N=60 N=60 = dose Placebo qq x 2 SC N=60 100 mg qq x 2 SC N=60 open label extension 200 mg qq x 2 SC N=60 300 mg qq x 2 SC N=60 19
Summary ALN-PCSsc is promising first-in-class PCSK9 synthesis inhibitor Generally well tolerated in this study No SAE s and no discontinuations due to AE s All AEs mild or moderate in severity Similar LDL-C reduction to published data reported for anti-pcsk9 Mabs* in subjects with and without statin co-medication Substantial reductions in LP(a), total cholesterol, and non-hdl cholesterol, with no change in HDL Durability supports bi-annual, low volume SC dose regimen, to be confirmed in larger studies ALN-PCSsc advances in ORION Development Program Phase 2 ORION-1 study to begin Q4 2015 20 * Zhang XL., et al., BMC Med., 2015