The Medicines — Medicines — Technical Presentation (March 2017)
17 slides from The Medicines's technical presentation, Mar 17, 2017
Slide 1: Background: Major progress is being made in ASCVD
Background Major progress is being made in ASCVD PCSK9 inhibition is now a validated target for reducing LDL-C and ASCVD1 PCSK9 mAb therapy requires 12-26 injections per year statins2 Adherence data with PCSK9 mAbs show no substantial improvement over Poor adherence and LDL-C variability are associa
Slide 2: Rationale and objective: Inclisiran, a novel agent to address unmet needs
Rationale and objective Inclisiran: a novel agent to address unmet needs Harnessing RNAi offers an alternative treatment for PCSK9 and LDL-C1 Inclisiran, a synthetic siRNA molecule, inhibits PCSK9 synthesis in the liver2 In Phase I, 300 mg inclisiran lowered LDL-C 50-60% for 84 days (n=69)3 • • Obje
Slide 3: Methods: Trial design
Methods Trial design N=61 Day 360 Extended follow-up Day 360 Extended follow-up 4 Screening (Day -14 to Day -1) Randomization (Day 1, n=501) One dose starting regimen Randomized (n=501) Two dose starting regimen Placebo N=65 200 mg N=60 300 mg N=61 500 mg N=65 Treated (n=497) Placebo N=62 100 mg N=6
Slide 4: Patients: High-risk CV patients, balanced by randomization
Patients High-risk CV patients, balanced by randomization One dose starting regimen Two dose starting regimen Placebo N=65 Inclisiran N=186 Placebo N=62 Inclisiran N=184 Age 62 63 63 64 Mean years Prior ASCVD 69.2 67.9 74.2 68.3 % LDL-C 128.5 125.9 125.2 133.0 Mean mg/dL Apo-B 102.4 103.2 104.6 107.
Slide 5: Safety: Adverse events similar to placebo
Safety No safety concerns: Adverse events similar to placebo Safety population One dose starting regimen Two dose starting regimen Placebo N=65 Inclisiran N=186 Placebo N=62 Inclisiran N=184 n (%) n (%) n (%) n (%) Any TEAE 46 (70.8) 140 (75.3) 50 (80.6) 142 (77.2) Severe 2 (3.1) 11 (5.9) 7 (11.3) 1
Slide 6: Safety: Liver and muscle enzymes
Safety No safety concerns: Liver and muscle enzymes No LFT elevations related to drug • Transient transaminase increases - no differences between randomized - 0.8% placebo - 0.8% inclisiran groups No difference in incidence of myalgias or CPK enzyme elevation • One clinically relevant case of myonec
Slide 7: Safety: Other relevant parameters
Safety No safety concerns: Other relevant parameters No No No No thrombocytopenia neuropathy immunogenicity (no anti-drug antibodies) pro-inflammatory symptoms or elevated markers 8
Slide 8: Clamped PCSK9 knockdown: one dose starting regimen
Efficacy: One dose starting regimen Clamped PCSK9 knockdown End of study if LDL-C back to baseline 20 Placebo 0 200 mg -20 300 mg -40 500 mg -60 -80 0 30 60 90 120 150 180 210 240 270 Days from first injection 9 Mean percent change (±95% CI) P-value for all comparisons to placebo <0.0001
Slide 9: Clamped PCSK9 knockdown: two dose starting regimen
Efficacy: Two dose starting regimen Clamped PCSK9 knockdown End of study if LDL-C back to baseline 20 Placebo 0 100 mg -20 200 mg -40 300 mg -60 -80 0 30 60 90 120 150 180 210 240 270 Days from first injection 10 Mean percent change (±95% CI) P-value for all comparisons to placebo <0.0001
Slide 10: Robust, sustained LDL-C reductions: 300 mg optimal
Efficacy: One dose starting regimen Robust, sustained LDL-C reductions – 300 mg optimal 300 mg 300 mg 9 months time adjusted 50.9% reduction 38.4% reduction mean 41% reduction 10 0 -10 -20 -30 -40 -50 -60 Placebo 200 mg 300 mg 500 mg 0 30 60 90 120 150 180 210 240 270 Days from first injection 11 Me
Slide 11: Robust, sustained LDL-C reductions: optimal start regimen 300 mg x2
Efficacy: Two dose starting regimen Robust, sustained LDL-C reductions – optimal start regimen 300 mg x2 9 months time adjusted 55.5% 52.6% mean 50% reduction 10 0 -10 -20 -30 -40 -50 -60 Placebo 100 mg 200 mg 300 mg 0 30 60 90 120 150 180 210 240 270 Days from first injection 12 Mean percent change
Slide 12: Individual patient responses (%) at day 60
Efficacy: Two dose starting regimen Individual patient responses (%) at day 180 Placebo Inclisiran 300 mg 60 rcent reduction Percent reduction 40 20 0 -20 -40 Mean 52.6% -60 -80 Max 80.9% -100 13 Change in LDL-C (percent) Pe All patients responded
Slide 13: Individual patient responses (mg/dL) at day 60
Efficacy: Two dose starting regimen Individual patient responses (mg/dL) at day 180 Placebo Inclisiran 300 mg 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 ute reduction Absolute reduction Mean -64.2 mg/dL Max -122.0 mg/dL 14 Change in LDL-C (mg/dL) Absol 39 mg/dL (1mMol/L) 78 mg/dL (2mMol/L) All patien
Slide 14: Conclusions
Conclusions Two 300 mg starting dose regimen for inclisiran selected No safety concerns Optimal dosage 300 mg given twice as starting regimen then Q6 monthly • • All patients responded with significant LDL-C lowering At 6 months, mean LDL-C of 52.6% (64 mg/dL), and up to 81% (122 mg/dL) Unique attri
Slide 15: Implications: Inclisiran will move into phase III trials
Implications Inclisiran will move into phase III trials In an ORION-1-like population, inclisiran 300 mg delivers sustained LDL-C lowering of 60-65 mg/dL In a CVOT, this is likely to confer substantial reductions in MACE ORION-4 will study CV outcomes with inclisiran in high risk primary secondary p
Slide 16: Online publication: New England Journal of Medicine, 17th March 2017
Online publication New England Journal of Medicine, 17th March 2017 T he NEW ENGLAND JOURNAL of MEDICINE II o_R_I_GI_N_A_L_A_R_TI_c_LE Inclisiran in Patients at High Cardiovascular Risl< with Elevated LDL Cholesterol Kausik K. Ray, M.D., Ulf Landmesser, M.D., Lawrence A. Leiter, M.D., David Kallend,
Slide 17: Online publication: New England Journal of Medicine
Online publication e New England Journal of Medicine, 17% March 2017 the NEW ENGLAND JOURNAL of MEDICINE | ORIGINAL ARTICLE | Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol Kausik K. Ray, M.D., Ulf Landmesser, M.D., Lawrence A. Leiter, M.D., David Kallend, M.D., Rob