The Medicines — Medicines — Technical Presentation (November 2016)
14 slides from The Medicines's technical presentation, Nov 15, 2016
Slide 1: Background and rationale
Background and rationale Inclisiran: Under investigation for LDL-C lowering ASCVD remains a challenge to global health1 LDL-C reduction is a proven strategy to prevent ASCVD2 Statins are the cornerstone of treatment but with limitations2 mAbs that block PCSK9 have demonstrated significant LDL-C lowe
Slide 2: PCSK9 synthesis inhibition via RNA interference
PCSK9 synthesis inhibition via RNA interference Inclisiran harnesses a natural catalytic process Synthetic double strand 21-23mer oligonucleotide RISC - RNA induced silencing complex 5’ 3’ RISC degrades PCSK9 mRNA catalytically to halt PCSK9 protein synthesis in the liver Chemically modified to prev
Slide 3: Patient population
Patient population High cardiovascular risk and elevated LDL-C Inclusion criteria Age >18 years With ASCVD - LDL-C >70 mg/dL High risk primary prevention LDL-C >100 TG <400 mg/dL eGFR >30 mL/min Maximally tolerated statin Stable lipid Rx for >30 days Exclusion criteria Significant comorbidity HbA1c
Slide 4: Study design and statistics
Study design and statistics Dose finding - placebo controlled Statistics Sample size of 480 patients allowed for 15% drop out rate >90% power to detect 30% LDL-C in at least 1 treatment group Pre-specified interim analysis plan Follow-up cut-off 25 Oct 2016 497 patients followed to 90 days 189 patie
Slide 5: Patient characteristics
Patient characteristics Baseline demographics well balanced Total=501 Inclisiran Placebo Pooled 100 mg 200 mg 300 mg 500 mg N=127 N=374 N=62 N=123 N=123 N=66 Age mean (years) 62 64 65 63 64 62 BMI (kg/m2) 30 29 29 29 29 28 White 117 (93%) 357 (93%) 57 (92%) 114 (93%) 114 (93%) 63 (95%) Male 75 (59%)
Slide 6: Safety of inclisiran: Treatment emergent adverse events
Safety of inclisiran to day 90 Treatment emergent adverse events (TEAE) Total=497 Inclisiran Day 1-90 Placebo Pooled 100 mg 200 mg 300 mg 500 mg N=127 N=370 N=61 N=122 N=122 N=65 Any TEAE 69 (54%) 198 (54%) 38 (62%) 64 (52%) 68 (56%) 28 (43%) Serious 5 (4%) 22 (6%) 8 (13%) 6 (5%) 6 (5%) 2 (3%) Sever
Slide 7: Safety of inclisiran: Liver and muscle TEAE
Safety of inclisiran to day 90 Liver and muscle TEAE1 Total=497 Inclisiran Day 1-90 Placebo Pooled 100 mg 200 mg 300 mg 500 mg N=127 N=370 N=61 N=122 N=122 N=65 ALT >3x ULN 0 1 (0.3%) 0 0 1 (0.8%) 0 AST >3x ULN 0 1 (0.3%) 0 0 1 (0.8%) 0 ALP >2x ULN 0 3 (0.8%) 1 (1.6%) 0 2 (1.6%)2 0 Bilirubin >2x ULN
Slide 8: Safety of inclisiran: First injection TEAE
Safety of inclisiran to day 90 First injection TEAE1,2 Total=497 Inclisiran Placebo Pooled 100 mg 200 mg 300 mg 500 mg AE terms N=127 N=370 N=61 N=122 N=122 N=65 Injection site erythema 0 4 (1.1%) 0 2 (1.6%) 1 (0.8%) 1 (1.5%) Injection site pruritus 0 1 (0.3%) 0 0 1 (0.8%) 0 Injection site rash 0 0
Slide 9: Efficacy of one dose of inclisiran
Efficacy of one dose of inclisiran up to day 90 Significant, durable PCSK9 and LDL-C lowering PCSK9 LDL-C p-value for all comparisons to placebo <0.0001 p-value for all comparisons to placebo <0.0001 -80 -60 -40 -20 0 0 30 60 90 Mean percent change ( ± 95% CI) Placebo (N=124) 100mg (N=59) 200mg (N=1
Slide 10: Efficacy of one dose: other lipid parameters
Efficacy of one dose of inclisiran up to day 90 Other lipid parameters - change from baseline Total=4941 Inclisiran Day 90 Placebo 100 mg 200 mg 300 mg 500 mg N=124 N=61 N=122 N=122 N=65 Total cholesterol mean (SD) -1% (16) -22% (12) -26% (14) -28% (15) -30% (11) Triglyceride median 3% 1% -11% -10%
Slide 11: Efficacy of 300 mg one and two doses versus placebo on LDL-C
One dose and two doses of inclisiran up to day 180 Efficacy of 300 mg versus placebo on LDL-C Days from first injection Available data as of 25 Oct 2016 - 80 - 60 - 40 - 20 0 0 30 60 90 120 150 180 Percentage change ( “ 95% CI) Placebo (N=22) 300mg (N=21) - 80 - 60 - 40 - 20 0 0 30 60 90 120 150 180
Slide 12: Individual patient response: absolute change in LDL-C
Individual patient response at day 180 Absolute change in LDL-C from baseline Change in LDL-C (mg/dL) Mean -3.1 Median 2 mg/dL Mean -64.9 Median -64 mg/dL Placebo Two doses (N=23) 300 mg Two doses (N=28) Available data as of 25 Oct 2016 32.5 - 91 - 125 - 75 - 25 25 - 26.5 - 122 - 125 - 75 - 25 25
Slide 13: Conclusions
Conclusions Inclisiran: Phase III-ready investigational compound Inclisiran inhibits PCSK9 synthesis by RNA interference and lowers LDL-C significantly One dose of 300 mg achieves mean 51% LDL-C reduction Two doses of 300 mg achieve mean 57% LDL-C reduction Inclisiran is well tolerated with no mater
Slide 14: Conclusions
Conclusions Inclisiran: Phase Ill-ready investigational compound + Inclisiran inhibits PCSK9 synthesis by RNA interference and lowers LDL-C significantly - One dose of 300 mg achieves mean 51% LDL-C reduction - Two doses of 300 mg achieve mean 57% LDL-C reduction + Inclisiran is well tolerated with