Slide 1: Safety and Efficacy of Obicetrapib in Patients with Heterozygous Familial Hypercholesterolemia
Safety and Efficacy of Obicetrapib in Patients with Heterozygous Familial Hypercholesterolemia Stephen J. Nicholls, Adam J. Nelson, Marc Ditmarsch, John J.P. Kastelein, Christie M. Ballantyne, Kausik K. Ray, Ann Marie Navar, Steven E. Nissen, Anne C. Goldberg, Liam R. Brunham, Erin Wuerdeman, Annie
Slide 2: Disclosures
Disclosures • Research support: AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi- Regeneron and LipoScience • Consulting and honoraria: AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi
Slide 3: Background
Background • Heterozygous familial hypercholesterolemia (HeFH) is associated with an increased risk of premature CVD. • Many patients with HeFH fail to achieve LDL-C targets despite use of existing lipid lowering therapies. • Obicetrapib is a cholesteryl ester transfer protein (CETP) inhibitor which
Slide 4: Objective
Objective To evaluate the efficacy, safety and tolerability of obicetrapib, as an adjunct to maximally tolerated lipid-modifying therapies, in patients with HeFH and suboptimal LDL-C control.
Slide 5: Study Design
Study Design Main Inclusion Criteria Study Design: Randomized, double-blind, placebo-controlled • HeFH diagnosed by – Genetic confirmation • Patients (n=354) Obicetrapib 10mg (n=236) Safety FU – WHO criteria / Dutch Clinical Network • HeFH – Simon Broome criteria • ≥18 years • On maximally tolerated
Slide 6: Demographics
Demographics Placebo Obicetrapib Parameter (N=118) (N=236) Age (yrs) 56.6 57.0 Females (%) 55.1 53.0 White (%) 93.2 92.8 BMI (kg/m2) 29.6 29.3 Diabetes (%) 22.0 19.9 Statin use(%) 83.9 88.6 High intensity statin use (%) 67.8 78.8 Ezetimibe use (%) 50.0 53.8 PCSK9 inhibitor use (%) 22.6 14.0
Slide 7: Baseline Lipid Parameters
Baseline Lipid Parameters Placebo Obicetrapib Parameter (N=118) (N=236) LDL-C (mg/dL) 119.9 123.4 Non-HDL-C (mg/dL) 146.7 148.4 Apolipoprotein B (mg/dL) 105.3 107.2 HDL-C (mg/dL) 50.2 53.2 Triglycerides (mg/dL) 139.9 133.6 Lp(a) (nmol/L) 34.9 45.8
Slide 8: Percent Change in LDL-C with Obicetrapib
Percent Change in LDL-C with Obicetrapib Percent Change in LDL-C Placebo-adjusted Percent Change in LDL-C 10.3 4.0 5.9 4.8 Percent Change LDL-C LS Mean Change (%) 0.3 -32.3 -33.5 -31.1 -36.1 -39.6 -36.3 Placebo Obicetrapib -41.5 Both P<0.0001 from baseline Day Day
Slide 9: Individual Changes in LDL-C at Day 84
Individual Changes in LDL-C with Placebo and Obicetrapib at Day 84 Placebo Obicetrapib Mean Change from Baseline (%) Mean Change from Baseline (%) 3% achieved LDL-C lowering >50% 34% achieved LDL-C lowering >50%
Slide 10: Percent of Patients Achieving LDL-C Goals
Percent of Patients Achieving LDL-C Goals Placebo Obicetrapib Percent
Slide 11: Percent Change in non-HDL-C and ApoB
Percent Change in non-HDL-C and ApoB Placebo-adjusted Percent Placebo-adjusted Percent Change in non-HDL-C Change in ApoB LS Mean Change (%) LS Mean Change (%) -24.4 -34.5 -24.4 -25.8 -34.5 -37.5 -25.8 -37.5 Day Day
Slide 12: Percentage Change in HDL-C and Triglycerides
Percentage Change in HDL-C and Triglycerides Placebo-adjusted Percent Placebo-adjusted Percent Change in HDL-C Change in Triglycerides 138.7 121.4 LS Mean Change LDL-C LS Mean Change (%) -5.1 -11.7 Day Day
Slide 13: Percent Changes in LDL Particles and hsCRP
Percent Change in LDL Particles and hsCRP Placebo-adjusted Percent Change Placebo-adjusted Percent in LDL Particles at Day 180 Change in hsCRP Percent Change Percent Change -52.5 -8.8 -102.4 -16.8 LDL Particles Day
Slide 14: Percent Changes in Lp(a)
Percent Changes in Lp(a) Placebo-adjusted Percent Individual Percent Change in Lp(a) Changes in Lp(a) Placebo % Change Lp(a) % LS Mean Change 3% achieved >50% lowering Obicetrapib % Change Lp(a) -45.9 -45.9 -54.3 -54.3 Day 38% achieved >50% lowering
Slide 15: Safety and Tolerability
Safety and Tolerability Placebo Obicetrapib Parameter (N=118) (N=236) Treatment emergent adverse events (%) 70.3 63.7 Study drug related adverse events (%) 6.8 4.3 Mild (%) 4.2 2.1 Moderate (%) 2.5 2.1 Severe (%) 0 0 Adverse events leading to drug discontinuation (%) 6.8 4.3 Adverse events leading t
Slide 16: Events of Special Interest
Events of Special Interest Placebo Obicetrapib Parameter (N=118) (N=236) AST or ALT >3x ULN (%) 0 0 Bilirubin >2x ULN (%) 1.7 0 CK >5x ULN (%) 3.4 1.3 New diabetes or worsening glycemic control (%) 22.0 20.5 HbA1c increase >0.5% from baseline (%) 5.1 3.4 eGFR <30 or >25% decrease eGFR (%) 8.5 4.3 Ma
Slide 17: No Significant Change in Blood Pressure with Obicetrapib
No Significant Change in Blood Pressure with Obicetrapib Systolic BP Diastolic BP Change Systolic BP (mmHg) Change Systolic BP (mmHg) Placebo Placebo Obicetrapib Obicetrapib 0.3 0.1 0.3 -0.1 -0.5 -0.6 -0.4 -0.6 -0.2 -1.6 -1.3 -0.2 -0.7 -0.7 -0.7 -1.3 -1.2 -1.7 -1.4 -1.8 Day Day
Slide 18: Limitations
Limitations • The study evaluated the effect of obicetrapib for 365 days, the effect of longer treatment requires further evaluation. • The Lp(a) lowering was observed in a cohort who were not required to have elevated levels at study entry. • Additional studies will evaluate the impact of obicetrap
Slide 19: Summary
Summary • Obicetrapib reduced placebo-adjusted LDL-C 36.3% at day 84 and 41.5% at day 365 with >50% reductions observed in 34% of patients • Obicetrapib resulted in placebo-adjusted reductions in Lp(a) by 54.3%, independent of lowering atherogenic lipid parameters and raising HDL-C. • Obicetrapib wa