Slide 1: New Insights on CETP Inhibition from Genetic Research and Clinical Trials
Exhibit 99.1 New Insights on CETP Inhibition from Genetic Research and Clinical Trials John J.P. Kastelein, MD PhD FESC Emeritus Professor of Medicine Department of Vascular Medicine Academic Medical Center (AMC) of the University of Amsterdam 1
Slide 2: Disclosures
Disclosures • Dr Kastelein reports consultancies with 89Bio, CiVi Biotech, CSL-Behring, Draupnir Bio, Menarini Ricerce, Madrigal, North Sea Therapeutics, Novartis, Silence Therapeutics, CinCor, Scribe Therapeutics • Dr Kastelein is acting Chief Medical Officer (CMO) of Staten Biotech and Chief Scie
Slide 3: Genomic Validation of LDL-C Reduction and CETP Inhibition for CVD Reduction
Genomic Validation of LDL-C Reduction and CETP Inhibition for CVD Reduction 3
Slide 4: CETP loss of function, The Ashkenazi Jewish Longevity Gene Project
CETP loss of function, The Ashkenazi Jewish Longevity Gene Project 4
Slide 5: The CETP gene variant is associated with exceptional longevity and healthy aging phenotype
The CETP gene variant is associated with exceptional longevity and healthy aging phenotype CETP I405V genotype and lipoprotein characteristic and plasma CETP levels in families with exceptional longevity vs control P value Variable CETP I405V Genotype VV CETP I405V Genotype IV CETP I405V Genotype II
Slide 6: CETP is a genomically-validated target associated with lower cardiovascular risks
CETP is a genomically-validated target associated with lower cardiovascular risks The Copenhagen City Heart study demonstrated the link between CETP inactivating mutations and lower cardiovascular risk The Copenhagen City Heart Study • Prospective study in 10,261 individuals • Up to 34 years follow-
Slide 7: Association of CETP score with risk of Major Cardiovascular Events
Association of CETP score with risk of Major Cardiovascular Events Mendelian randomization analyses suggest that the causal effect of CETP inhibition on the risk of cardiovascular events appears to be determined by changes in the concentration of apoB-containing lipoproteins rather than changes in H
Slide 8: More potent CETP inhibitors are more efficacious for ASCVD risk reduction
More potent CETP inhibitors are more efficacious for ASCVD risk reduction Odds Ratio Ference, BA., et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. Jama 318.10 (2017): 947-956. 8
Slide 9: Is there evidence for an additive effect between CETP inhibition and other mechanisms?
Is there evidence for an additive effect between CETP inhibition and other mechanisms?
Slide 10: Joint inhibition of CETP and PCSK9 has additive effects on lowering LDL-C, ApoB and CAD risk
Joint inhibition of CETP and PCSK9 has additive effects on lowering LCL-C, ApoB and a lower risk of CAD LDL-C ApoB Mendelian randomization study to explore the associations of combined reduction of CETP and PCSK9 Cupido, AJ et al., Joint Genetic Inhibition of PCSK9 and CETP and the Association With
Slide 11: Novel Mendelian Randomization Data
Novel Mendelian Randomization Data
Slide 12: Genetic study design: Mendelian Randomization
Genetic study design: Mendelian Randomization • Selected genetic instruments within and around CETP (the gene) • Instruments weight using: CETP concentration or Apo-A1 • Inference of the study: CETP activity • Results presented as: lower CETP concentration, higher Apo-A1 and lower ApoB-100 concentra
Slide 13: Cardiovascular Outcomes
Cardiovascular Outcomes Data on file 13
Slide 14: Dementia Related Outcomes
Dementia Related Outcomes Data on file 14
Slide 15: New Insights on CETP Inhibition from Clinical Trials
New Insights on CETP Inhibition from Clinical Trials 15
Slide 16: Torcetrapib was a one off
Torcetrapib was a one off 16
Slide 17: Dalcetrapib did not move the needle on LDL-C
Dalcetrapib did not move the needle on LDL-C 17
Slide 18: Evacetrapib's CVOT was underpowered and too short
Evacetrapib 's CVOT was underpowered and too short 18
Slide 19: Anacetrapib: REVEAL study results were initially misinterpreted
Anacetrapib: REVEAL study results were initially misinterpreted based on the reported 41% LDL-C Reduction versus the actual 17% reduction ➢ At 4.1 years, two important learnings: Learning 1: Predictable MACE benefit Learning 2: Baseline levels were too low • 9% drop in MACE is exactly predicted by t
Slide 20: HDL-C increase is not linked to any efficacy or safety parameter in the REVEAL trial
HDL-C increase is not linked to any efficacy or safety parameter in the REVEAL trial Association between increased therapeutically achieved plasma Brian Ference (U Cambridge) specifically HDL-C in response to treatment with CETPi and the risk of all- investigated the increase in HDL-C in REVEAL, cau
Slide 21: Conclusions
Conclusions • There is overwhelming genomic evidence that demonstrate reduced cardiovascular risk in individuals with naturally lower CETP activity • The cardiovascular benefit of lower CETP activity is linked to lower LDL-C / ApoB, not higher HDL-C, and seems to be independent and additive to other