Targeting PCSK9 in Clinical Practice Guidance and Future JOHN J.P. - PowerPoint PPT Presentation

Targeting PCSK9 in Clinical Practice Guidance and Future JOHN J.P. KASTELEIN PROFESSOR OF MEDICINE UNIVERSITY OF AMSTERDAM THE NETHERLANDS

Faculty Disclosure Declaration of financial interests For the last 3 years and the subsequent 12 months: I I have received a research grant(s)/ in kind support A From current sponsor(s) YES NO B From any institution YES NO II I have been a speaker or participant in accredited CME/CPD A From current sponsor(s) YES NO B From any institution YES NO III I have been a consultant/strategic advisor etc A For current sponsor(s) YES NO B For any institution YES NO IV I am a holder of (a) patent/shares/stock ownerships A Related to presentation YES NO B Not related to presentation YES NO

Faculty Disclosure Declaration of non-financial interests: • Professor of Medicine • Academic Medical Center, University of Amsterdam, The Netherlands • Consultancy for Affiris, Amgen, Akcea, CiVi Biopharma, Corvidia, CSL Behring, Esperion, Dezima, Gemphire, Ionis, North Sea Therapeutics, Regeneron, Staten Biotech

ASCVD remains the #1 global cause of death ● …Should ASCVD prevention be a public health priority? Top 10 global causes of death, WHO 2018 The cost of ASCVD British Heart Foundation

Complacency Risk factor Population ● …Does the world really need new LDL -C- attributable risk (%) lowering drugs? LDL-C/apoB 49.2 – Efficacy : 15% of ASCVD patients have LDL-C >70 Smoking 35.7 mg/dL despite perfect therapy – Side effects / adherence : in reality, only 4% of Psychosocial 32.5 ASCVD patients receive perfect therapy; 31% Abdominal 20.1 obesity receive HI-statins Hypertension 17.9 – Costs : PCSK9 inhibitors would theoretically Diet 13.7 enable >99% to achieve LDL-C <70 mg/dL Yusuf, Lancet 2004; Steen, BMJ Open 2017; Cannon, JAMA Cardiol 2016

Cumulative LDL-C exposure ● Lifetime exposure matters ● The lower, the better; The younger, the better LDL-C (mM) Adj HR (95% CI) <0.5 0.69 (0.56-0.85) 0.5-1.3 0.75 (0.64-0.86) 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 reference

Addressing the unmet need PCSK9 inhibitors are the only option ● Ezetimibe is not potent enough… ● PCSK9-inhibiting mAbs are the only available alternative ● Who should receive them? In theory, everyone would benefit… …But who are eligible? ASCVD Heterozygous Homozygous Statin intolerance patients FH FH

Where do we go from here? ● Low frequency injectables ● Statin intolerance ● Other lipid targets to pursue – Lp(a) – apoC-III – AngPTL3

Inclisiran – siRNA PCSK9 inhibition ● >50% LDL-C lowering when administered once per 6 months

Inclisiran – Two-yearly PCSK9 inhibition ● ORION-1 phase 2 trial: >50% LDL-C reduction 180 days after 2 nd dose Ray KK, N Engl J Med 2017

Inclisiran – Small variability in LDL-C ● LDL-C variability is associated with ASCVD risk ● Inclisiran consistently lowers LDL-C, in contrast to other LLT %-increase in death / ASCVD per SD LDL-C variability Ray, N Engl J Med 2017; Bangalore, JACC 2015

Safety of inclisiran ● More than 1,550 patient-years of safety data accumulated to date without material safety observations ● Phase 3 trials ongoing with 3,660 subjects , fully enrolled ● ORION-4 CVOT will recruit first patients soon ● Reassuring safety data accumulating rapidly

Where do we go from here? ● Low frequency injectables ● Statin intolerance ● Other lipid targets to pursue – Lp(a) – apoC-III – AngPTL3

Statin intolerance – A major gap in ASCVD prevention Statin eligibility based on treatment Statin- Actual Statin guidelines eligible statin- intolerant ◦ 39% to 50% of adults aged 40 – 65 (Europe patients users patients and U.S.) North ◦ Almost all individuals >65 years 133M 50M 5.0 to 13M America Actual statin-usage Western ◦ U.N.: ±8% to 12%; increasing 158M 60M 6.0 to 16M Europe ◦ Norway: 13.7% ◦ U.S.: 14.3%; increasing Japan 46.5M 18M 1.8 to 4.7M Statin intolerance, cohort n=107 835: 12.8 to Total 337.5M 128M ◦ Side effects in 17.4%, leading to 33.7M discontinuation in 10.3% Lee, JAMA Cardiol 2016; Hawkes BMJ 2017; Mortensen Circ 2017; CDC Health 2016; Stroes EHJ 2015

Statin intolerance – A major gap in therapeutic ASCVD prevention PCSK9 Very effective inhibitors Ezetimibe Safe but modestly effective Bempedoic In development; acid Promising in combination with ezetimibe CETP inhibition In development; Promising alternative

Statin intolerance – Bempedoic acid ● Four phase 3 lipid-lowering studies consistently showed LDL-C reductions of 20% to 30% ● In combination with ezetimibe (combination pill) LDL-C reduction of up to 48% ● CLEAR OUTCOMES CVOT ongoing ● Bempedoic acid / ezetimibe combination pill may be a valuable option for statin-intolerant patients

Statin intolerance – CETP inhibition Non-HDL-C difference 1) Mendelian randomization studies LDL vs. HDL: LDL matters; HDL is irrelevant 2) Trials of CETP inhibitors

Statins attenuate LDL-C reduction of CETP inhibition Genetics Reduced CETP activity protects against CVD, but only among individuals without variants related to statin action (HMGCR) CVD risk Explained by discordance between apoB and CETPi only LDL-C, also seen in clinical trials of combination therapy REVEAL trial CETPi & statin MACE reduction greater in low-dose atorvastatin Atorvastatin dose No additional CVD protection of CETPi in 0.87 (0.79 – 0.96) Low individuals with genetic variants 0.94 (0.86 – 1.03) High mimicking statin action

Statin intolerance – Obicetrapib (TA-8995) Phase 2: TULIP trial ◦ Baseline apoB 100 mg/dL ◦ ApoB reduction -34% Phase 3 / CVOT (OASIS): Low-dose / no statin ◦ Baseline apoB 130 - 140 mg/dL ◦ Proposed duration: 4 years ◦ Absolute apoB reduction: 45.9 mg/dL ◦ Expected RRR ± 25% Phase 3 trial in planning phase ◦ N ±10 000

Other lipid targets to pursue mRNA Lp(a) inhibitors siRNA apoC-III inhibitors AngPTL3 mAbs

Targeting Lp(a) with antisense APOA inhibition APOA antisense Prakash TP, Nucleic Acids Res 2014

Targeting Lp(a) with antisense APOA inhibition Weekly dose ED 50 of 3.9 mg (0.05 mL) Viney, Stroes, Tsimikas, Lancet 2016

What is the clinical potential of Lp(a) inhibition? ● Lp(a) is a validated ASCVD risk factor – Causal relationship very likely ● …However, Mendelian randomization data: Lp(a) 100 mg/dL ≈ LDL-C 39 mg/dL (1 mmol/L) Burgess, JAMA Cardiol 2018; Nordestgaard EHJ 2010

Conclusions • There is no reason for complacency – ASCVD is the number 1 cause of death globally • Statins are not enough for the majority of high-risk patients – PCSK9 inhibition is the only answer • Low-frequency injectables (inclisiran) might have an even more profound impact on improving global ASCVD burden • Cumulative LDL-C exposure matters – Start young and go low • Statin intolerance is a major clinical problem and the bempedoic acid/ezetimibe combination and CETP inhibition hold promise for the future • Improved understanding of Lp(a) / apoC-III / remnant lipoproteins opens a multitude of new therapeutic avenues