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

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

Jan 27, 2024 155 likes •407 views

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

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Targeting PCSK9 in Clinical Practice

Guidance and Future

JOHN J.P. KASTELEIN PROFESSOR OF MEDICINE UNIVERSITY OF AMSTERDAM THE NETHERLANDS

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Faculty Disclosure

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 Declaration of financial interests For the last 3 years and the subsequent 12 months:

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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

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ASCVD remains the #1 global cause of death

  • …Should ASCVD prevention be a public health priority?

Top 10 global causes of death, WHO 2018

British Heart Foundation

The cost of ASCVD

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Complacency

  • …Does the world really need new LDL-C-

lowering drugs?

– Efficacy: 15% of ASCVD patients have LDL-C >70 mg/dL despite perfect therapy – Side effects / adherence: in reality, only 4% of ASCVD patients receive perfect therapy; 31% receive HI-statins – Costs: PCSK9 inhibitors would theoretically enable >99% to achieve LDL-C <70 mg/dL

Risk factor Population attributable risk (%)

LDL-C/apoB 49.2 Smoking 35.7 Psychosocial 32.5 Abdominal

  • besity

20.1 Hypertension 17.9 Diet 13.7

Yusuf, Lancet 2004; Steen, BMJ Open 2017; Cannon, JAMA Cardiol 2016

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Cumulative LDL-C exposure

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

  • Lifetime exposure matters
  • The lower, the better; The younger, the better
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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?

ASCVD patients Heterozygous FH Homozygous FH In theory, everyone would benefit… …But who are eligible? Statin intolerance

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Where do we go from here?

  • Low frequency injectables
  • Statin intolerance
  • Other lipid targets to pursue

– Lp(a) – apoC-III – AngPTL3

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Inclisiran – siRNA PCSK9 inhibition

  • >50% LDL-C lowering when administered once per 6 months
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Inclisiran – Two-yearly PCSK9 inhibition

  • ORION-1 phase 2 trial: >50% LDL-C reduction 180 days after 2nd dose

Ray KK, N Engl J Med 2017

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Inclisiran – Small variability in LDL-C

  • LDL-C variability is associated with ASCVD risk
  • Inclisiran consistently lowers LDL-C, in contrast to other LLT

Ray, N Engl J Med 2017; Bangalore, JACC 2015

%-increase in death / ASCVD per SD LDL-C variability

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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
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Where do we go from here?

  • Low frequency injectables
  • Statin intolerance
  • Other lipid targets to pursue

– Lp(a) – apoC-III – AngPTL3

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Statin intolerance – A major gap in ASCVD prevention

Statin eligibility based on treatment guidelines

  • 39% to 50% of adults aged 40 – 65 (Europe

and U.S.)

  • Almost all individuals >65 years

Actual statin-usage

  • U.N.: ±8% to 12%; increasing
  • Norway: 13.7%
  • U.S.: 14.3%; increasing

Statin intolerance, cohort n=107 835:

  • Side effects in 17.4%, leading to

discontinuation in 10.3%

Lee, JAMA Cardiol 2016; Hawkes BMJ 2017; Mortensen Circ 2017; CDC Health 2016; Stroes EHJ 2015

Statin- eligible patients Actual statin- users Statin intolerant patients North America 133M 50M 5.0 to 13M Western Europe 158M 60M 6.0 to 16M Japan 46.5M 18M 1.8 to 4.7M Total 337.5M 128M 12.8 to 33.7M

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Statin intolerance – A major gap in therapeutic ASCVD prevention

PCSK9 inhibitors Ezetimibe Bempedoic acid CETP inhibition Very effective Safe but modestly effective In development; Promising in combination with ezetimibe In development; Promising alternative

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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
  • f up to 48%
  • CLEAR OUTCOMES CVOT ongoing
  • Bempedoic acid / ezetimibe combination pill may be a valuable
  • ption for statin-intolerant patients
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Statin intolerance – CETP inhibition

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

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Statins attenuate LDL-C reduction of CETP inhibition

Genetics Reduced CETP activity protects against CVD, but

  • nly among individuals without variants related

to statin action (HMGCR) Explained by discordance between apoB and LDL-C, also seen in clinical trials of combination therapy REVEAL trial MACE reduction greater in low-dose atorvastatin

Atorvastatin dose Low High 0.87 (0.79 – 0.96) 0.94 (0.86 – 1.03) CVD risk CETPi only CETPi & statin

No additional CVD protection of CETPi in individuals with genetic variants mimicking statin action

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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%
  • N ±10 000

Phase 3 trial in planning phase

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Other lipid targets to pursue

Lp(a) apoC-III AngPTL3 mRNA inhibitors siRNA inhibitors mAbs

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Targeting Lp(a) with antisense APOA inhibition

APOA antisense

Prakash TP, Nucleic Acids Res 2014

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Targeting Lp(a) with antisense APOA inhibition

Weekly dose ED50 of 3.9 mg (0.05 mL)

Viney, Stroes, Tsimikas, Lancet 2016

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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

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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