The future of lipid-lowering drugs Vasculaire geneeskunde From bench - - PowerPoint PPT Presentation

Vasculaire geneeskunde ‘From bench to bedside’ 11 september 2020 Hotel Theater Figi, Zeist

Jan Albert Kuivenhoven Department of Pediatrics, Section Molecular Genetics University Medical Center Groningen, the Netherlands

The future of lipid-lowering drugs

A current plethora of lipid-lowering drugs......

Adapted from Hegele RA, CircRes 2019

Five evidence-based drugs to reduce LDLc* Phase II & III clinical trials to reduce high Lp(a), Tg, LDLc

INCLIRISAN

Treating homozygous familial hypercholesterolemia Treating rare monogenic disorders

• lysosomal adic lipase deficiency
• familial LCAT deficiency
• lipoprotein lipase deficiency
• familial chylomicronemia syndrome

Increasing cellular chol.efflux

∗ ∗ ∗ ∗

* Validated with Mendelian Randomization studies Under development Registered

ACL HMGCR NPC1L1

Treating homozygous familial hypercholesterolemia * Bempedoic acid/Ezetimibe - NDA filed Febr 2019

ABE

June, 2020

Lipid-lowering drugs

• To reduce
• LDL cholesterol
• reduce atherosclerotic cardiovascular disease (ASCVD)
• Triglycerides
• ASCVD
• severe hypertriglyceridemia
• patients witn insulin resistance
• Lipoprotein(a)
• ASCVD
• To treat rare monogenic disorders of lipid metabolism
• To modulate steps in the reverse cholesterol pathway to reduce

atherosclerosis

Managing very severe hypercholesterolemia

Extracorporeal removal of lipoproteins Nonspecific plasma exchange / plasmapheresis / specific targeted approaches to remove LDL/Lp(a). No randomized ASCVD outcome trials

• Monoclonal Ab against

ANGPTL3 (Evinakumab)

• Gene therapy (ongoing)

AAV8.TBG.hLDLR (RGX-501)

ApoB mRNA ApoB protein

Lipidation of apoB

Triglycerides

MTP

VLDL ASO

Lomitapide – inhibitor of lipidation of ApoB by microsomal transport protein (MTP) Mipomersen – antisense oligonucleotide (ASO) against APOB Block hepatic production of VLDL (precursor of LDL)

Liver

LDL cholesterol lowering to treat ASCVD

Block hepatic cholesterol synthesis

• HMGCR inhibition (statins)

Citrate Acetyl-CoA Cholesterol HMGCR Acetate Citrate Lyase

LDLR LDLc

Need of functional LDLR Lysosomal degradation

LDLR Small Intestine NPC1L1 ABCG5/G8 Reduced cholesterol uptake

Blocking intestinal cholesterol re-uptake

• NPC1L1 inhibition (ezetimibe)
• Bile acid sequestrants (colesevalam)

Prevent lysosomal degregation of LDLR

• PCSK9 inhibition
• monoclonal antibodies (alirocumab, evolocumab)
• antisense oligonucleotide therapy (Inclirisan)
• ABE (one time lifelong?)
• ACL inhibition (bempedoic acid,

Nexletol/Nexlizet) (since Febr 2019)

Triglyceride-lowering drugs to treat ASCVD

Omega-3 (n-3) fatty acid preparations (‘fish oils’)

• Vascepa (eicosapent ethyl). Reduce-it. 25% risk reduction on top of statin therapy. Effects beyond

triglycerides anticipated.

• Epanova (eicosapentaenoic acid and docosahexaenoic acid) - ongoing

Fibrates (PPAR alpha agonists: gemfibrozil/fenofibrate/bezafibrate)

• not indicated to treat ASCVD (inconsistent outcome trials – especially in combination with statins)

Pemafibrate

• Selective PPAR modulator that reduces TG levels by ≤ 45% and improves a wide range of quantitative

metabolic subphenotypes, except for LDL-C levels. Large phase III ASCVD trial (Prominent)

A new drug to treat (severe) hypertriglyceridemia and possibly insulin resistance

Downregulation of apolipoprotein CIII (apoCIII)

ASO (volanesorsen) Monoclonal antibodies (in the works)

Phase III trials in 66 FCS patients completed (NEJM 2019; adverse effects)

• familial chylomicronemia syndrome
• familial partial lipodystrophy
• improving insulin sensitivity

New drugs to possibly treat (severe) dyslipidemia and possibly type 2 diabetes

Downregulation of angiopoetin-like protein 3 (Angplt3)

Monoclonal antibodies (Evinakumab)

• hypolipidemic effects (Tg, LDLc and HDLc)
• reducing LDLc independent of LDLR!
• phase III trial completed for FH (NEJM, Raal

Aug, 2020)

• familial chylomicronemia syndrome
• familial hypercholesterolemia
• lipodystrophies
• type 2 diabetes

ASO (IONIS-ANGPTL3-LRx (Gal-Nac)) Hypolipidemic effects in healthy volunteers with hypertriglyceridemia Phase II trial in T2D patients (Jan, 2020) – 90% success

Promise to lower Lp(a) to reduce atherosclerosis

ASO: APO(a)LrX. A phase 2 dose-ranging and safety study ongoing in patients with hyperlipoproteinemia[a] and cardiovascular disease; Phase 3 outcomes trial initiated in Dec 2019 (n=7600; Lp(a) above 70mg/dl). Outcome 2024 Lp(a) is

• atherogenic via its LDL-like moiety
• proinflammatory via its OxPL content
• antifibrinolytic via its apo(a) moiety

Risk factor for both ASCVD and calcific aortic valve disease Mendelian Randomization studies: LPA is causally related to ASCVD PCSK9i lower Lp(a) to a limited extent.

Current options to treat atherogenic dyslipidemia

Decreasing LDLc

• statins
• ezetimibe
• bile acid sequestrants
• monoclonal Ab’s against PCSK9
• mipomersen, lomitapide
• awaiting ASO against PCSK9 and LDLR gene therapy
• ABE against PCSK9 and ANGPTL3

Decreasing triglycerides (remnant cholesterol?)

• eicosapent ethyl (Vascepa). Effects not only mediated by moderate Tg reduction?
• other fish oil based therapies: Epanova
• awaiting outcomes trials to downregulate ApoCIII and Angptl3

Decreasing Lp(a) – hypothesis tested

• awaiting outcome trials with ASOs

Are these drugs actually used?

Adherence to guidelines to prevent cardiovascular diseases: The LifeLines cohort study J W Balder 1, S Scholtens, J K de Vries, L M van Schie, S M Boekholdt, G K Hovingh, P W Kamphuisen, J A Kuivenhoven PMID: 26314714 Results: For primary prevention, 77% (2515 of 3268) of those eligible for LLD treatment did not report using these drugs, while for secondary prevention this was 31% (403 of 1302). Patients with diabetes mellitus were treated best (67%) for primary prevention. Notably, of the patients with stroke, only 47% (182 of 386) reported LLD treatment.

Future of novel lipid-lowering drugs. Promising but vulnerable

Adapted from Hegele RA, CircRes 2019

INCLIRISAN ACL HMGCR NPC1L1

• 2. efficacy and safety of antisense
• ligonucleotide (ASO) drugs
• PCSK9 - inclirisan
• APOC3 - volanesorsen
• LPA - APO(a)LRx

‘Newcomers’ largely dependent of

• 1. long-term safety of monoclonal

antibodies

• PCKS9i – alirocumab,

evolocumab

• ANGPTL3 – evinacumab
• APOC3
• 3. All are expensive and (as yet) not

available to most high risk patients.

The future of lipid-lowering drugs – small molecule inhibitors?

Adapted from Hegele RA, CircRes 2019

INCLIRISAN

∗ ∗

ACL HMGCR NPC1L1

When costs remain a main hurdle

• bempedoic acid
• gemcabene
• GPR146 antagonists?*

GPR146i GPR146 deficiency protects against hypercholesterolemia and

• atherosclerosis. Cell, Nov 27, 2019

Treating ‘residual atherosclerosis risk’ associated with high TG and low HDLc. Antihyperglycemic agents

Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk in multiple RCT trials.

• E. J. Northa and J.D. Newman, Curr Opin Cardiol 2019

Zelniker TA et al Circulation. 2019

Treating ‘residual atherosclerosis risk’ associated with high Tg and low HDLc. Guided lifestyle intervention.

Primary care-led weight management for remission of type 2 diabetes (DiRECT): an

• pen-label, cluster-randomized trial.

Mean bodyweight fell by 10·0 kg (SD 8·0) - almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs

Lean ME, Lancet. 2018

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.

Stekovic S. Cell Met 2019, Sept 3.

Thoughts associated with the future of lipid-lowering drugs

No 1

• Lifestyle advice. Need of governmental intervention. Works!

No 2

• Adherence to guidelines with currently available drugs

No 3

• Focus on lowest cost drugs with good efficacy

Stop the chase for new drugs that are never going to used in the general patient at increased ASCVD risk

When combining guided lifestyle interventions with available drugs, we already work towards personalized lipid-lowering therapy

Atherosclerosis sta tarts i in childhood

Treated when clinical events have occured How should we best proceed? Start early!

Thank you for your attention!

Background literature 1) Hegele RA et al. CircRes 2019 2) Ray K, Lancet, Sept 2019; x< 3) Zwol WV et al J Clin Med. 2019; PMID: 31340607