Pipe Cleaners in the Pipeline: Mechanisms of action for novel cardiovascular drugs on the clinical horizon

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Cardiovascular Pipeline in Decline Pipe Cleaners in the Pipeline: Mechanisms of action for novel cardiovascular drugs on the clinical horizon Matthew J. Campen, Ph.D., M.S.P.H.

1 Cardiovascular Pipeline in Decline Pipe Cleaners in the Pipeline: Mechanisms of action for novel cardiovascular drugs on the clinical horizon Matthew J. Campen, Ph.D., M.S.P.H. UNM Regents Professor of Pharmaceutical Sciences Reasons for Candidate Failure JACC Basic Transl Sci. 1, ; 2016 Heart Failure: Early Stages Novel Drugs by Disease Class Hypertension and Heart Failure Entresto Ularitide Hyperlipidemia Mipomersen MTTP Inhibitors PCSK9 Inhibitors Heart Failure: Early Stages Compensatory Mechanisms are progressively activated: Increased Sympathetic Activity Improves cardiac performance Fluid Retention (RAAS activation) Increases volume return to the heart Myocardial Hypertrophy Stimulated by Angiotensin II, epinephrine Entresto (Valsartan/Sacubitril) Dual-acting Angiotensin Receptor Blocker (valsartan) plus Neprilysin inhibitor (sacubitril) Sacubitril is a prodrug that is hydrolyzed to active inhibitor Entresto is approved (2015) for NYHA II-IV heart failure patients with reduced ejection fraction (HFrEF) 1

AT 1 receptor vasoconstriction, sympathetic activation, cell growth, sodium and fluid retention. 3. AT 2 receptor vasodilation & inhibition of cell growth 4. Blockage of AT1 Inactive Metabolites a.

2 Percent Baseline AT-II Pressure Response 6/19/2017 Angiotensin II AT 1 Receptor Blockers (ARB) 1. Angiotensin II can also be formed directly from angiotensin I and angiotensinogen without going through ACE pathway. Neprilysin (Neutral Endopeptidase) 2. AT 1 receptor vasoconstriction, sympathetic activation, cell growth, sodium and fluid retention. 3. AT 2 receptor vasodilation & inhibition of cell growth 4. Blockage of AT1 Inactive Metabolites a. feedback inhibition on renin b. levels of plasma renin angiotensin II c. stimulation of AT2 & vasodilation. Campbell. Nature Reviews Cardiology 14, , 2017 Preclinical Data Supporting the Value of a Neprilysin Inhibitor and ARB in Reducing Blood Pressure PARADIGM-HF Trial Reported Clear Benefits of Entresto Compared to ACEi, Alone Vehicle Telmisartan (0.1 mg/kg) Candoxatril (10 mg/kg) Telmi + Candox ( mg/kg) Time (Hour) McMurray et al., NEJM, 371: , 2014 Decompensation in Heart Failure Entresto (Valsartan/Sacubitril) Side effects are consistent with an ARB Angioedema Hypotension Hyperkalemia Renal failure In the PARADIGM-HF clinical trial, discontinuation due to side effects of Entresto was 10%, compared to 12% with enalapril 2

Management of Acute Decompensation Evidence for Congestion Orthopnea High venous pressure

Abdominal-Jugular reflex Evidence for Low Perfusion Narrow pulse pressure Cool extremities

(Cardiorentis AG) Atrial Natriuretic Peptide analogue Indicated for acute cardiac failure

congestion and associated sympotoms Ularitide Benefits Short-Term Symptomology in Acute

specific receptor (NPR-A) Activates particulate guanylyl cyclase to produce cyclic GMP cgmp

3 Management of Acute Decompensation Evidence for Congestion Orthopnea High venous pressure Distended jugular vein Edema (WET) Ascites (fluid in abdomen) Valsalva Square Wave Abdominal-Jugular reflex Evidence for Low Perfusion Narrow pulse pressure Cool extremities Sleepiness ACEi hypotension Declining serum Na + Renal dysfunction Urodilatin Ularitide (Cardiorentis AG) Atrial Natriuretic Peptide analogue Indicated for acute cardiac failure (decompensation) Selective venous vasodilator Reduces cardiac wall stress Reduces pulmonary congestion and associated sympotoms Ularitide Benefits Short-Term Symptomology in Acute Cardiac Decompensation; No Long-Term Benefits Urodilatin Ularitide (Cardiorentis AG) Acts on a specific receptor (NPR-A) Activates particulate guanylyl cyclase to produce cyclic GMP cgmp stimulates vasodilation (venous) and diuresis (kidney) Anker et al., Eur Heart J. 36: , Packer et al, NEJM. 376: , 2017 Components of an Advanced, Vulnerable Arterial Plaque Uptake, Processing and Fate of Cholesterol and Lipids Glossary: LPL = lipoprotein lipase HL = hepatic lipase FFA = free fatty acids 3

Cholesterol Feedback Signaling Mipomersen (Kynamro) 1 st in class injectable 2 nd gen antisense

Inhibits ApoB mrna from transcribing FDA approved for homozygous familial hypercholesterolemia

Action of Antisense Oligos Bays. Clinical Lipidology, 44:530-543, 2009 Thomas et al., JACC.

Elevates Serum ALT, Interacts with Statins May interact with statins Risk of liver fat

4 Cholesterol Feedback Signaling Mipomersen (Kynamro) 1 st in class injectable 2 nd gen antisense oligo linked by phosphorothioate instead of phosphodiester Sugar molecules are also modified Inhibits ApoB mrna from transcribing FDA approved for homozygous familial hypercholesterolemia (Genzyme via ISIS) Other antisense oligos and microrna are in development for various targets Action of Antisense Oligos Bays. Clinical Lipidology, 44: , 2009 Thomas et al., JACC. 62: , 2013 Mipomersen Reversibly Reduces LDL-C, Lp(a) and ApoB Mipomersen Reversibly Elevates Serum ALT, Interacts with Statins May interact with statins Risk of liver fat accumulation because VLDL production/secreyion is blocked Thomas et al., JACC. 62: , 2013 Thomas et al., JACC. 62: ,

Novel Pathways: MTTP Inhibition Novel Pathways: MTTP Inhibition Microsomal triglyceride transfer protein (MTTP) is essential for transferring triglycerides to: ApoB48 in

effects are most commonly reported side effect Multicenter, double-blind, 12-week trial, included 84 patients with hypercholesterolemia.

5 mg daily for the second 4 weeks and 10 mg daily for the last 4 weeks (n = 28) Ezetimibe 10 mg daily and AEGR-733 administered with the dose titration described above (n =

, Nature Clinical Practice Cardiovascular Medicine 2008 Novel Pathways: PCSK9 inhibition Proprotein convertase subtilisin/kexin type 9 Binds to LDLR and induces endosomal

TM (Amgen) bococizumab (Phase 3) Approved for heterozygous familial hypercholesterolemia clinical atherosclerotic cardiovascular disease who require additional lowering of

5 Novel Pathways: MTTP Inhibition Novel Pathways: MTTP Inhibition Microsomal triglyceride transfer protein (MTTP) is essential for transferring triglycerides to: ApoB48 in enterocytes ApoB100 in Hepatocytes Inhibition of MTTP therefore blocks production of Chylomicrons and VLDL Lomitapide (Juxtapid) is an MTTP inhibitor CYP3A4 metabolized; GI effects are most commonly reported side effect Multicenter, double-blind, 12-week trial, included 84 patients with hypercholesterolemia. Randomly assigned ezetimibe 10 mg daily (n = 29) Lopitamide (AEGR) 5 mg daily for the first 4 weeks, 7.5 mg daily for the second 4 weeks and 10 mg daily for the last 4 weeks (n = 28) Ezetimibe 10 mg daily and AEGR-733 administered with the dose titration described above (n = 28) Lopitamide efficacy comparable to ezetimibe, slightly more adverse events (but mild and considered safe) Approved in 2012 Samaha et al., Nature Clinical Practice Cardiovascular Medicine 2008 Novel Pathways: PCSK9 inhibition Proprotein convertase subtilisin/kexin type 9 Binds to LDLR and induces endosomal uptake and degradation Reduced LDLR=increased circulating LDL PCSK9 antibodies are being tested as therapeutics: alirocumab, Praluent (Aventis/Regeneron) evolocumab, Repatha TM (Amgen) bococizumab (Phase 3) Approved for heterozygous familial hypercholesterolemia clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C PCSK9 Diagram Betteridge. Nature Reviews Endocrinology 9:76-78, Calculated LDL Cholesterol Levels over Time (Intention-to-Treat Analysis). Adverse Events of Interest and Laboratory Values: Safety Analysis. Robinson JG et al. N Engl J Med 2015;372: Robinson JG et al. N Engl J Med 2015;372:

Cumulative Incidence of Cardiovascular Events.

and transferred to the liver for excretion HDL also has putative anti-inflammatory, antioxidative, platelet antiaggregatory, anticoagulant, and profibrinolytic activities HDL contains the antioxidant

Increases reverse cholesterol transport. 2. Enhances NO and PG effects on smooth muscle and platelets 3. Inhibits platelet and monocyte binding to damaged endothelium cells.

6 Cumulative Incidence of Cardiovascular Events. HDL Good Cholesterol HDL are protective lipoproteins that decrease the risk of CHD HDL participates in reverse cholesterol transport, the process by which excess cholesterol is acquired from cells and transferred to the liver for excretion HDL also has putative anti-inflammatory, antioxidative, platelet antiaggregatory, anticoagulant, and profibrinolytic activities HDL contains the antioxidant enzymes Paraoxonase PAF acetylhydrolase Glutathione peroxidase Sabatine MS et al. N Engl J Med 2015;372: HDL Physiological Role HDL -Three proposed beneficial effects: 1. Increases reverse cholesterol transport. 2. Enhances NO and PG effects on smooth muscle and platelets 3. Inhibits platelet and monocyte binding to damaged endothelium cells. CETP: cholesteryl ester transfer protein Besler et al., EMBO Molecular Medicine, 4: , 2012 ILLUMINATE Study Enrolled >15k patients with coronary artery disease Compared Torcetrapib + Atorvastatin vs atorvastatin alone Mean increase of 72.1% in high-density lipoprotein cholesterol (HDL-C) Mean decrease of 24.9% in LDL-C Small mean decrease of 9% in triglycerides compared with baseline (all P <.001 vs atorvastatin only). Significant in Blood Pressure (mean = 5.4 mmhg) Significant in mortality Dalcetrapib Hoffman LaRoche Dal-OUTCOMES Trial HDL increased, but no clinical benefit NEJM 367: ,

DEFINE Trial (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) Anacetrapib Merck CETP inhibitor Increase HDL 138% Decreased LDL 36% No increase in BP or adverse events

7 DEFINE Trial (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) Anacetrapib Merck CETP inhibitor Increase HDL 138% Decreased LDL 36% No increase in BP or adverse events Will HDL Targeting Lead to Clinical Benefits? HDL is not a simple molecule, but rather a complex subcellular particle with lipids and proteins with diverse functions Oxidative environments can impair those functions and actually make HDL a pro-inflammatory lipoparticle Proteomic, lipidomic studies are ongoing to better understand the link to CVD Currently overall cholesterol efflux, as a functional marker, is the best link between CVD and HDL Besler et al., EMBO Molecular Medicine, 4: , 2012 Cholesterol Efflux Capacity Summary While the cardiovascular drug pipeline is declining, novel drugs continue to achieve FDA approval New technologies (antisense oligos, antibodies) will play a larger role due to specificity of targets, but will also face challenges related to route of administration and bioavailability. Identification of novel pathways, such as MTTP and PCSK9, will be crucial for maintaining a healthy drug discovery pipeline Traditional targets and biomarkers will change as we get new information from big data GWAS and omic approaches The future ain t what it used to be. Yogi Berra Khera and Rader. ATVB, 33: ,

2017 Summer MAOFP Update

2017 Summer MAOFP Update. Cardiology Update 2017 Landmark Trials Change Practice Guidelines David J. Strobl, DO, FNLA Heart Failure: Epidemiology More than 4 million patients affected 400,000 new cases