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Lipid-Altering Drug Development and Research Update 2016
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Harold Bays MD, FTOS, FACC, FACE, FNLAMedical Director / PresidentL‐MARC Research Center
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Disclosures
• Dr. Harold Bays is owns no pharmaceutical stocks or patents. In the past 12 months, Dr. Harold Bays’ research site has received research grants from Amarin, Amgen, Ardea, Arisaph, AstraZeneca, Bristol Meyers Squibb, Catabasis, Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Ferrer/Chiltern, Gilead, GSK, Hanmi, Hisun, Hoffman LaRoche, Home Access, Janssen, Johnson and Johnson, Kowa, Merck, Necktar, Novartis, NovoNordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Takeda, and TIMI. In the past 12 months, Dr. Harold Bays has served as a consultant/advisor for Alnylam, Amgen, AstraZeneca, Eli Lilly, Ionis (ISIS), Merck, Novartis, Pronova, Regeneron, Sanofi and Takeda. In the past 12 months, Dr. Harold Bays has served as a speaker for Amarin, Amgen, Astra Zeneca, Eisai, Regeneron, Sanofi and Takeda.
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INTRODUCTION:What is a free resource for lipid-altering
drugs in development?
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2016 Lipid-Altering Drug Development and Research Update
• Drug approval process• PCSK9 development process• Bempedoic acid• CETP inhibitors• Other lipid-altering drugs• Conclusion
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What is the process by which drugs are developed, and how do FDA approval
processes affect the clinical use of lipid-altering drugs?
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Process of Food and Drug Development ApprovalNew chemical entity (NCE) or new molecular entity (CME)
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• Drug Discovery
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Process of Food and Drug Development ApprovalNew chemical entity (NCE) or new molecular entity (CME)
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• Preclinical Testing
Bays HE. Expert Rev Cardiovasc Ther. 2011 Mar;9(3):265‐77.
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Process of Food and Drug Development ApprovalNew chemical entity (NCE) or new molecular entity (CME)
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• Investigational New Drug (IND) Application• Clinical Trials (Phase 1 – 4)• Special Protocol Assessment / Agreement (SPA)• New Drug Application (NDA)• Prescription Drug User Fee Act (PDUFA) of 1992• FDA Advisory Committee
Bays HE. Expert Rev Cardiovasc Ther. 2011 Mar;9(3):265‐77.
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Process of Food and Drug Development ApprovalNew chemical entity (NCE) or new molecular entity (CME)
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• FDA Advisory Committee Meeting
Bays HE. Expert Rev Cardiovasc Ther. 2011 Mar;9(3):265‐77.
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Process of Food and Drug Development ApprovalNew chemical entity (NCE) or new molecular entity (CME)
[(Decision not necessarily the same as FDA Advisory Committee (e.g., EMDAC*)]
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• Reject• Approve• Contingency FDA Approval Decision
• Commitment to outcomes trials• Risk Evaluation and Mitigation Strategy
• Post‐Approval additional regulatory treatment indications
Bays HE. Expert Rev Cardiovasc Ther. 2011 Mar;9(3):265‐77. * Endocrine and Metabolic Drug Advisory Committee
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Legal Relevance of a SPA: The case of icosapent ethyl
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• October 2013: FDA submitted notification it would not honor its SPA, regarding icosapent ethyl (AMR101 EPA‐only omega‐3 fatty acid)
• January 2014: The FDA rejected the SPA appeal
• August 2015: US District Court Judge upheld First Amendment protection for off‐label use of prescription drugs
• March 2016: A settlement was reach with the FDA regarding the content of promotional programs, including truthful and non‐misleading educational presentations of clinical trial and scientific data, not necessarily applicable to the indicated use
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Process of Food and Drug Development ApprovalNew chemical entity (NCE) or new molecular entity (CME)
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What is/was unique about PCSK9 inhibitor drug development?
First subject treatedwith PCSK9 mAb
PCSK9‐targeted mAb preclinicalPCSK9 discovery
Proof of concept in animals
Phase II studies published
Human targetvalidation
PCSK9: rapid progress from discovery to clinic in less than a decade
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Seidah NG. Proc Natl Acad Sci USA 2003;100:928–33. Abifadel M. Nat Genet 2003;34:154–6. Maxwell KN. Proc Natl Acad Sci USA 2004;101:7100–5. Rashid S. Proc Natl Acad Sci USA 2005;102:5374–79. Cohen JC. NEJM 2006;354:1264–72. Zhao Z. Am J Hum Genet 2006;79:514–23. Hooper AJ. Atherosclerosis 2007;193:445–8. Chan JC. Proc Natl Acad Sci USA 2009;106:9820–5. Stein, et al. NEJM 2012;366:1108–18. McKenney, et al. JACC 2012;59:2344‐53. Stein, et al. Lancet 2012;380:29–36. Roth, et al. NEJM 2012;367:1891–900. Giugliano, et al. Lancet 2012;380:2007–17. Koren, et al. Lancet 2012;380:1995–2006. Raal, et al. Circulation 2012;126:2408–17. Sullivan, et al. JAMA 2012:308:2497–506.
2000 2001 2002 2007 2008 20112003 2004 2005 2006 2009 2010 2012 2013
First Phase III data available
2015
Alirocumab & evolocumabapproved
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PCSK9 Inhibitor development programs are unique in their:
• Biology and Safety• Mechanism• Efficacy• Approved indicated use• Potential concerns of high efficacy• Administration
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What is/was unique about PCSK9 inhibitor drug biology and safety?
Bays HE. Expert Rev. Cardiovasc. Ther. 2(4), (2004)
Small Molecules
Prodrugs
Bays H. Chapter 44: Investigational Agents Affecting Atherogenic Lipoproteins. Clinical Lipidology: A Companion to Braunwald's Heart Disease, by Christie Ballantyne MD. ISBN‐13: 978‐1‐4160‐5469‐6 ISBN‐10: 1‐4160‐5469‐3 Saunders. Dec 2008; 530‐543.
Antisense Oligonucleotides (ASO’s)
Medicines in Development Biologics: 2013 Report
http://www.phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf
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What is/was unique about PCSK9 inhibitor drug mechanism?
Monoclonal Antibodies Nomenclature and Safety Considerations
25Catapano AL and Papadopoulos N. Atherosclerosis. 2013;228(1):18-28.
Mouse mAb(-omab)
Chimeric mAb(-ximab)
Humanized mAb(-zumab)
Fully Human mAb(-umab)
• Mouse variable• Mouse constant• No repeated
dosing
Mouse variableMouse constant
Human variableHuman constant
• All mouse variable
• Human constant
• Part mouse variable
• Human constant
• Human variable• Human
constant• Repeated
dosing possible
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What is/was unique about PCSK9 drug approved indications?
Statin Prescribing Information Indicated Use
INDICATIONS AND USAGE[atorvastatin] is an inhibitor of HMG‐CoA reductase (statin) indicated as an adjunct therapy to diet to:• Reduce the risk of MI, stroke, revascularization procedures, and angina in patients without CHD, but with multiple risk factors
• Reduce the risk of MI and stroke in patients with type 2 diabetes without CHD, but with multiple risk factors• Reduce the risk of non‐fatal MI, fatal and non‐fatal stroke, revascularization procedures, hospitalization for CHF, and angina in patients with CHD
• Reduce elevated total‐C, LDL‐C, apo B, and TG levels and increase HDL‐C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia
• Reduce elevated TG in patients with hypertriglyceridemia and primary dysbetalipoproteinemia• Reduce total‐C and LDL‐C in patients with homozygous familial hypercholesterolemia (HoFH)• Reduce elevated total‐C, LDL‐C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy
FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020702s056lbl.pdf. Accessed 10/8/2015.
PCSK9 Inhibitor EuropeanPrescribing Information Indications
[PCSK9 INHIBITOR] is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non‐familial) or mixed dyslipidaemia, as an adjunct to diet:
• In combination with a statin or statin with other lipid lowering therapies in patients unable to reachLDL‐C goals with the maximum tolerated dose of a statin
• Alone or in combination with other lipid‐lowering therapies in patients who are statin‐intolerant, orfor whom a statin is contraindicated
The effect of [PCSK9 INHIBITOR] on cardiovascular morbidity and mortality has not yet been determined
PCSK9 = proprotein convertase subtilisin/kexin type 9.
PCSK9 Inhibitor USPrescribing Information Indications
• [PCSK9 INHIBITOR] is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL‐C
• The effect of [PCSK9 INHIBITOR] on cardiovascular morbidity and mortality has not been determined
PCSK9 = proprotein convertase subtilisin/kexin type 9.
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What is/was unique about PCSK9 inhibitor efficacy?
“Optimal LDL [cholesterol] 50 to 70 mg/dl: Lower is better and physiologically normal”
50 70 90 110 130 150 170 190 210
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HUNTER-GATHERERHUMANS
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Mean Total Cholesterol, mg/dLO’Keefe et al. J Am Coll Cardiol. 2004;43:2142-2146.
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What is/was unique about PCSK9 inhibitor administration?
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VS
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What about other lipid-altering drugs in development?
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
Bays H, Stein EA. Expert Opin Pharmacother. 2003;4(11):1901-1938.
Acetyl coenzyme A
3-Hydroxy-3-methylglutaryl coenzyme A
Mevalonate
Isopentenyl pyrophosphate
Famesyl pyrophosphate
Squalene
Esterified cholesterol
Cholesterol packaged into ApoB containing very-low-density lipoproteins
Intermediate-density lipoproteins
Low-density lipoprotein cholesterol
3-Hydroxy-3-methylglutaryl coenzyme A reductase
Squalene synthase
Acyl-coenzyme A: cholesterol acyl trasferase
Microsomal triglyceride transfer protein
Endothelial lipoprotein lipase
Hepatic lipase
Isopentenyl tRNADolichol
Coenzyme Q10 Isoprenylated proteins
Unesterified (free) cholesterol
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
• December 2006: Torcetrapib (CETP inhibitor) development was discontinued because of increased all‐cause mortality and cardiovascular events in the combination atorvastatin and torcetrapib group, versus the atorvastatin alone group
• May 2012: Dalcetrapib (CETP inhibitor) development was discontinued due to lack of clinically meaningful efficacy
• July 2015: Announcement that the data safety monitoring board (DSMB) recommended continuing the phase 3 evacetrapib (CETP inhibitor) cardiovascular outcome study, based upon an interim futility analysis. (Last patient visit in ACCELERATE ‐ which is evaluating evacetrapib in approximately 12,000 patients with high‐risk atherosclerotic cardiovascular disease (ASCVD) was expected in July 2016.)
• September 2015: TA‐8995 (CETP inhbitor) development was acquired for $1.55 billion ($300 million in cash)
• October 2015: ACCELERATE study was stopped, and evacetrapib development program was discontinued
• November 2015: After an evaluation which included futility, the Data Monitoring Committee recommended continuation of the REVEAL study (anacetrapib), with projected conclusion in early 2017. “No additional interim efficacy analyses are planned.”
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Conclusions
• Despite a 37% decrease in LDL-C and a 130% increase in HDL-C, evacetrapib did not reduce the primary composite endpoint of major adverse CV events (MACE):• Myocardial infarction• Stroke• Hospitalization for unstable angina• Cardiovascular death• Coronary revascularization
• A “borderline significant” (p=0.06) reduction in all-cause mortality was observed in the evacetrapib group.
• The failure of decreases in LDL-C to result in an overall morbidity-mortality benefit emphasizes the limitations of surrogate endpoints
• The findings continue to challenge the hope that CETP inhibition might successfully address residual CVD risk
Nicholls, 65th Annual ACC Meeting. Chicago Ill. 2016 41
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MACE (Major Adverse Cardiovascular Events)Usual components
• Non-fatal myocardial infarction• Ischemic stroke• Hospitalization for unstable angina• Death
• Cardiovascular death• Sudden death• Overall “all cause” mortality
Sometimes components• Revascularization (coronary and/or peripheral vessels)• Heart failure
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
DGAT1 = Small intestine, liver, and adipose tissueDGAT2 = Liver and adipose tissue
Harris WS, Bulchandani D. Curr Opin Lipidol 2006;17:387-393Bays HE. Expert Rev. Cardiovasc. Ther. 6(3), 391–409 (2008)
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
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ApoCIII
• Apolipoprotein C-III (ApoC-III) is a small protein that resides on various lipoproteins
• Inhibits lipoprotein/hepatic lipases• Impairs hepatic uptake of triglyceride (TG)-rich
lipoproteins (such as lipoprotein remnants)• Generally promotes hypertriglyceridemia. • May contribute to insulin resistance• May contribute to atherosclerosis.
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Gemcabene (CI‐ 1027)Acetyl CoA Carboxylase Inhibitor
300, 600, and 900 mg daily LDL‐C reductions compared to placebo 17.0, 25.5, and 28.7 %
Acquired by Gemphire to develop as orphan drug in HoFH
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
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NLA Annual Summary 2016: Lipid-Altering Drugs in Development
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SUMMARY AND TAKE-HOME MESSSAGE
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Lipid-altering therapies that reduce atherogenic cholesterol and atherogenic lipoproteins may not always have ASCVD outcomes data upon regulatory approval. Such lipid-altering agents are most likely to
ultimately be shown to reduce ASCVD risk when:
• The hypothesis of the potential benefit of the therapeutic agent is based upon:• An accepted mechanism of action• Applicable genetic models• Epidemiological studies known to reduce ASCVD risk.
• Supported by experimental animal studies.• Supported by aggregated phase II or later phase human clinical trial data with post
hoc or interim analyses demonstrating reductions in ASCVD events, without substantive and clinically meaningful adverse effects.
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Bays HE, Jones PH, Orringer CE, Brown WV, Jacobson TA. National Lipid Association Annual Summary of Clinical Lipidology2016. J Clin Lipidol. 2016 Jan‐Feb;10(1 Suppl):S1‐S43.
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