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Pharmac: Devices and Drugs

Heart drugs – the missing links

John Elliott

Chairs: Rob Doughty & Rajesh Nair

Cardiac Drugs - The Missing Links

(Drugs we should have in New Zealand)

John Elliott

University of Otago Christchurch

Christchurch Hospital

Conflicts of Interest

• Clinician

• Scientist

• Principal Site Investigator in many international pharmaceutical trials

• Member Cardiovascular Subcommittee of PTAC, Pharmac.

• Presented yesterday at sponsored Breakfast meeting

Pick on 3 Missing Links

• Rosuvastatin

• Entresto

• PCSK9 Inhibitors

• Ivabradine

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Pick on 3 Missing Links – when were they approved by the FDA?

• Rosuvastatin 2003

• Entresto 2015

• PCSK9 Inhibitors 2015

• Ivabradine 2015

Not discussing any unproven drugs

Or the importance of exercise/lifestyleRosuvastatin

• Statin approved by FDA in 2003

• More potent than other statins

• No clinical endpoint studies vs placebo in CAD patients – the 7th

statin

• JUPITER – Primary prevention in men >50 and women>60 with increased CRP and 1 CV risk factor. Reduced CV events. Greatest benefit in those achieving LDL <1.8mmol/L

• METEOR – delayed progression of carotid atherosclerosis

• ASTEROID – regression of coronary atherosclerosis assessed by intravascular ultrasound

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RosuvastatinRosuvastatin

Brewer Am J Cardiol 2003 92(4) (Suppl) 23K-29K

3 years ago in Australia (2015)

• Of 29,022 prescriptions for lipid modifying agents

• 11,856 Atorvastatin

• 9537 Rosuvastatin

• 4285 Sinvastatin

• 1229 Ezetimibe

Minutes of Cardiovascular Subcommittee of PTAC 17.2.16

• Rosuvastatin is a new medication…not as many studies conducted…lower risk subgroups with surrogate endpoints..

• Limited evidence that rosuvastatin may have a role in patients who were intolerant of other statins

• If cost neutral to atorvastatin, consider criteria for rosuvastatin if LDL >2.5mmol/L on max tolerated dose of atorvastatin.

Minutes of Cardiovascular Subcommittee of PTAC 17.2.16

• Rosuvastatin is a new medication…not as many studies conducted…lower risk subgroups with surrogate endpoints..

• Limited evidence that rosuvastatin may have a role in patients who were intolerant of other statins

• If cost neutral to atorvastatin, consider criteria for rosuvastatin if LDL >2.5mmol/L on max tolerated dose of atorvastatin.

•Limp wristed

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FDA News Release - April 29, 2016. For Immediate Release

FDA approves first generic Crestor

• The U.S. Food and Drug Administration today approved the first generic version of Crestor (rosuvastatin calcium) tablets for the following uses:

• in combination with diet for the treatment of high triglycerides (hypertriglyceridemia) in adults;

• in combination with diet for treatment of patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia), a disorder associated with improper breakdown of cholesterol and triglycerides;

• either alone or in combination with other cholesterol treatment(s) for adult patients with homozygous familial hypercholesterolemia, a disorder associated with high low-density lipoprotein (LDL) cholesterol.

“The FDA is working hard to get first-time generic drugs

approved as quickly as possible so patients can have

increased access to needed treatments,” said Kathleen

Uhl, M.D., director of the Office of Generic Drugs in the

FDA’s Center for Drug Evaluation and Research. “The

FDA requires that generic drugs meet rigorous scientific

and quality standards.”

FDA News Release - April 29, 2016. For Immediate Release

FDA approves first generic Crestor

FDA approved generic rosuvastatin2 years ago

• But in New Zealand we wait

• Currently available for $1 a day

• No process for facilitating or inviting submissions

Does that matter?

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ARE WE REACHING TARGET LDL-CHOLESTEROL LEVELS

IN PATIENTS PRESENTING WITH ACUTE CORONARY

SYNDROMES (ACS)?John M Elliott, Rachel M Elliott, Lorraine Skelton, Chris Frampton, A Mark Richards.

Department of Medicine, Christchurch School of Medicine and Health Sciences

One year after admission for ACS,

- 89% were still receiving a statin but only

- 62% had had LDL-C levels retested and

- 71% had LDL-C levels <2.5mmol/L

- only 39% had LDL-C levels <2.0mmol/L.

CSANZ Auckland 2006

Rosuvastatin

• We need more lipid lowering agents in New Zealand

• Why cant we have subsidised access to a generic statin that happens to be the most potent

• And its cheap, even in Australia

Trends in Australian Expenditure on CV Drugs Trends in Australian Expenditure on CV Drugs

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Trends in Australian Expenditure on CV Drugs

Entresto (Sacubitril and Valsartan)

• Sacubitril inhibits neprilysin which is an endopeptidase that normally breaks down natriuretic peptides, bradykinin and adrenomedullin

• Increases circulating natriuretic peptides

• Vasodilation and lower blood pressure

PARADIGM – HF Study (Entresto)• Participants with heart failure (New York Heart

Association class II-IV) due to reduced LVEF (≤40%)

• Randomized to LCZ696 (Entresto) 200 mg twice daily (n = 4,187) versus enalapril 10 mg twice daily (n = 4,212) in addition to standard therapy.

• Concomitant Medications: Digitalis: 29%, Beta-blocker: 93%, Mineralocorticoid antagonist: 54%

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PARADIGM – HF Study (Entresto) PARADIGM –HF Substudy Okumura et al

• Methods and Results—We examined the effect of study treatment in the following subgroups: diuretics (yes/no), digitalis glycoside (yes/no), mineralocorticoid receptor antagonist (yes/no), and defibrillating device (implanted defibrillating device, yes/no). We also examined the effect of study drug according to β-blocker dose (≥50% and <50% of target dose) and according to whether patients had undergone previous coronary revascularization.

• Conclusions—The benefit of sacubitril/valsartan, over an angiotensin-converting enzyme inhibitor, was consistent regardless of background therapy and irrespective of previous coronary revascularization or β-blocker dose.

https://doi.org/10.1161/CIRCHEARTFAILURE.116.003212 Circulation: Heart Failure. 2016;9:e003212. Originally published September 12, 2016

Entresto approved in other countries

• UK – NICE March 2016

• Canada March 2016

• Australia July 2017

• Republic of Ireland December 2017

• Approved in 37 European countries

• NB PARADIGM –HF published 2014

Product:

Active

Ingredient:

Dosage Form:

New Zealand

Sponsor:

Manufacturers:

Entresto 24/26

Sacubitril/valsartan 50mg equivalent to 24.3mg

sacubitril and 25.7mg valsartan

Film coated tablet

Novartis New Zealand Limited

Novartis Pharma Stein AG, Stein, Switzerland

Novartis Singapore Pharmaceutical

Manufacturing Pte Limited, Singapore

NEW ZEALAND GAZETTE, No. 99

— 3 NOVEMBER 2016Pursuant to section 20 of the Medicines Act 1981, the Minister

of Health hereby consents to the distribution in New Zealand of

the new medicines set out in the Schedule hereto:

Schedule

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• Authority Required Chronic heart failure

• Clinical criteria: Patient must be symptomatic with NYHA classes II, III or IV,

• AND Patient must have a documented left ventricular ejection fraction (LVEF) of less than or equal to 40%,

• AND Patient must receive concomitant optimal standard chronic heart failure treatment, which must include the maximum tolerated dose of a beta-blocker, unless contraindicated or not tolerated,

• AND Patient must have been stabilised on an ACE inhibitor at the time of initiation with this drug, unless such treatment is contraindicated according to the TGA-approved Product Information or cannot be tolerated; OR

• Patient must have been stabilised on an angiotensin II antagonist at the time of initiation with this drug, unless such treatment is contraindicated according to the TGA-approved Product Information or cannot be tolerated,

• AND The treatment must not be co-administered with an ACE inhibitor or ARB.

Entresto – Australian PBS – July 2017 PTAC Meeting February 2017 - Entresto

PTAC Meeting February 2017 - Entresto

Aim was Enalapril 10mg bd,

average achieved dose was 18.9mg/day (Letter to Editor, Dec 2014)

• In New Zealand we have not used trial proven ACE inhibitor for 20 years

• Our use of ARB’s is limited

• Comparison of new agent vs Enalapril scientifically valid

PTAC Meeting February 2017 - Entresto

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•But PARAGON-HF is testing Entresto in HFpEF patients

PTAC Meeting February 2017 - EntrestoSubsequent Cardiovascular Subcommittee Meetings• One 6 months later in September 2017 .

• Frustrations expressed

• No meeting of Cardiovascular Subcommittee planned for 2018

• There will be further delays through Subcommittee and PTAC approvals

• Result is delay in possible funding till 2019

PARADIGM – HF (Entresto)

2018

2014

PARADIGM – HF (Entresto)

2018

2014New Zealanders are still

on the placebo curve

Days since proof of benefit

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PCSK9 Inhibitors• Large body of evidence that they lower LDL cholesterol

levels either alone or when added to max tolerated dose of statin

• Large body of evidence that they reduce CV endpoints.

• Alirocumab – ODYSSEY studies, ODYSSEY OUTCOMES

• Evolocumab – FOURIER studies

ODYSSEY OUTCOMES

0.4 0.65 1.3 1.8 mmol/L

ODYSSEY OUTCOMES

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ODYSSEY OUTCOMES ODYSSEY OUTCOMES

>2.6 mmol/L

PCSK9 Inhibitors In New Zealand in 2018 PCSK9 Inhibitors In New Zealand in 2018

• We wait

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Now

2018

How long will New Zealanders

follow the placebo curve

PHARMAC MODEL• Effectively lowered prices paid for patented drugs

• Saved New Zealand money

• But New Zealanders have paid a price

PHARMAC MODEL• Effectively lowered prices paid for patented drugs, Saved New Zealand

money

• But New Zealanders have paid a price

• Delayed access or no access to drugs with proven benefits in NZ

201820182014?

Given the diverging curves in the CV endpoint studies, the

effects of these delay will be magnified over time…We

continue to live on the placebo curve

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Does that matter?

Inequities

• Inequities between nations

• New Zealand’s health affected by political decisions

• I don’t want to continue living on the placebo curve

PHARMAC MODEL

• Effectively lowered prices paid for patented drugs,

• Saved New Zealand money

• But New Zealanders have paid a price

• Delayed access or no access to drugs with proven benefits in New Zealand

• Given the diverging curves in the CV endpoint studies, the effects of these delay will be magnified over time

• We continue to live on the placebo curve