pcsk9 inhibitors pp

PCSK9 Inhibitors

Hyperlipidemia and Atherosclerosis1

Established Therapies For Hyperlipidemia

HMG-CoA Reductase Inhibitors2

Decrease hepatic production of cholesterol via synthesis blockade Increases density of LDL cell surface receptors in the liver which

increases uptake from the plasma Most reduction in LDL

Ezetimibe3 Blocks cholesterol absorption in the intestines causing liver to absorb

LDL from blood stream Niacin4

Reduces FFA release from fat tissue and increases lipoprotein lipase action

Established Therapies For Hyperlipidemia

Bile Acid Resins5

Bind to bile and prevent its reabsorption, thereby depleting cholesterol stores

Used in mild hyperlipidemia with no hypertriglyceridemia Fibrates6

Increase lipoprotein lipase activity, uptake of triglycerides from plasma, and increased synthesis of HDL

Used mainly for hypertriglyceridemia

PCSK9 Inhibitors7

PCSK9 Inhibitors

There are three drugs in this class being developed All are monoclonal antibodies for subcutaneous injection

Alirocumab Currently marketed by Sanofi

Evolocumab Will be released soon by Amgen

Bococizumab Expected release around 2017-2018 by Pfizer

Alirocumab (Praluent) – Sanofi7

Stability at room Temp: 24 hours Refrigeration and light protection required Pre-filled glass syringes or pre-filled pens Administered at either 75 mg or 150 mg subcutaneously q 2

weeks Room temp for 30-40 minutes before administration Currently FDA approved for addition to maximally tolerated statin

dose for Familial Hypercholesterolemia or those with clinical ASCVD with sub optimal LDL-Lowering (prescribing info)

$14,600 for 1 year of therapy

Clinical Trials For Alirocumab With Results

Trial Name

Patient Population

Treatments * In addition to statin

Result

Odyssey Options I8

ASCVD and HLD uncontrolled by atorvastatin

1)Alirocumab *2)Ezetimibe *3)Placebo *4)Double atorvastatin dose5)Switch to rosuvastatin 40

2 times > reduction in LDL

Odyssey Combo I9

CVD and HLD uncontrolled by max tolerated statin dose

1) Alirocumab *2) Placebo *

45.9 % > reduction in LDL

Odyssey Combo II10

CVD and HLD uncontrolled by max tolerated statin dose

1) Alirocumab2) Ezetimibe

29.8 % > reduction in LDL at week 24

Clinical Trials For Alirocumab With Results

Trial Name

Patient Population


Result

NCT0164447411

Moderate CV risk Not on HLD therapy

1) Alirocumab2) Ezetimibe

31 % > reduction in LDL

Odyssey Long Term12

(open label)

HLD currently on therapy In addition to background therapy:

1) Alirocumab2) Placebo

61.9 % > reduction of LDL

1.6 % < CV events

Clinical Trials For Alirocumab Awaiting Results

Trial Name

Patient Population Treatments * In addition to statin

Endpoint

Odyssey FH II

FH and statin treatment failure

1) Alirocumab *2) Placebo *

% Δ in LDL at week 24

Odyssey Options II

HLD currently on rosuvastatin 1) Alirocumab2) Ezetemibe3) Placebo


Odyssey High FH

FH patients receiving therapy In addition to background therapy:1) Alirocumab2) Placebo


Efficacy and Safety in CHD and FH

High CV risk or FH uncontrolled on current therapy

In addition to background therapy:1) Alirocumab2) Placebo



Trial Name

Patient Population Treatments * In addition to statin

Result

Odyssey Choice II

HLD uncontrolled by non-statin therapy


% change in LDL at week 24

Odyssey MONO

Non FH HLD 1) Alirocumab2) Placebo


Odyssey Choice I

Low, medium, high CV risk

With or without statin therapy




Trial Name

Patient Population


Result

Odyssey Alternative

HLD and low, moderate, or high CV risk

1) Alirocumab2) Ezetimibe3) Atorvastatin4) Placebo

% change in LDL at 24 weeks

Odyssey Escape

FH receiving apheresis 1) Alirocumab2) Placebo

apheresis requirements normalized to baseline schedule

Odyssey Outcomes

Post MI taking max tolerated rosuvastatin or atorvastatin dose

1) Alirocumab *2) Standard MI therapy

Time to 1st event (CV death, MI, hosp for UA, or ischemic stroke)

Clinical Trials For Evolocumab With Results

Trial Name

Patient Population


Result

DESCARTES13 Background therapy of:

DietAtorvastatin 10 mgAtorvastatin 80 mgAtorvastatin 80 + Zetia

In addition to background therapy:1) Evolocumab2) Placebo

Diet: 55.7 % > reduction Atorv 10: 61.6 % > reductionAtorv 80: 56.8 % > reduction Atorv 80 + zetia: 48.5 % > reduction


Trial Name

Patient Population


Result

GAUSS II14 Uncontrolled HLD 2 or more statin intolerances

1) Evolocumab2) Ezetimibe

20 % > reduction in LDL at 12 weeks

MENDEL II15 < 10 % CV risk and HLD 1) Evolocumab2) Ezetimibe3) Placebo

40 % > reduction than ezetimibe50 % > reduction than placebo


Trial Name

Patient Population


Result

RUTHERFORD II16

FH and HLD uncontrolled by current therapy

In addition to background therapy:

1) Evolocumab2) Placebo

60 % > reduction in LDL

LAPLACE II17 HLD uncontrolled on current therapy

1) Low intensity simvastatin, atorvastatin, or rosuvastatin

2) High intensity atorvastatin or rosuvastatin

3) Evolocumab4) Ezetimibe5) Placebo

40 to 50 % > reduction in LDL than ezetimibe55 to 75 % > reduction than placebo


Trial Name

Patient Population

Treatments * In addition to

statin

Result

TESLA Part B18

FH uncontrolled on current therapy

In addition to background:1) Evolocumab2) Placebo

30.9% > reduction than placebo

OSLER and OSLER II19

(open label)

HLD receiving therapy In addition to background:1) Evolocumab2) No change

4.4 % more AEs0.6 % > neurocognitive AE1.23 % less CV events(HR = 0.47 p<.003)

Clinical Trials For Evolocumab Awaiting Results

Trial Name

Patient Population


Endpoint

NCT01953328

JapaneseHigh CV risk and HLD

1) Low intensity atorvastatin2) High intensity

atorvastatin

1) Evolocumab2) Placebo

% change in LDL at week 10 and 12

NCT02304484(open label)

CVD and HLD In addition to background:1) Evolocumab2) No change

2 year safety endpoints

HAUSER-RCT 10-17 years oldFH uncontrolled by statin

1) Evolocumab *2) Placebo *



Trial Name

Patient Population


Result

FLOREY Moderate to low CV riskNo current therapy

1) Evolocumab2) Evolocumab +

atorvastatin3) Placebo

% change in LDL fractional catabolic rate at 60 days

NCT01984424

Statin intolerance history

Atorvastatin run in:1) Evolocumab *2) Ezetimibe *

% change in LDL at 22 and 24 weeks

GLAGOV CVD and currently on therapy

In addition to background:1) Evolocumab2) Placebo

Nominal change in % artheroma volume at week 78


Trial Name

Patient Population


Result

EBBINGHAUS CVD and non FH HLDExtension of FOURIER

FOURIER study patients on either statin plus evolocumab or statin plus placebo

Average change in spatial working memory

FOURIER CVD and non FH HLD 1) Evolocumab + statin2) Statin

Time to 1st event

Current Lipid Treatment Guidelines20

Clinical ASCVD

LDL > 190 mg/dL

DM 1 or 2 and age 40-75

ASCVD 10 y risk > 7.5 % and age 40-75

High intensity statin unless > 75 years old or intolerant

High intensity statin unless intolerant

High intensity statin unless 10 year ASCVD < 7.5 %

Moderate to high intensity statin

Current Lipid Treatment Guidelines20

No recommendation on LDL targets Addition of non-statin drug may be considered if baseline LDL >

190 Addition of non-statin drug in suboptimal statin response or

complete statin intolerance is considered a reasonable option

Why is there such a preference for statins? Why are there no longer LDL targets?

The Actual Evidence Statin drugs are the only class with actual mortality and morbidity

benefits studied in randomized controlled trials No RCT evidence that adjuncts to statin therapy add clinical benefit Actually evidence to the contrary:

AIM HIGH: niacin added to statin when LDL < 80 mg/dL provides no benefit23

ACCORD: adding fenofibrate to statin in patients with DM provides no benefit22

Focus Shift from LDL lowering to mortality and morbidity benefit No evidence for target LDL levels in terms of ASCVD event risk

reduction High intensity statin therapy ( > 50 % LDL reduction) provides more

clinical benefit than moderate intensity therapy ( 30-50 % LDL reduction)27

IMPROVE-IT21

High Risk Patients within 10 days of ACS

Placebo + Simvastatin 40 mg

Ezetimibe 10 mg + Simvasatatin 40 mg

Time to first event (CV death, MI, hospitalization for UA, coronary artery

revascularization > 30 days post randomization, or stroke)

Implications of IMPROVE-IT21

Ezetimibe + moderate intensity simvastatin produces modest ASCVD event rate reduction 6.4 % RRR (HR 0.936 p < 0.016)

Evidence that lowering LDL, not statin intensity, should be the goal

Further reduction of LDL beyond statins should be implemented

So can we expect PCSK9 inhibitors to show real clinical benefit based on the results of IMPROVE-IT?

Problems With IMPROVE-IT Ezetimibe also reduced expression of thrombomodulin, platelet

endothelial cell adhesion molecule, and vitronectin receptor24

Also improved multiple indices of platelet reactivity24

Conclusion that LDL reduction mediates ezetimibe ASCVD risk reduction is confounded

No evidence that these results extend to other lipid lowering agents

No evidence that addition to high intensity statin is also beneficial

How Much Did We IMPROVE-IT? Addition of ezetimibe reduced the risk of any endpoint, but did not reduce

deaths. Results were mainly driven by reduction in MI and stroke rates

The Average cost of MI in medicare patients is about 20,000 dollars (30 day total treatment)25

The average cost of a stroke over a patient lifetime has been estimated as about 100,000 dollars (all subtypes averaged)26

Assuming these are the only two events that occurred (probably most expensive scenario): in one year, 1 in 350 patients (NNT) treated with simvastatin but no Zetia

would cost an average of 60,000 dollars to healthcare In contrast, treating 350 patients for a year with Zetia would cost

($250/30 days * 12 month/year * 350 patients) about 1 million dollars. (good Rx)

This is a very expensive price for society to pay for such a small benefit

IMPROVE-IT and PCSK9 Inhibitors IMPROVE-IT does not necessarily ensure the clinical benefit of PCSK9I’s PCSK9 inhibitors cost $12,000 more per patient-year Given previous assumptions, for PCSK9 inhibitors to be cost neutral the

NNT would need to be 4 (compared to 350 for zetia) Even assuming $500,000/event cost, the NNT would need to be 33 Increasing statin intensity has a NNT/year of about 50, so PCSK9I’s

achieving an NNT of 33 is unlikely6

Health plan reactions will probably include: Negotiating lower prices from manufacturers in exchange for exclusivity Limiting beneficiary access through high coinsurance raising premiums for all members Involved prior auth process including proof of adequate exercise, adequate

trial of two statins, adequate trial of moderate statin with zetia, laboratory tested statin intolerance.

Recommended Use of PCSK9I’s

Based on current guidelines, available evidence, and economic considerations: Patients with FH or ASCVD and statin resistance (on max dose) for

additional LDL lowering is a reasonable strategy. Discuss with patient costs vs uncertain clinical benefit

In FH patients to avoid apheresis 2nd line to addition of ezetimibe for statin intolerant patients No evidence to support use of PCSK9I’s as monotherapy or for

arbitrary reduction of statin dose In complete statin intolerance, PCSK9I monotherapy should be considered

only after careful risk assessment and patient preference

Sources Clinicaltrials.gov

All trials with no published data 1Xue-Qiao Zhao. Pathogenesis of atherosclerosis. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 25, 2013.) 2Zocor® [package insert]. Whitehouse Station, NJ: Merck and Co. Inc; 1999. 3Zetia® [package insert]. Whitehouse Station, NJ: Merck and Co, Inc; 2001. 4Niaspan® [package insert]. North Chicago, IL: AbbVie Inc; 2015 5Questran® [package insert]. Spring Valley, NY: Par Pharm Co Inc; 2013. 6Tricor® [package insert]. North Chicago, IL: AbbVie Inc; 2013. 7Praluent® [package insert]. Bridgewater, NJ: Sanofi-Aventis LLC; 2015. 8Bays H1, Gaudet D1, Weiss R1, et al. Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. J

Clin Endocrinol Metab. 2015 Aug;100(8):3140-8. doi: 10.1210/jc.2015-1520. Epub 2015 Jun 1. 9Kereiakes DJ1, Robinson JG2, Cannon CP3, Lorenzato C4, Pordy R5, Chaudhari U6, Colhoun HM7. Efficacy and safety of the proprotein convertase

subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015 Jun;169(6):906-915.e13. doi: 10.1016/j.ahj.2015.03.004. Epub 2015 Mar 13.

10Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015 May 14;36(19):1186-94. doi: 10.1093/eurheartj/ehv028. Epub 2015 Feb 16.

11Eli M. Rotha, Marja-Riitta Taskinenb, Henry N. Ginsbergc, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: Results of a 24 week, double-blind, randomized Phase 3 trial. International Journal of Cardiology. Sept 14; 176(1): 55-61.

12Jennifer G. Robinson, M.D., M.P.H., Michel Farnier, M.D., Ph.D., Michel Krempf, M.D, et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. The new England journal of medicine. april 16, 2015: 372(16).

13Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. doi: 10.1056/NEJMoa1316222. Epub 2014 Mar 29.

14Stroes E1, Colquhoun D2, Sullivan D3, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2541-8. doi: 10.1016/j.jacc.2014.03.019. Epub 2014 Mar 30.

Sources 15Koren MJ1, Lundqvist P2, Bolognese M3, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III

clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2531-40. doi: 10.1016/j.jacc.2014.03.018. Epub 2014 Mar 29. 16Raal FJ1, Stein EA2, Dufour R3, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2):

a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):331-40. doi: 10.1016/S0140-6736(14)61399-4. Epub 2014 Oct 1 17Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C

lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014 May 14;311(18):1870-82. doi: 10.1001/jama.2014.4030.

18Raal FJ1, Honarpour N2, Blom DJ3, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):341-50. doi: 10.1016/S0140-6736(14)61374-X. Epub 2014 Oct 1.

19Sabatine MS1, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1500-9. doi: 10.1056/NEJMoa1500858. Epub 2015 Mar 15.

20Neil J. Stone, Jennifer G. Robinson, Alice H. Lichtenstein, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Circulation. 2014;129:S46-S48.

21Virani SS1, Akeroyd JM2, Nambi V3, Maddox TM4, Gillette MA5, Michael Ho P4, Rumsfeld J4, Petersen LA2, Ballantyne CM6. Implications for Ezetimibe Therapy Use Based on IMPROVE-IT Criteria. Am J Med. 2015 Jun 10. pii: S0002-9343(15)00511-2. doi: 10.1016/j.amjmed.2015.05.027.

22DiNicolantonio JJ1, Chatterjee S2, Lavie CJ3, Bangalore S4, O'Keefe JH5. Ezetimibe Plus Moderate-dose Simvastatin After Acute Coronary Syndrome: What Are We IMPROVEing On? Am J Med. 2015 Aug;128(8):914.e1-4. doi: 10.1016/j.amjmed.2015.01.034. Epub 2015 Feb 27.

23Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255-67. doi: 10.1056/NEJMoa1107579. Epub 2011 Nov 15.

24Miller M1, DiNicolantonio JJ, Can M, Grice R, Damoulakis A, Serebruany VL. The effects of ezetimibe/simvastatin versus simvastatin monotherapy on platelet and inflammatory biomarkers in patients with metabolic syndrome. Cardiology. 2013;125(2):74-7. doi: 10.1159/000347134. Epub 2013 May 7.

25Kim N1, Bernheim SM, Ott LS, Han L, Spivack SB, Xu X, Volpe M, Liu A, Krumholz HM. An administrative claims measure of payments made for Medicare patients for a 30-day episode of care for acute myocardial infarction. Med Care. 2015 Jun;53(6):542-9.

26Taylor TN1, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996 Sep;27(9):1459-66. 27van der Harst P, Voors AA, van Veldhuisen DJ. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med.

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