PCSK9 Inhibitors

PCSK9 InhibitorsDr. Ankur Banik2nd Year PGTDept Of General MedicineBMCH

I am going to be presenting on the much anticipated PCSK9 inhibitors; the touted game changers in the field of lipid disorder. In order to fully understand the impact of these agents, we must understand the full picture of why we treat hyperlipidemia and how our understanding of cholesterol modifying therapies has evolved over time.1

BackgroundPCSK 9 inhibitors are a group of newer drugs against dyslipidemia primarily having role in reduction of LDL-cholesterol.Patients who are eligible for statin therapy but are considered to be statin intolerant, or having sub optimal response to statins, inhibition of proprotein convertase subtilism/kexin type9 (PCKS9) has been proposed as an alternative mechanism of action for lowering LDL cholesterol.2

Hyperlipidemia and Atherosclerosis

Lets begin with a basic overview of how hyperlipidemia leads to serious health complications: endothelial dysfunction occurs due to many factors, including high blood glucose, smoking, and oxidized LDL particles. LDL begins to enter the endothelium and activate resident macrophages to produce chemokines and inflammation. Macrophages cells collect under the intima and become foam cells as they scavenge LDL particles. This process leads to necrosis and apoptosis with even more inflammatory consequences. Smooth muscle cells and ECM begin to abnormally proliferate. The luminal exterior becomes fibrous and the internal portions of this mass become necrotic and calcified. As the mass becomes larger, it occludes blood flow, or disrupts the coagulation resistant luminal epithelium layer, causing clot formation and downstream ischemia. These two events lead to clinical events including angina pain, myocardial infarction, and stroke. The development of these sequalae are most related to elevated levels of low density lipoprotein particles, which is why LDL has been the target of most pharmaceutical therapies to date. 3

Established Therapies For HyperlipidemiaHMG-CoA Reductase InhibitorsDecrease hepatic production of cholesterol via synthesis blockadeIncreases density of LDL cell surface receptors in the liver which increases uptake from the plasmaMost reduction in LDLNiacinReduces FFA release from fat tissue and increases lipoprotein lipase action

Early in our investigation into atherosclerosis and CVD, etiologic studies demonstrated that LDL levels were the most consistent predictors of CVD, but other cholesterol levels, such as HDL and triglycerides were also deemed important. Therefore, many medications were developed to treat patients with abnormal lipid levels, particularly high LDL levels, in an attempt to prevent atherosclerosis and clinically evident CVD. Statins or HMG CoA inhibitors have become the most successful of these drugs. They work by inhibiting cholesterol synthesis in the liver, increasing LDL receptor density on the liver cells, and thereby reducing LDL levels in the blood. Ezetemibe blocks cholesterol absorption from the intestines, again reducing levels in the blood stream both directly and through liver absorption. Niacin increases lipoprotein lipase action, increasing fat storage in HDLs and uptake of triglycerides into tissues.4

Established Therapies For HyperlipidemiaBile Acid ResinsBind to bile and prevent its reabsorption, thereby depleting cholesterol storesUsed in mild hyperlipidemia with no hypertriglyceridemiaFibratesIncrease lipoprotein lipase activity, uptake of triglycerides from plasma, and increased synthesis of HDLUsed mainly for hypertriglyceridemiaEzetimibeBlocks cholesterol absorption in the intestines causing liver to absorb LDL from blood stream

Bile acid resins bind to bile and cause its excretion out of the body. This depletes cholesterol stores and impairs the digestion and absorption of fats. Fibrates increase lipoprotein lipase activity like niacin, and are used mainly in the treatment of hypertriglyceridemia.5

Why the need for newer drugs ?

Limitations of current therapiesStatins typically reduce LDL-C levels by 30-40% max depending on the dose and CVE by 30-35% at best even on optimum dose therapy.Efficiency of statins: Doubling the dose of the statin decreases the LDL level further by only 6%Side effects: Muscle weakness, GI intolerance, risk of Type II diabetes etc.Functional limitations of statins as a therapeutic class: Target level for LDL-C is not met consistentlyPoor adherence to long term regime of dosing

11/22/2016Pharma Reading: Group No. 67

Increasing the dosage of statins due to lack of efficiency/progression of disease may not result in proportionate decrease in cholesterol level.Rhabdomyolosis: Muscle breakdown and degradation, pain in muscles, myopathyIntolerance: Gastrointestinal disturbances, immune reactions, etc.NCEP-ATP: National Cholesterol Education Program Adult Treatment Panel7

11/22/2016Pharma Reading: Group No. 68

New Approaches to LDL ReductionEzetimibe is and will be the only cholesterol absorption inhibitor in clinical useSqualene synthase inhibitor development was discontinued because of liver toxicityThe thyroxine receptor agonist Eprotirome study in FH (Akka) was halted for toxicity in animals

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PCSK 9 Inhibitors: Mechanism of actionPCSK9 is a protease that degrades LDL receptors on hepatocytes.

11LDL Receptor Function and Life Cycle

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12PCSK9 & LDL Receptor Expression

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13Anti-PCSK9 & LDL Receptor Expression13

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The PCSK9 inhibitors have a unique mechanism of action. Normally, PCSK9 (proprotein convertase subtilisin/kexin 9) binds to LDL receptors as LDL causes receptor mediated endocytosis. This ultimately leads to the degradation of the LDL receptor in the resulting lysosome. PCSK9 inhibitors prevent this process from occurring, allowing LDL receptors to be recycled to the cell surface. This effectively achieves the same end as statinsincrease LDL receptor density.

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Emerging TherapiesRNAi TherapeuticsGenetic targets11/22/2016Pharma Reading: Group No. 615

CVD: Cardiovascular DiseaseGOF: Gain-of-function mutation, activating certain genes abnormally as a result of mutationCHD: Coronary Heart DiseaseLOF: Loss-of-function mutation, deactivating certain genesIndian population with Hypercholesterolemia: 13.9% in four representative regions of India both rural and urban15

11/22/2016Pharma Reading: Group No. 616

Comparison with Statins: Statins act on the HMG-CoA reductase enzyme interrupting the chain synthesis of cholesterol.Enzymatic inhibition of Statin vs Genetic modulation and receptor modulation of PCSK-9 inhibitors MabsDiffused target (Statins) vs Specific, well defined and differentiated genetic target (PCSK-9)16

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The PCSK9 protein appears to control the number of low-density lipoprotein receptors

PCSK9 InhibitorsThere are three drugs in this class being developedAll are monoclonal antibodies for subcutaneous injection

AlirocumabCurrently marketed by Sanofi Evolocumabmarketed by AmgenBococizumabExpected release around 2017-2018 by Pfizer

PCSK9 Inhibitors: General FactsReduce LDL-C in the range of 40-72% from baseline either in combination with statins or as monotherapy.Also reduce apoB and total cholesterol significantly.Modest increase in HDL-C and decrease in TG.Given by s.c injections once or twice a month.Safety and tolerability profile have so far been excellent.The cost of these drugs are pretty high.

Alirocumab (Praluent) Sanofi7Stability at room Temp: 24 hoursRefrigeration and light protection requiredPre-filled glass syringes or pre-filled pensAdministered at either 75 mg or 150 mg subcutaneously q 2 weeksRoom temp for 30-40 minutes before administrationCurrently FDA approved for addition to maximally tolerated statin dose for Familial Hypercholesterolemia or those with clinical ASCVD with sub optimal LDL-Lowering $14,600 for 1 year of therapy

Alirocumab is newly on the market. Some notable features for clinicians are its room temperature stability for 24 hours and requirement for refrigeration and protection from light. It comes in prefilled pens or syringes at 75 and 150 mg doses to be given twice weekly. It garnered FDA approval for addition to max tolerated statin dose in FH and ASCVD patients with sub-optimal LDL lowering.

Now that we have introduced the PCSK9 inhibitors, lets discuss the evidence we have seen to date in clinical trials.20

Clinical Trials For Alirocumab Trial NamePatient PopulationTreatments * In addition to statinResultOdyssey Options I8ASCVD and HLD uncontrolled by atorvastatin1)Alirocumab *2)Ezetimibe *3)Placebo *4)Double atorvastatin dose5)Switch to rosuvastatin 40 2 times > reduction in LDLOdyssey Combo I9CVD and HLD uncontrolled by max tolerated statin doseAlirocumab *Placebo *45.9 % > reduction in LDLOdyssey Combo II10CVD and HLD uncontrolled by max tolerated statin doseAlirocumabEzetimibe29.8 % > reduction in LDL at week 24

Several important studies for Alirocumab have published results.

Options I compared the addition alirocumab to atorvastatin 20 or 40 mg to the addition of ezetimibe or placebo, the doubling of the atorvastatin dose, or the switching to rosuvastatin 40 mg. Alirocumab reduced LDL by at least twice as much as all comparators. (44.1 % and 54 % reduction for 20 and 40 mg atorvastatin respectively)

COMBO 1 and 2 basically demonstrated that in addition to statins, Alirocumab produces additional reduction in LDL by 45 % compared to placebo and 30 % compared to ezetimibe.21

Clinical Trials For Alirocumab Trial NamePatient PopulationTreatments * In addition to statinResultNCT0164447411Moderate CV risk Not on HLD therapyAlirocumabEzetimibe31 % > reduction in LDL Odyssey Long Term12(open label)HLD currently on therapy In addition to background therapy:

AlirocumabPlacebo61.9 % > reduction of LDL

1.6 % < CV events

Another RCT demonstrated alirocumab monotherapy to be superior in LDL reduction than ezetimibe monotherapy (by 31 %) in patients with moderate CV risk.

The biggest study, arguably, was Odyssey long term, which in addition to showing that alirocumab was far superior to placebo in reducing LDLs when added to background therapy, also demonstrated 1.6 % less pooled CV events when safety data were analyzed. 22

Clinical Trials For EvolocumabTrial NamePatient PopulationTreatments * In addition to statinResultDESCARTES13Background therapy of:

DietAtorvastatin 10 mgAtorvastatin 80 mgAtorvastatin 80 + ZetiaIn addition to background therapy:EvolocumabPlaceboDiet: 55.7 % > reduction Atorv 10: 61.6 % > reductionAtorv 80: 56.8 % > reduction Atorv 80 + zetia: 48.5 % > reduction

Evolocumab has several important Phase three RCTs with published results as well.

DESCARTES demonstrated vast superiority over placebo when added to diet, low or high intensity atorvastatin, and high intensity atorvastatin plus ezetimibe

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DESCARTES: UC LDL-C Goal AchievementDiet AloneDiet + Atorvastatin10 mgDiet + Atorvastatin80 mgDiet + Atorvastatin80 mg +Ezetimibe 10 mgLDL-C < 70 mg/dL at Week 52Total

DESCARTES: Other Lipids

06%-202463%(-17 to 25)-9%(-26 to 13)2%ApoBLp(a)HDL-CApoA1Triglycerides-42%-50-40-30-20-10010-1%2%-2-10123-6%(-21 to 1)-28%(-49 to -6)-30-25-20-15-10-50

Placebo QMEvolocumab 420 mg QMPercent Change fromBaseline, Mean (%)Percent Change fromBaseline, Median (%)Percent Change fromBaseline, Median (%)Percent Change fromBaseline, Mean (%)Percent Change fromBaseline, Mean (%)-6-4-20246-10-8Error bars represent standard errorData in parentheses represent Q1 to Q3

Clinical Trials For EvolocumabTrial NamePatient PopulationTreatments * In addition to statinResultGAUSS II14Uncontrolled HLD 2 or more statin intolerancesEvolocumabEzetimibe20 % > reduction in LDL at 12 weeksMENDEL II15< 10 % CV risk and HLDEvolocumabEzetimibePlacebo40 % > reduction than ezetimibe50 % > reduction than placebo

GAUSS II demonstrated that evolocumab was superior to ezetimibe in reducing LDL as early as week 12 in those who were intolerant to two or more statins

MENDEL II demonstrated superior LDL lowering than ezetimibe and placebo in patients with < 10 % CVD risk26

Clinical Trials For EvolocumabTrial NamePatient PopulationTreatments * In addition to statinResultRUTHERFORD II16FH and HLD uncontrolled by current therapyIn addition to background therapy:

EvolocumabPlacebo60 % > reduction in LDLLAPLACE II17HLD uncontrolled on current therapyLow intensity simvastatin, atorvastatin, or rosuvastatinHigh intensity atorvastatin or rosuvastatin

EvolocumabEzetimibePlacebo40 to 50 % > reduction in LDL than ezetimibe55 to 75 % > reduction than placebo

RUTHERFORD II affirmed the superiority of evolocumab to placebo in reducing LDL in patients with FH inadequately controlled by current therapy

LEPLACE II compared addition of evolocumab, ezetimibe or placebo to patients randomized to baseline statin therapies of various agents and intensities. Across all statins and intensities, evolocumab produced greater reductions in LDL than ezetimibe or placebo27

Clinical Trials For EvolocumabTrial NamePatient PopulationTreatments * In addition to statinResultTESLA Part B18FH uncontrolled on current therapyIn addition to background:EvolocumabPlacebo30.9% > reduction than placebo OSLER and OSLER II19(open label)HLD receiving therapyIn addition to background:EvolocumabNo change4.4 % more AEs0.6 % > neurocognitive AE1.23 % less CV events(HR = 0.47 p 190 mg/dLDM 1 or 2 and age 40-75ASCVD 10 y risk > 7.5 % and age 40-75High intensity statin unless > 75 years old or intolerantHigh intensity statin unless intolerantHigh intensity statin unless 10 year ASCVD < 7.5 %Moderate to high intensity statin

According to the most recent AHA/ guidelines, its all about statins. There are four main groups which have proven benefits in morbidity and mortality when receiving statin therapy: clinical CVD, high baseline LDLs, older patients with diabetes, and > 7.5% ASCVD 10 year risk. The only decisions to make are 1) whether to initiate a statin or not and 2) at what intensity?

(high intensity > 50% reduction in LDLs moderate intensity 30 50 %)30

Current Lipid Treatment GuidelinesNo recommendation on LDL targetsAddition of non-statin drug may be considered if baseline LDL > 190Addition 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 new treatment guidelines also trash the established standard of treating patients to a target LDL level. Furthermore, the addition of other cholesterol medications to statins to achieve further reduction of LDL is considered unnecessary. It is only recommended in patients with very high baseline LDLs. Even patients who cannot tolerate max doses of statins are merely instructed to maintain whatever dose of statin they can tolerate. The addition of other therapies is relegated to the status of reasonable option. 31

The Actual EvidenceStatin drugs are the only class with actual mortality and morbidity benefits studied in randomized controlled trialsNo RCT evidence that adjuncts to statin therapy add clinical benefitActually evidence to the contrary:AIM HIGH: niacin added to statin when LDL < 80 mg/dL provides no benefit23ACCORD: adding fenofibrate to statin in patients with DM provides no benefit22Focus Shift from LDL lowering to mortality and morbidity benefit No evidence for target LDL levels in terms of ASCVD event risk reductionHigh intensity statin therapy ( > 50 % LDL reduction) provides more clinical benefit than moderate intensity therapy ( 30-50 % LDL reduction)

If we ignore the established practice of many years, and look at the strongest RCT evidence to date, we see that Statin drugs are the only class of drug with proven mortality and morbidity benefits.

For a long time, no evidence even existed that addition of other therapies to statins added any benefit beyond LDL lowering.

In fact Niacin added to statins and fenofibrate added to statins actually failed to show any clinical benefit beyond lipid profile changes

This strict reevaluation of evidence led experts to conclude that the only evidence based therapy for improving patient outcomes is to give statins to those groups that benefit most. All other therapies are generally considered optional because there is uncertainty in their actual benefit.

The expert panel also found no evidence to support treating patients to specific goals of LDL. They only found evidence that reducing LDLs 30-50 % with statin therapy provided benefit to certain groups, and reducing LDLs more than 50 % with statin therapy provided incremental benefit for some groups.32

Recommended Use of PCSK9IsBased 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 benefitIn FH patients to avoid apheresis2nd line to addition of ezetimibe for statin intolerant patientsNo evidence to support use of PCSK9Is as monotherapy or for arbitrary reduction of statin doseIn complete statin intolerance, PCSK9I monotherapy should be considered only after careful risk assessment and patient preference

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Clinical Approval in Europe and USAThe European Medicines Agency in July 2015 has approved Evolocumab as an adjunct to diet in patients who are unable to reach their recommended LDL-C goals despite taking optimal dose of statins. They have also approved it of use in homozygous FH.US FDA are yet to approve of Evolocumab.US FDA have approved Alirocumab in patients with FH, clinical ASCVD in conjunction with maximally tolerated statin therapy and diet modification failing to reach LDL-C targets and statin intolerance.

Praluent - alirocumab Clinical ApplicationContraindications:Serious hypersensitivity reactionBlack Box warnings: noneWarning and Precautions:Hypersensitivity reactionsPotential for immunogenicityPraluent [package insert].

Praluent - alirocumab Clinical ApplicationPregnancy:Category CLactation:Unknown if excreted in human breast milkHuman IgG is present in human milk, but data suggest breast milk IgG antibodies do not enter infant circulation in substantial amountsPraluent [package insert].

Praluent - alirocumab Drug InteractionsDrug Interactions Precipitant Drugs: Statin reduces half-life of alirocumab to 12 daysNot clinically significantPraluent [package insert].

Praluent - alirocumab Monitoring ParametersEfficacy Monitoring:LDL-C within 4 to 8 weeksPraluent [package insert].

Praluent - alirocumab Prescription InformationDosing:Initial dose: 75 mg SC every 2 weeksMax dose: 150 mg SC every 2 weeks

Cost: NY Times accessed 8/11/1575 mg or 150 mg injection: $14,600/yearPraluent [package insert].

Praluent - alirocumab Prescription InformationAdministration:Warm to room temperature for 30 to 40 min prior to useInject SC into stomach, upper arm, or thighsRotate injection sites

Praluent [package insert].

Take Home MessagesPCSK 9 inhibitors are probably the most promising amongst all the newer dyslipidemic drugs with the potential to be the next wonder drug after statins.They have already been approved for use in FH, statin intolerance, failure to achieve LDL-C goals despite optimal doses of statins in high risk individuals.Although the results of a few long term trials are awaiting, efficacy and safety wise they have shown great results.High cost of therapy remains an issue.

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