My students Shahid Raja and Poulomi Jana had presented this topic in our 22nd Student Scientific Society Conference in the department of Propaedeutic of Internal Diseases No.2

1. PCSK-9 INHIBITORS
PreparedandPresentedby:
ShahidRaja
PoulomiJana

2. ABSTRACT
• Cardiovascular diseases: leading cause of morbidity and mortality in the
world.
• Elevated Low-Density Lipoprotein-Cholesterol (LDL-C) levels is the major
riskfactor.
• Lower levels of LDL-C can effectively reduce the risk of cardiovascular
diseases.
• PCSK-9 plays animportant role in regulating the degradation of hepatic LDL
receptorsthatremoveLDL-Cfromthecirculation.
• PCSK-9 inhibitors area new class of agents for the treatment to reduce LDL-
Clevels.
• Two PCSK-9 inhibitors, alirocumab andevolocumab,have beenapproved to
treathypercholesterolemia.
• Through the inhibition of PCSK-9 and increased recycling of LDL receptors,
serumLDL-Clevelscanbesignificantlyreduced.

3. CHOLESTEROL SYNTHESIS
• Liveristhemajororganwherecholesterolissynthesized.
• AcetylCoAismetabolizedintoHMGCoA
• HMG CoA undergoes a reaction catalyzed by HMG CoA
reductase enzyme to make Mevalonate and this is the rate
limiting stepincholesterolsynthensis.
• Mevalonate undergoes a series of reaction to convert into
cholesterol.
• Cholesterol will have a negativefeedback effecton HMG CoA
reductaseaswellasthegeneencodingfortheLDLreceptor.
• So there will be less LDL receptors expressed on the cell
membraneofhepatocyte.

4. CHOLESTEROL SYNTHESIS
• The cholesterol is converted into cholesterol ester by ACAT enzyme
(Acylcholesterolacyltransferase).
• Now thecholesterol ester will be loaded on to ApoB100 to make VLDL
molecule
• VLDL is released into the circulation and VLDL undergoes metabolism
tomakefirstIDLandthenLDLmolecules.
• 60% of circulatingLDL will gobackto the liverand40% is taken upby
extrahepatictissues.
• So for LDL to get into the cells it has to bind to LDL receptor that is
expressedonthecellmembraneofhepatocytes.
• LDL receptor has got an extracellular domain and also a cytoplasmic
domain.
• LDL interacts with the LDL receptor and it is internalized into the
cytoplasmmakingaLDL-LDLreceptorendosome.

5. CHOLESTEROL SYNTHESIS
• Theendosomefuseswiththelysosome.
• Inthelysosome,LDLisbrokendownandthecholesterolgetsintothecell.
• In theendosome, thereisadrop in thepH andbecauseof thedrop in thepH
there will be change in the confirmation of the interaction of LDL receptor
with the LDL. So because of the change in that conformation, LDL receptor
will be circulated back to the surface of the hepatocyte membrane or any
othercell.
• So,itmeans thereisarecycling ofLDL receptor.LDLreceptor comesback to
themembraneagain. Note,that LDLreceptor isa short livedmolecule witha
halflifeofonly20minutes.Soevery5minutesitundergoesrecycling.
• Thereceptor is recycledback. It means there is availabilityof LDL receptor
onthesurface.

6. PCSK-9
• PCSK-9 (Proprotein convertasesubtilisin/kexin type 9 serine protease)controls theamount
of cholesterol that is presentinsidethe cell.It means, ifthere is more cholesterol insidethe
cell,PCSK-9aresynthesizedandtheybindtotheextracellulardomainof theLDLreceptor.
• Because of the binding of PCSK-9 with the LDL-LDL receptor complex the entire thing
becomesapartoftheendosome.
• PCSK-9 boundLDL receptordoes not undergoconfirmation changeand the entirecomplex
istakenupbythelysosome.
• Instead ofLDL receptors recirculating back tothe surface because ofthe bound PCSK-9, it
isdegradedbythelysosome,intoaminoacids.

7. PCSK-9
• LDL receptordoes not comeback to thesurface of
hepatocytestotakeupmoreLDLmolecules.
• So, PCSK-9 molecules enhances the degradation
of LDL receptor, thereby decreases the availability
of LDL receptor on the surface of plasma
membrane. Because of this, the circulating LDL is
nolongergettingintothecell.
• Shortly after its discovery in 2001, the gene
encoding PCSK9 was implicated in familial
hypercholesterolemia(FH).

8. PCSK-9 INHIBITORS
• There are 2 PCSK-9 inhibitors that has been approved
by the FDA, Evolocumab (Repatha) and Alirocumab
(Praluent).
• These aremonoclonalantibodies, which arereferred as
PCSK-9inhibitors.
• These monoclonal antibodies bind with the PCSK-9
molecules. Hence PCSK-9 cannot bind to the LDL
receptor.
• ThusLDLreceptorscan berecycled,therebyenhancing
LDLmoleculereuptakebythehepatocytes.
• ThusreducingtheamountofcirculatingLDL.

9. PCSK-9 INHIBITORS (INDICATION)
• Thedrugsareapprovedforthefollowingindications:
• PatientswithheterozygousFH
• IndividualswithASCVD(Atheroscleroticcardiovasculardisease)
• Patientswhoareunabletoachieveasufficientlylowcholesterolleveloncurrentlyprescribedmedications
• Patientswhoareunabletotolerateothercholesterolloweringmedications.
• Onereview ofstudies foundthatPCSK-9inhibitors slash LDLlevelsby anaverageof47%.This canprevent heartattacks
orstrokes:Thedrugswereshowntoreducetheriskofheartattackby27%.
• Bothmedications,EvolocumabandArilocumabhavetheoptiontobeinjectedsubcutaneously.
• Evolocumab(Repatha),140mgeverytwoweeksor420mgmonthly.
• Alirocumab(Praluent),75-150mgeverytwoweeks.
• PCSK9inhibitorscanbeusedwithstatinstoboosttheirbenefit.ThecombinationcanlowerLDLlevelsbymorethanhalf.

10. PCSK-9 INHIBITORS (SIDE EFFECTS)
• Commonadverseeffects(seenin≥5percentoftreatedpatients)included:
• upperrespiratorytractinfections
• nasopharyngitis
• influenza(symptomssuchassorethroat,runnynoseandfever)
• injectionsitereactions(redness,itchingorpainatthesiteofinjection)
• nausea,diarrheaandfatiguemayoccuraswell
• Forevolocumab,backpainwasadditionallydescribed.
• Andlastly,thismedicationmaycauseariseinbloodsugarlevel.
• Thesedrugsmayalsocauseanallergicreactionincertainpeople.

11. MANAGEMENT OF LDL

12. CHALLENGES
• Thesedrugsaren’tcheap.Theprice
tagringsinatmorethan$14,000per
year.
• Butuntilsuchtimethatnovelgenetic
therapiesaredevelopedwellenough
tobetestedonhumans,PCSK9
inhibitorsremainthenewestyetsafe
weaponwhichclinicianshaveattheir
disposalinthebattleagainst
atheroscleroticdisease.

13. THANK YOU