Experience with Lojuxta® in Italy

Experience with Lojuxta® in Italy Review of the recent experience of Lojuxta® in Italy with Lojuxta® used as an adjunct to apheresis

Claudia Morozzi Department of Molecular Medicine,

Sapienza University Rome, Italy

2

Traditional lipid-lowering therapies (statins and ezetimibe) are largely ineffective in HoFH patients, and extracorporeal lipoprotein apheresis (LA) forms the mainstay of treatment. Lomitapide is a microsomal triglyceride transfer protein inhibitor approved for the treatment of HoFH as an adjunct to LA. We undertook to examine the efficacy and safety of lomitapide in seven HoFH patients treated with LA in the Lipid Clinic and Therapeutic Apheresis Unit in Rome, Italy outside of a clinical trial setting.

Background

3

Methods Seven patients with genetically determined HoFH were treated with lomitapide in the normal course of their therapy. All patients received LA either weekly or biweekly. Lomitapide was administered according to the approved EU prescribing information. LDLC levels, liver enzymes and hepatic fat were monitored. Length of follow-up varied between 12 and 50 weeks.

4

Pa#ent Age Sex Diagnosis Muta#on(s),DNALDL-receptorac#vity,%ofcontrol/normal Comorbidi#es

1MD 32 Male HoFH TGC→TGGexon7,C331W(FH-Avellino-1) 9 SlightaorAcvalvedisease

2ST 24 Female HoFH g→a+1intron10,abnormalmRNAs(FH-Agrigento) <3

CAD+aorAcvalvedisease;bypass2009;aorAcand

mitralvalvesreplaced2009

3EAL 23 Female HoFH CCG→CTGexon14,P664L(FH-Frosinone-1) NA SlightaorAcvalvedisease

4SC 25 Male HoFHc.268G→A,p.D90N(D69N)c.666C→A,p.C222X(C201X)bothintheheterozygousstate

NA SlightaorAcvalvedisease

5AT 26 Female DHeFH TGT*CGTexon8,C358R(FH-Napoli-1)GTG→ATGexon10,V502M(FH-Bari-2) 10 ModerateaorAcvalvedisease

6YR 30 Female DHeFHDeleAonspromotersandexons1–2andc.1775G→A,Gly571Glu(bothin

theheterozygousstate)13.6 SlightaorAcvalvedisease

7RM 28 Female DHeFH DeleAon2bpexon10,Fs472(FH-Frosinone2) 20 ModerateaorAcvalvedisease

CAD,coronaryarterydisease;HoFH,homozygousfamilialhypercholesterolaemia;DHeFH,doubleheterozygousfamilialhypercholesterolaemia

Patient demographics

5

Pa#entLastpharmacotherapies

priortolomitapide

LAtreatmentTreatmentwithlomitapide+LA

startedStarted DuraAon(years) Frequency

1MD Intolerance 1990 25 Biweekly(weeklyunAlJuly2010) March2010

2ST SimvastaAn20mg/dayEzeAmibe10mg/day 1996 19 Biweekly

(weeklyunAlWeek27) January2014

3EAL SimvastaAn20mg/dayEzeAmibe10mg/day 2003 12 Biweekly July2014

4CS RosuvastaAn20mg/dayEzeAmibe10mg/day 2004 11 Weekly April2015

5AT AtorvastaAn40mg/dayEzeAmibe10mg/day 2011 4 Biweekly April2015

6YR RosuvastaAn10mg/dayEzeAmibe10mg/day 1993 22 Biweekly August2014

7RM RosuvastaAn5mg/dayEzeAmibe10mg/day 1996 19 Weekly April2015

LA,lipoproteinapheresis

Treatment history

6

Results After titration, lomitapide doses ranged from 10–30 mg/day for most (5/7) patients. One patient received lomitapide 50 mg/day and another 5 mg/day. Three patients achieved LDLC reductions of >50%. The patient on the lowest lomitapide dose did not gain significant benefit. Gastrointestinal adverse events were managed via alterations to dietary fat intake.

7

Pa#ent

Currentlomitapidedose(doseatnadir),mg

LDLCnadir*,mg/dL(percentchange,%) Adverseevents Notesonadverseeventmanagement

1MD

50(60) 49(83) MildGI

GIsymptomscorrectedwithdietarymodificaAons

2ST

30(30) 74(80) TransientALT/ASTelevaAons

LFTsresolvedontemporaryinterrupAonoflomitapide

3EAL 30(20) 150(40) Noneofnote

4CS 20(10) 150(5) Noneofnote

5AT 5(5) 101(32) Noneofnote Dosewillbeincreasedsoon

6YR 20(20) 62(76) Noneofnote ALTandASTlevelsincreased,butnot>3xULN

7RM 10(10) 126(36) Noneofnote

*Timeaveragedlow-densitylipoproteincholesterol;GI,gastrointesAnal;CPK,creaAnephosphokinase;ULN,upperlimitofnormal;ALT,alanineaminotransferase;AST,aspartateaminotransferase;LFT,liverfuncAontest

Efficacy and tolerability outcomes

SummaryofpaAentcases

PaAentcase1(MD)Male,age32yearsDiagnosis:HoFHMutaAon:• TGC→TGG(exon7)C331W• FH-Avellino-1• LDL-RacAvity9%ofcontrolComorbidityprofile:veryslightaorAcvalvedisease(clinicallynotsignificant)Candidateforapheresis:• StartedLAtreatmentin1990(6yearsold),alongwithmaximalLLT(staAn+ezeAmibe)• Lipoproteinapheresisschedulewaschangedfromweeklytobi-weeklywhenonlomitapideLomitapidedose:50mg/day,downAtraAonfrom60mg/daywasdeterminedtoachieveanopAmalbalanceforthepaAent

9HoFH,homozygousfamilialhypercholesterolaemia;LDL-R,low-densitylipoproteinreceptor;LLT,lipid-loweringtherapy

Pa#entMD:plasmaTCandLDLClevelsover#me

TC,totalcholesterol;LDLC,low-densitylipoproteincholesterol;LA,lipoproteinapheresis;QW,weekly;Q2W,bi-weekly10

0

50

100

150

200

250

300

350

400

450

500

MAR

MAR

AP

RIL

MAY

JUNE

JULY

AUGU

ST

SEPT

SEPT

OCT

DE

CFEB

APR

JUL

OCT

GE

N

MAR

JUN

SEP

DEC

MAR

JUN

SEP

NOV

FEB

MAY

AU

GNOV

DEC

JAN

FEB

FEB

MAR

MAR

MAY

MAY

JUN

JUL

JUL

AUG

AUG

SEP

OCT

NOV

TC

LDLC

2010 2011 201420132012

ΔTC:-64.8%ΔLDLC:-77.1%

2015Year

LAtreatmentintervalchanged:

QWtoQ2W

ΔTC:-62.9%ΔLDLC:-50%

Lomitapide60mg/day+biweeklyLA

Lomitapide50mg/day+biweeklyLA

EndofPhase3clinicaltrial

Lipidlevel,mg/dL

0

50

100

150

200

250

300

350

400

450

MAR

MAR

AP

RIL

MAY

JUNE

JULY

AUGU

ST

SEPT

SEPT

OCT

DE

CFEB

APR

JUL

OCT

GE

N

MAR

JUN

SEP

DEC

MAR

JUN

SEP

NOV

FEB

MAY

AU

GNOV

DEC

JAN

FEB

FEB

MAR

MAR

MAY

MAY

JUN

JUL

JUL

AUG

AUG

SEP

OCT

NOV

HDLC

NONHDLC

HDLC,high-densitylipoproteincholesterol;nonHDLC,non-high-densitylipoproteincholesterol;LA,lipoproteinapheresis;QW,weekly;Q2W,bi-weekly

Lipidlevel,mg/dL

11

Pa#entMD:plasmaHDLCandnonHDLClevelsover#me

ΔnonHDLC:−84.4%

ΔnonHDLC:−65.6%

LAtreatmentinterval

changed:QWtoQ2W Lomitapide60mg/day+biweeklyLA

2010 2011 201420132012 2015Year

Lomitapide50mg/day+biweeklyLA

EndofPhase3clinicaltrial

AST,aspartateaminotransferase;ALT,alanineaminotransferase;CPK,creaAnephosphokinase;LA,lipoproteinapheresis;QW,weekly;Q2W,bi-weekly

Pa#entMD:plasmaALT,AST,andCPKlevelsover#me

0

100

200

300

400

500

600

MAR

MAR

AP

RIL

MAY

JUNE

JULY

AUGU

ST

SEPT

SEPT

OCT

DE

CFEB

APR

JUL

OCT

GE

N

MAR

JUN

SEP

DEC

MAR

JUN

SEP

NOV

FEB

MAY

AU

GNOV

DEC

JAN

FEB

FEB

MAR

MAR

MAY

MAY

JUN

JUL

JUL

AUG

AUG

SEP

OCT

NOV

ALT

AST

CPK

2010 2011 201420132012

Level,IU/L

2015

EndofPhase3clinicaltrial

Year

LAtreatmentinterval

changed:QWtoQ2W

Lomitapide60mg/day+biweeklyLA

12

Lomitapide50mg/day+biweeklyLA

PaAentMD

•  Outcomes:– LAcombinedwithlomitapide50mg/dayresultedinasignificantreducAoninLDLC

– TheaddiAonoflomitapideallowedthefrequencyofLAtobereducedfromweeklytobi-weekly

– Safetyparametersshowednosignificantchangesinthelongterm

LA,lipoproteinapheresis;LDLC,low-densitylipoproteincholesterol

13

PaAentcase2(ST)Female,age24years(bornSeptember1991)Diagnosis:HoFHMutaAon:•  g→a+1(intron10),abnormalmRNAs•  LDL-RacAvity<3%(receptornegaAve)Comorbidityprofile:CAD(1996),aorAcvalvedisease(2008),aorAcandmitralvalvereplacement(January2009)Candidateforapheresis:•  StartedtreatmentinFebruary1996(4.5yearsold),alongwithmaximalLLT(staAn+ezeAmibe)

•  Weeklylipoproteinapheresis,extendedtobi-weeklywhenlomitapidedosewasAtratedupto30mg/day

StarAngdoseoflomitapide5mg,escalatedupto10mg,20mg&30mg/day

15HoFH,homozygousfamilialhypercholesterolaemia;CAD,coronaryarterydiseaseLDL-R,low-densitylipoproteinreceptor;LLT,lipid-loweringtherapy

16TC,totalcholesterol;LDLC,low-densitylipoproteincholesterol;HDLC,high-densitylipoproteincholesterol;TG,triglycerides;nonHDLC,non-high-densitylipoproteincholesterol;Lx,lomitapidexmg/day

Pa#entST:plasmalipidandlipoproteinprofileover#me

NolomitapideintakeduringWeeks34−37andWeeks42−43

NolomitapideintakeduringWeeks76−77andWeeks84−85

0

100

200

300

400

500

600

700

3 6 9 12151821242730333639424548515457606366697275788184879093

Δ%LDLC:−46Δ%TG:−33

Δ%LDLC:−20Δ%TG:−18

Δ%LDLC:−83Δ%TG:−77 Δ%LDLC:−83

Δ%TG:−77

Δ%LDLC:-30Δ%TG:-65

TCLDLCHDLCTGnonHDLCLi

pidlevel,mg/dL

Measurement

L5 L20 L30L10

WeeklyLA BiweeklyLA

0

20

40

60

80

100

120

1 4 7 1013161922252831343740434649525558616467707376798285889194

AST

ALT

CPK

GGT

17LDL-C,low-densitylipoproteincholesterol;LA,lipoproteinapheresis;Lx,lomitapidexmg/day

Pa#entST:plasmaAST,ALT,CPK&GGTlevels

Measurement

Level,IU/L

NolomitapideintakeduringWeeks34−37andWeeks42−43

NolomitapideintakeduringWeeks76−77andWeeks84−85

L5 L20 L30L10

WeeklyLA BiweeklyLA

PaAent2(ST)

•  Outcomes:– Regressionofxanthomas

– RegressionofADLCAocclusion– AorAcvalvereplacementin2009

– TheaddiAonoflomitapideallowedthefrequencyofLAtobereducedfromweeklytobiweekly

ADLCA,anteriordescendinglercoronaryartery;LA,lipoproteinapheresis

19

Foto Tommasa con data laurea Nov,252015CardiovascularPerfusionist

PaAentcase3(EAL)

Female,age23yearsDiagnosis:HoFHMutaAon:•  CCG→CTG(exon14),P664LComorbidityprofile:nocoronaryarterydisease;veryslightaorAcvalveinsufficiency(notclinicallysignificant)Candidateforapheresis:biweeklylipoproteinapheresisStarAngdoseoflomitapide5mg/day,escalatedupto10mg,20mgand30mg/dayprogressively

20HoFH,homozygousfamilialhypercholesterolaemia;LDL-R,low-densitylipoproteinreceptor

0

100

200

300

400

500

600

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53

TC

LDLC

HDLC

TG

PaAentEAL:plasmalipidprofileoverAme

ΔLDLC:-16.97%ΔTG:-19.87%

ΔLDLC:-33.3%ΔTG:-41.0%

LDL-C,low-densitylipoproteincholesterolLA,lipoproteinapheresis

Measurement

Lipidlevel,mg/dL

Lomitapide5mg/day

Lomitapide20mg/dayLomitapide10mg/day

BiweeklyLA

Lomitapide30mg/day

0

20

40

60

80

100

120

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53

AST

ALT

CPK

GGT

PaAentEAL:plasmaAST,ALT,GGT&CPK

ΔLDLC:-16.97%ΔTG:-19.87%

ΔLDLC:-33.3%ΔTG:-41.0%

LDL-C,low-densitylipoproteincholesterolLA,lipoproteinapheresis

Measurement

Level,IU/L

Lomitapide5mg/day

Lomitapide20mg/dayLomitapide10mg/day

BiweeklyLA

Lomitapide30mg/day

PaAentEAL

•  Outcomes:– LDLCreboundpost-apheresisappearedtobebluntedwithlomitapide

– AST,ALTandGGTlevelsremainedstableandbelowULNduringlomitapidetreatment

LDLC,low-densitylipoproteincholesterol;AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase;ULN,upperlimitofnormal

PaAentcase4(SC)Male,age25yearsDiagnosis:HoFHMutaAons:• c.268G→A,p.D90N(D69N)• c.666C→A,p.C222X(C201X)Bothintheheterozygousstate• LDL-RacAvitynotcurrentlyavailableComorbidityprofile:coronaryheartdisease;slight-moderateaorAcvalvediseaseCandidateforapheresis:commencedLAtreatmentin2004,alongwithmaximalLLT(staAn+ezeAmibe).LAschedulewaschangedfromweeklytobi-weeklywhenonLomitapide.StarAngdoseoflomitapide5mg/day,escalatedupto10mg/dayand20mg/dayprogressively

24HoFH,homozygousfamilialhypercholesterolaemia;LDL-R,low-densitylipoproteinreceptor;LLT,lipid-loweringtherapy

0

50

100

150

200

250

300

350

400

450

500

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 35 37 39 41 43 45 47 49

TC

LDLC

HDLC

nonHDLC

TG

25TC,totalcholesterol;LDLC,low-densitylipoproteincholesterol;HDLC,high-densitylipoproteincholesterol;nonHDLC,non-high-densitylipoproteincholesterol;TG,triglycerides

Lomitapide5mg/day

WeeklyLA

Measurement

Lipidlevel,mg/dL

Lomitapide10mg/day Lomitapide20mg/day

LAtreatmentintervalchanged:

QWtoQ2W

26

PaAentSC:plasmaAST,ALT,GGT&CPK

AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase;CPK,creaAnephosphokinase;LA,lipoproteinapheresis

Measurement

Level,IU/L

0

20

40

60

80

100

120

140

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45

AST

ALT

GAMMAGT

CPK

Lomitapide5mg/day

WeeklyLA

Lomitapide10mg/day Lomitapide20mg/day

LAtreatmentintervalchanged:

QWtoQ2W

PaAentSC

•  Outcomes:– ReboundLDLClevelspost-apheresisappearedtobebluntedwithlomitapide

– AST,ALTandGGTremainedstableandbelowULNduringlomitapidetreatment

LDLC,low-densitylipoproteincholesterol;AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase;ULN,upperlimitofnormal

PaAentcase5(AT)

DHeFH,doubleheterozygousfamilialhypercholesterolaemia;LDL-R,low-densitylipoproteinreceptor

Female,age26yearsDiagnosis:DHeFHMutaAons:• TGT→CGT(exon8),C358R• GTG→ATG(exon10),V502M• LDL-RacAvity10%ofnormalComorbidityprofile:nocoronaryheartdisease;moderateaorAcvalvedisease(notclinicallysignificant)Candidateforapheresis:biweeklylipoproteinapheresisStarAngdoseoflomitapide5mg/day

0

50

100

150

200

250

300

1 2 3 4 5 6

TCLDLCHDLCnonHDLCTG

Pa#entAT:plasmalipidandlipoproteinprofileover#me

TC,totalcholesterol;LDLC,low-densitylipoproteincholesterol;HDLC,high-densitylipoproteincholesterol;nonHDLC,non-high-densitylipoproteincholesterol;TG,triglycerides

Lomitapide5mg/day

BiweeklyLA

Measurement

Lipd

level,mg/dL

30

0

50

100

150

200

250

1 2 3 4 5 6

AST

ALT

GGT

CPK

Pa#entAT:plasmaAST,ALT,GGT&CPKlevels

AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase;CPK,creaAnephosphokinase;LA,lipoproteinapheresis

Measurement

Level,IU/L

Lomitapide5mg/day

BiweeklyLA

PaAentAT

•  Outcomes:– Byweek5,LDLCreboundappearedtobeslightlybluntedwithlomitapide5mg/day

– CPKlevelsfellsteadilyduringfirstfewweeksoflomitapidetreatment,andthenstabilised

– AST,ALTandGGTremainedstable

LDLC,low-densitylipoproteincholesterol;CPK,creaAnephosphokinase;AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase

Female,age30yearsDiagnosis:DHeFHMutaAons:•  DeleAonspromotersandexons1–2andc.1775G→A,Gly571Glu(bothintheheterozygousstate)

•  LDL-RacAvity13.6%ofcontrolComorbidityprofile:nocoronaryheartdisease;veryslightaorAcvalveinsufficiency(notclinicallysignificant)Candidateforapheresis:biweeklylipoproteinapheresisStarAngdoseoflomitapide5mg,escalatedupto10mg&20mg/dayprogressively

32DHeFH,doubleheterozygousfamilialhypercholesterolaemia;LDL-R,low-densitylipoproteinreceptor

PaAent6(YR)

0

50

100

150

200

250

300

350

400

450

500

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37

TC

LDLC

HDLC

TG

33

Pa#entYR:plasmalipidprofileover#me

LDLC,low-densitylipoproteincholesterolLA,lipoproteinapheresis

BiweeklyLA

Lomitapide5mg/dayLomitapide20mg/dayLomitapide10mg/day

NolomitapideinWeek20

RosuvastaAnstoppedfromWeek31

Measurement

Lipd

level,mg/dL

34

0

50

100

150

200

250

300

350

400

450

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37

AST

ALT

CPK

GGT

Pa#entYR:AST,ALT,CPK&GGTlevelsover#me

AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase;CPK,creaAnephosphokinase;LA,lipoproteinapheresis

Measurement

Level,IU/L

BiweeklyLA

Lomitapide5mg/dayLomitapide20mg/dayLomitapide10mg/day

NolomitapideinWeek20

RosuvastaAnstoppedfromWeek31

PaAentYR

•  Outcomes:– LDLCreboundpost-apheresiswasbluntedwithlomitapide,andtheeffectappearedtobemoremarkedathigherdoses

– AST,ALTlevelsincreasedwithlomitapide10mgand20mg/daybutdidnotexceed3xULN

LDLC,low-densitylipoproteincholesterol;AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase;ULN,upperlimitofnormal

36

July, 24 2013 Physics

PaAentcase7(RM)Female,age28yearsDiagnosis:DHeFHMutaAons:•  DeleAon2bp(exon10),Fs472(FHFrosinone2)•  LDL-RacAvity20%ofnormalComorbidityprofile:nocoronaryheartdisease;moderateaorAcvalvedisease(notclinicallysignificant)Candidateforapheresis:weeklylipoproteinapheresisStarAngdoseoflomitapide5mg/day,escalatedupto10mg/day

37DHeFH,doubleheterozygousfamilialhypercholesterolaemia;LDL-R,low-densitylipoproteinreceptor

0

50

100

150

200

250

300

350

400

450

500

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

TC

LDLC

HDLC

non-HDLC

TG

38

Pa#entRM:plasmalipidprofileover#me

TC,totalcholesterol;LDLC,low-densitylipoproteincholesterol;HDLC,high-densitylipoproteincholesterol;nonHDLC,non-high-densitylipoproteincholesterol;TG,triglycerides

Lipd

level,mg/dL

Lomitapide5mg/day

WeeklyLA

Measurement

Lomitapide10mg/day

39AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase;CPK,creaAnephosphokinase;LA,lipoproteinapheresis

Measurement

Level,IU/L

Lomitapide5mg/day

WeeklyLA

Lomitapide10mg/day

0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

AST

ALT

GGT

CPK

Pa#entRM:plasmaAST,ALT,GGT&CPKlevels

PaAentRM

•  Outcomes:– LDLCreboundpost-apheresisappearedtobebluntedwithlomitapide

– ALT,ASTandGGTremainedstableduringlomitapidetreatment

LDLC,low-densitylipoproteincholesterol;AST,aspartateaminotransferase;ALT,alanineaminotransferase;GGT,gamma-glutamyltranspepAdase

Timeaveraged

LDL

Clevel,mg/dL

Lomitapidedose,mg

60 30 20 10 5 20 10

%changeinLDLC

–83 –80 –40 –5 –32 –76 –36

Baselinevalueswerecalculatedasthemeanof2-3AmeaveragedLDLCvaluespriortoadministraAonoflomitapide.*Meanof2–3pre-lomitapideAmeaveragedLDLCvalues;**LowestrecordedAmeaveragedLDLClevel

Time averaged LDLC levels at baseline and nadir for each of the seven patients

42

Conclusion Lomitapide is an effective adjunct to LA in patients with HoFH. Adverse events are manageable; GI adverse events can be managed with a low-fat eating plan.