experience with lojuxta® in italy
TRANSCRIPT
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.