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Marcello Arca, MDDepartment of Internal Medicine and Allied Sciences
Regional Center for Rare Diseases of Lipid MetabolismSapienza University of Rome, Italy
Treatment of severe FH : Lomitapide
2ndSevere FH Course
Muscat, 2-3 December 2018
Disclosures
Arca has received payments for the provision of:
• Grants and consulting services: Aegerion,Akcea/Ionis, Alfasigma, Amgen, Amryt, Chiesi,Pfizer, Regeneron, Sanofi.
• Participation as a speaker at scientific meetings:Aegerion, Alfasigma, Amgen, Amryt, Pfizer,Sanofi
Lomitapide
Lomitapide is 99.8% bound to plasma proteins
Lomitapide mean terminal half life is 39.7 hrs
CYP3A4 is involved in lomitapide metabolism(M1 and M3 are the inactive metabolites)
Lomitapide undergoes extensive metabolismin the liver via oxidation, oxidative N-dealkylation and glucuronide conjugation
After single dose (60 mg), the time to reachthe Cmax is 6 hrs, in normals
Lomitapide is escreted in urine (55% as M1)and feces (33% as lomitapide)
Lomitapide is an MTP inhibitor
Triglycerides
Triglycerides
Apo B-100
MTP
VLDL
ChylomicronApo B-48
MTP
Hepatocyte
Enterocyte
↑TG results in ↑ hepatic fat
↑TG contributes to GI tolerability issues
MTP, microsomal trigyceride transfer proteinTG, triglycerides; GI, gastrointestinalCuchel M, Rader DJ. Curr Opin Lipidol 2013;24:246-50
-70%
-60%
-50%
-40%
-30%
-20%
-10%
0%
0 10 20 30 40 50 60 70 80
Mea
n %
Ch
an
ge
fro
m B
aselin
e (
95%
CI)
Study Week
Efficacy Phase Safety Phase
MeanDose (LOCF)(mg):
45 40 40
Cuchel et al. Lancet. 2012 online Nov 2. doi 10.1016/S0140-6736(12)61731
REDUCTION IN LDL-C LEVELS IN A PHASE 3 STUDY WITH LOMITAPIDE
Sustained efficacy
mean LDL-C reduction
~40-50% vs baseline
29 HoFH; aged >18 and older; median lomitapide dose 40 mg/day
Lomitapide efficacy – results of the phase 3 trial
0 10 18 26 36 46 56 66 78 90 102 114 126
17 17 16 17 17 17 17 17 17 17 17 17 17
Phase 3 Long-term extension
LDL-C, low-density lipoprotein cholesterolBlom DJ, et al. AHA. Orlando, Florida. 2015.
Time point, n (%)LDL-C goal
<2.5mmol/L <1.8mmol/L
Baseline 0 (0%) 0 (0%)
At end of Week 26 (n=23)1 8 (35%) 1 (4%)
At any time on treatment in phase 3(Weeks 0–78) (n=29)2 16 (55%) 9 (31%)
At any time on treatment in extension population (Weeks 0–126) (n=19)3 13 (68%) 9 (47%)
100
–10–20–30–40–50–60–70
Mea
n c
han
ge in
LD
L-C
, %±
SD
Week
TREATMENT-EMERGENT ADVERSE EVENTS
9
System organ class preferred term Efficacy phase
26 weeks
Safety phase
>26–78 weeks
n % n %
At least one adverse event 27 93 21 91
Gastrointestinal disorders 27 93 17 74
Infections and infestations 15 52 10 44
Investigations (e.g. weight loss, lab
abnormalities)
13 45 5 22
General disorders and administrative site
conditions
(e.g. fatigue, malaise)
8 28 7 30
Musculoskeletal and connective tissue
disorders
8 28 5 22
Injury, poisoning, and procedural
complications
(e.g. skin lacerations)
7 24 5 22
Nervous system disorders 6 21 3 13
Cardiac disorders 5 17 2 9
Hepatobiliary disorders 1 3 2 9
Lomitapide SPC, September 2017. Data on File
GASTROINTESTINAL TOLERABILITY AND SAFETY
• The most common adverse reactions are gastrointestinal effects including diarrhoea, nausea, dyspepsia and
vomiting.
• GI Adverse effects diminished in
frequency and severity over time
• To reduce the risk of
gastrointestinal adverse events,
patients should follow a diet
supplying less than 20% of
energy from fat
• Lomitapide may reduce the
absorption of fat soluble
nutrients. Patients should take
daily dietary supplements that
provide approximately 400 IU
vitamin E, and Omega 3 & 6
Long term changes in LDL-C, percent hepatic fat,
HOMA-IR, and hsCRP with lomitapide treatment
Dirk J. Blom et al. Circulation. 2017;136:332-335
LOMITAPIDE - OTHER REAL WORLD EVIDENCE – ITALIAN COHORT.
D’ERASMO ET AL. ADV THER 2017, 34:1200-1210
Methods
• Retrospective survey
• 15 patients with genetically confirmed HoFH
• On therapy for at least 6 months until July 2016
• No other criteria
• Five in Palermo, two in Cagliari, and one each in Naples, Rome, Milan, Chieti, Bari, Pisa, Ferrara and Orbassano
• Four patients were previously enrolled in the Phase 3 clinical trial and were continuing lomitapide treatment after the end of the trial
D’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
Demographics summary
Demographic factor Value
Genetic diagnosis, n
Mutation in LDLR
Mutation in LDLRAP1
10
5
Age, years 37.7±13.5
History of CV disease, n (%) 5 (33.3)
History of aortic stenosis, n (%) 6 (46.2)
Background LLT
Statin, n (%)
Statin + ezetimibe, n (%)
LDL apheresis, n (%)
4 (25)
9 (56.2)
10 (66.6)
Mean LDL-C at baseline, mg/dL 426.0±204.0
Mean dose of lomitapide, mg/day (range) 19.0±13.3 (5–60)
Mean duration of follow-up, months 32.3±29.7
CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapyD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
LDL-C value at baseline and nadirobserved in each patient
308
234
620
508470
168
267
843
551
726
242266
212
459
516
69 54 3975
144
25
104
44 41 45
134
231
44
157
280
0
100
200
300
400
500
600
700
800
900
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
LDL-
C, m
g/d
L
Patient ID
Baseline
Nadir
LDL-C, low-density lipoprotein cholesterolD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
Mean lipid
level ± SD,
mg/dL Baseline Nadir Last results Changes ∆, % Changes ∞, %
TC 492.7±201.0 132.0±58.5 167.8±92.0 68.5±16.9* 61.3±22.9*
LDL-C 426.0±204.0 81.9±56.0 113.7 ±86.8 76.5 ±16.7* 68.2±24.8*
HDL-C 45.0±17.8 40.7±12.1 44.0±13.8 –18.3±106.5 –26.5±106.6
Non HDL-C 447.7±204.1 90.9±58.6 123.3±87.0 75.3±16.9* 67.8±23.8*
TG 106.8±36.0 43.7±24.3 50.0±20.7 54.8 ±23.1* 52.8±20.5*
Plasma lipids changes with lomitapide
D, percentage reduction from baseline to nadir values; ∞, percentage reduction from baseline to last results; TC total cholesterol, HDL-C high density lipoprotein cholesterol, LDL-C low density lipoprotein cholesterol, NonHDL-C non-high density lipoprotein cholesterol, TG triglycerides; *significant P value <0.05 ; D’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
For patients on apheresis, plasma lipids profile is reported as the pre-apheresis values; data are reported for baseline with background therapies, at nadir of LDL-cholesterol and last reported results during follow-up after the adjunct of lomitapide
Wide between-subject variability in LDL-C reduction (range 13–97%)
Patients attaining EAS LDL-C targets1 (<100 and <70mg/dL) at any stage in the observation period2
9
8
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
<100 <70
Pati
ents
, n
LDL-C, mg/dL
LDL-C, low-density lipoprotein cholesterol1. Cuchel M, et al. Eur Heart J 2014;35:2146-57; cD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
60% 53%
Use of lipoprotein apheresis (LA)
*40% reduction in apheresis burden in the remaining four patientsHoFH, homozygous familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterolD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
500
400
300
200
100
0Baseline Nadir Last results
LA stoppedLA continued
LDL-
C, m
g/d
L
Compared to HoFH patients that continued LA, those that stopped LA, experienced more pronounced LDL-C
reductions during lomitapide treatment both at nadir and last visit
During follow-up, 8 patients (80%) permanently discontinued LA therapy based on the clinical
judgment of treating physicians*
100
80
60
40
20
0Baseline Followup
67
33
13
86
Pati
ents
, %
On LANo LA
What is driving variability in LDL-C responses?
ARH, autosomal recessive hypercholesterolaemia; HoFH, homozygous familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterolD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
500
400
300
200
100
0Baseline Nadir Last results
Lomitapide dose<10mg≥10<20mg≥20mg
LDL-
C, m
g/d
L
Lomitapide dose Genotype
100
80
60
40
20
0
Ch
ange
in L
DL-
C, %
ARHn=5
HoFHmissense
n=6
HoFH (othermutations)
n=4
No significant differencesbetween doses
No significant differencesbetween genotypes
Parameter Before lomitapide Nadir Last visit
Mean AST, U/L±SD 29.1±14.7 29.2±12.5 30.4±13.0
Normal, n 9 11 12
1x ULN time elevation, n 4 3 2
2x ULN time elevation, n 0 0 0
3x ULN time elevation, n 0 0 0
Mean ALT, U/L±SD 30.0±15.8 34.5±23.8 34.9±21.8
Normal, n 6 7 5
1x ULN time elevation, n 6 5 8
2x ULN time elevation, n 1 1 0
3x ULN time elevation, n 0 1 1
Degree of aminotransferase elevations accordingto range of normality
None of the patients developed persistent LFT elevations above 5x ULN
ALT, alanine aminotransferase; AST, aspartamine aminotransferase; LLT, lipid-lowering therapy; ULN, upper limit of normalD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
No AE DiarrhoeaNausea or vomiting
Abdominalpain
Patients, n (%) 8 (50.0) 7 (43.8) 3 (18.8) 2 (12.5)
Persistent,* n (%) - 4 (25.0) 2 (12.5) 1 (6.25)
Severity mild, n (%) - 2 (12.5) 2 (12.5) -
No patient had to stop lomitapide for persistent andsevere gastrointestinal side effects
*Defined as observed in more than two consecutive blood controlsAE, adverse eventD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
Summary of gastrointestinal AEs during treatment
• During 32.3±29.7 months follow-up, no patients stopped lomitapide due to AEs
• Most common AE was diarrhoea (53.3%), nausea and vomiting reported in three patients and abdominal pain in two patients
• Six patients were observed with Fibroscan/MRI; liver stiffness was within the normal range (n=5)
• At baseline, one of five patients had steatosis; increased in two patients at follow-up
Summary of tolerability and safety data
22AE, adverse event; MRI, magnetic resonance imagingD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
Target achievement and cardiovascular event rates with Lomitapide in HoFH
Data from two lomitapide studies: a single-arm, open label, Phase 3 clinical trial of lomitapide in adult patients with HoFH (NCT00730236; the‘pivotal trial’) and its single-arm extension study (NCT00943306; the ‘extension trial’).
Orphanet J Rare Dis. 2018 Jun 20;13(1):96
APHERESIS AS A COMPARATIVE THERAPY – OPTIMUM FREQUENCY TO ACHIEVE
RECOMMENDED LDL-C TARGETS
• If apheresis is administered every:
• 14 days = 26% reduction in
interval mean LDL-C
• Weekly = 36% reduction LDL-C
• 2 times a week = 47% reduction
LDL-C
• Based on the real world experience
with lomitapide showing up to 76%
reduction in LDL-C, apheresis would
need to be administered every day
to achieve a mean reduction in
LDL-C levels seen with lomitapide
Thompson et al. Atherosclerosis, 2015;18:16-20
In all patients as soon as possible• Dietary and life style recommendations• High potency statins plus ezetimibe
Lipoproteinapheresis
Weekly or bi-weekly
Lomitapide(start with low doses
and up-titrate)
Monitor patient’s health status(vascular status, liver function tests,
liver steatosis)
PCSK9 inhibitors(in patients with defective allele)
PCSK9 inhibitors(in patients with defective allele)
Patientsintolerant to lomitapide
Patientsintolerant to
statins/apheresis
Towards a tailored algorithm for the treatment of HoFH
Target LDL-C70–100mg/dL
+ +
HoFH, homozygous familial hypercholesterolaemia; LDL, low-density lipoproteinPCSK9, proprotein convertase subtilisin/kexin type 9
With special thanks to all the collaborating authors in HoFH and ARH
investigations
Individual lipid lowering therapies changesafter addition of lomitapide
ID Baseline Follow-up
1 Simvastatin 40mg + ezetimibe 10mg Oral LLT unchanged
2 Simvastatin 40mg + ezetimibe 10mg Oral LLT unchanged
3 LA + simvastatin + ezetimibe LA stopped after 3 months + oral LLT unchanged
4 LA + simvastatin + ezetimibe LA stopped after 2 months + ezetimibe stopped
5 NA NA
6 Rosuvastatin 40mg + ezetimibe 10mg + fenofibrate 145mg Oral LLT stopped
7 Rosuvastatin 40 mg + ezetimibe 10mg Oral LLT unchanged
8 LA + simvastatin 40 mg + ezetimibe 10mg LA stopped after 2 months + oral LLT unchanged
9 LA + simvastatin 40 mg + ezetimibe 10mg LA stopped after 2 months + oral LLT unchanged
10 LA + simvastatin 40 mg + ezetimibe 10mg LA stopped after 6 months + oral LLT unchanged
11 LA + atorvastatin 40 mg + ezetimibe 10mg LA stopped after 1 months + ezetimibe stopped
12 LALA stopped after 3 months; rosuvastatin 40mg + ezetimibe added
13 LA + rosuvastatin 20 mg + ezetimibe 10mg LA stopped after 1 month + oral LLT unchanged
14 LA LA
15 LA weekly + rosuvastatin 20mg LA bimonthly + oral LLT unchanged
LA, lipoprotein apheresis; LLT, lipid-lowering therapy; NA, not applicableD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
LDL-C VALUE AT BASELINE AND NADIR OBSERVED IN EACH PATIENT SHOWS UP TO 6 OUT OF 10 PATIENTS REACHED TARGET
308
234
620
508470
168
267
843
551
726
242266
212
459
516
69 54 3975
144
25
104
44 41 45
134
231
44
157
280
0
100
200
300
400
500
600
700
800
900
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Patient ID
Baseline
Nadir
LDL-C VALUE AT BASELINE AND NADIR OBSERVED IN EACH PATIENT OF A COHORT OF 15 PATIENTS RECEIVING TREATMENT WITH
LOMITAPIDE IN ITALY
• The addition of Lomitapide at the average dosage of 19 mg/day lowered LDL-C levels by 68.2 ± 24.8% and at the nadir by 76.5 ± 16.7%.
• At their last visit, 60% of patients showed LDL-C<100 mg/dL and 46.6% <70 mg/dL.
• 80% (8 of 10 patients) on apheresis were able to stop apheresis completely. The remaining 2 patients reduced apheresis by 40%
Adapted from D'Erasmo et al Adv Ther 2017 May;34(5):1200-1210.
Target levels: 100mg/dL70 mg/dL
NOVEL MECHANISM OF ACTION OF LOMITAPIDE TARGETS THE SOURCE OF LDL-C PRODUCTION IN THE LIVER AND FROM INTESTINAL ABSORPTION
30
Demographic, anthropometric and baseline characteristics
ID Origin Sex Age BMI Genotype Mutations CHD AoS CT HDL LDL TG Non HDL
1 Italy F 43 35.6 ARH c.432_433insA - - 399 64 308 134 335
2 Italy M 47 30.1 ARH c.432_433insA - + 301 40 234 130 261
3 Italy F 38 23.8 ARH c.432_433insA+c:65G>A + + 714 77 620 na 637
4 Italy F 48 20.7 ARH c.432_433insA+c:65G>A + + 564 40 508 82 524
5 Italy F 19 20.2 HoFH c.1135T>C + c.1195G>A - na 557 68 470 93 489
6 Italy F 23 19.3 HoFH c.265T>C + c.1775G>A - na 251 55 168 51 196
7 Italy F 34 20.8 ARH c.89-1G>C - - 331 41 267 117 290
8 Italy M 29 21.1 HoFH c.1646G>A + c.1846-?_2311+?del - - 900 30 843 134 870
9 Italy F 25 23.8 HoFH c.1618G>A +c.1775G>A - - 616 48 551 87 568
10 Italy M 38 20.8 HoFH c.1646G>A + + 748 na 726 72 741
11 Italy F 67 23.4 HoFH c.2054C>T - - 300 36 242 111 264
12 Italy M 49 25.6 HoFH c.1567G>A + - 341 59 266 80 282
13 Jordan M 52 22.5 HoFH c.1-156C>T + + 248 27 212 93 221
14 Italy M 32 19.9 HoFH c.2311+1 G>A - - 529 47 459 114 482
15 Italy F 20 17.3 HoFH c.68-?_1845+?del - + 592 37 516 198 555
AoS, aortic valve stenosis; ARH, autosomal recessive hypercholesterolaemia; BMI, body mass index; CHD, coronary heart disease; CT, total cholesterolHDL, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol; TG, triglyceridesD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
Maximum and last-visit reductions in LDL-Cobserved in each patient
-13
-45 -46
-61-66
-69
-77 -78 -79
-85 -85
-93 -94 -94 -95
-13
-45 -46-43
-66-69
-77 -78 -79-82
-85 -85
-94 -93 -95-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
12 11 15 7 14 5 2 1 13 6 4 9 3 10 8
LDL-
C c
han
ge f
rom
bas
elin
e, %
% nadir % last visit
LDL-C, low-density lipoprotein cholesterolD’Erasmo L, et al. Adv Ther 2017; doi:10.1007/s12325-017-0531-x
Patient ID
ADVERSE EFFECTS OF LOMITAPIDE RELATED TO THE MECHANISM OF ACTION
33
Prevention of
production and release
of VLDL-C by the liver
results in an increase
in hepatic fat
Prevention of
absorption of
chylomicrons from the
intestine results in GI
adverse effects
MEAN PERCENT CHANGE FROM BASELINE IN LDL-C
Blom et al. Circulation. 2017;136:332–335
Mean lipid
level ± SD,
mg/dL Baseline Nadir Last results
Changes ∆,
%
Changes ∞,
%
TC 492.7±201.0 132.0±58.5 167.8±92.0 68.5±16.9* 61.3±22.9*
LDL-C 426.0±204.0 81.9±56.0 113.7 ±86.8 76.5 ±16.7* 68.2±24.8*
HDL-C 45.0±17.8 40.7±12.1 44.0±13.8 –18.3±106.5 –26.5±106.6
Non HDL-C 447.7±204.1 90.9±58.6 123.3±87.0 75.3±16.9* 67.8±23.8*
TG 106.8±36.0 43.7±24.3 50.0±20.7 54.8 ±23.1* 52.8±20.5*
Plasma lipids changes with lomitapide
For patients on apheresis, plasma lipids profile is reported as the pre-apheresis values; data are reported for baseline with background therapies, at nadir of LDL-cholesterol and last reported results during follow-up after the adjunct of lomitapide
Lomitapide
