Lompitapide and Mipomersen

Raul D. Santos MD, PhDInCor-University of Sao Paulo

Brazil

1

Disclosure

• Honoraria received for consulting, speaker or researcher activities : Astra Zeneca, Amgen, Biolab, Kowa, Pfizer, Merck, Novo-Nordisk, PROCAPS, Sanofi/Regeneron.

2

Lomitapide and Mipomersen

• The importance of LDL-C lowering in HOFH

• MTP inhibition

– Lomitapide

• Apo B antisense therapy

– Mipomersen

HOFH Outcomes: South Africa Experience with classical LLT

Circulation 2011;124:2202-2207

50% Survival

Raal F J et al. Circulation. 2011;124:2202-2207

Thompson GR et al EHJ 2017 doi:10.1093/eurheartj/ehx317

On Treatment LDL-C and Mortality in HoFH

N=13325 y FUP

Lomitapide

Lomitapide: Mechanism of action

8Moriarty P & Santos RD In Clinical Lipidology: A companion to Braunwald’s Heart DIsease 2015

Lomitapide:!Mecanismo!de!ação!

13!p0300 Lomitapide causes a higher rate of gastrointestinal sideeffects and aminotransferase elevations than does ezeti-mibe. However, all adverse events disappeared after drugdiscontinuation.

s0145 Phase 3 Studyp0305 Research has shown that HoFH patients given an average

dose of 40mg/day of lomitapide had reductions in LDL-C,apoB, and TGconcentrationsof 50%, 49%, and 45%, respec-tively,after 26weeksof treatment. Similarly,Lp(a) andHDL-Clevelswerereduced at week 26, but theselevelsreturnedto baseline by week 78(Table 38-7). Of 29HoFH patientswho took lomitapide, 3 were able to discontinue LA, and3 otherspermanently increased the time interval betweenLA treatments.133

s0150 Safetyp0310 Phase3studiesindicate that themost common sideeffects

(seenin28%ofpatients) of lomitapidearediarrhea, nausea,vomiting,dyspepsia,andabdominal pain.133Approximatelyone third of study participantshad an elevation in at least

one liver enzyme to greater than or equal to three timesthe upper limit of normal. Approximately 14% of studypatientshad elevated liver enzymesat greater than or equalto five times the upper limit of normal. Dose reduction ortemporary drug discontinuation resulted in normalizationof liver enzymes. No clinically significant changesin biliru-bin, prothrombin time, or alkaline phosphatase occurred.As expected, because of lomitapide's mechanism ofaction,130meanhepaticfatcontent increasedapproximately7.6%onaverage(range0%–30%) byweek26,but nofurtherincreases were reported at week 78. Longer term hepaticsafety studiesof lomitapide still need to beconducted.

p0315Because individuals taking lomitapide must consume alow-fat diet, and because lomitapidecausesfat malabsorp-tion, patientsshouldconcomitantlybegivenvitaminE, lino-leic acid, alpha-linolenic acid, eicosapentaenoic acid, anddocosahexaenoic acid supplementation.134 As with mipo-mersen,becauselomitapidecancauseadverseeventssuchas liver toxicity, it is available in the United States onlythrough arisk evaluation and mitigation strategy program.

Comp. by: GAsokpandian Stage: Revises1 Chapter No.: 38 Title Name: BallantyneDate:22/8/14 Time:14:40:34 Page Number: 11

TABLE38-7t0040 Effectsof Lomitapide 5 to 60mg (Average Dose 40mg/day) on Plasma Lipids, Apolipoprotein B, andLipoprotein(a)

PATIENTPOPULATION(BASELINE: N=29)

% CHANGEINLDL-C

% CHANGEINAPOB

% CHANGEINTRIGLYCERIDES

% CHANGEINLP(A)

% CHANGEINHDL-C

Week 26 (n¼26) –50* –49* –45* –15* –12*

Week 56 (n¼26) –44* –45* –29* –19* 1

Week 78 (n¼26) –38* –43* –31* –1 –5

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Baseline lipid levels(n¼29): LDL-C¼336mg/dL; apoB¼259mg/dL; triglycerides¼92mg/dL; HDL-C¼43 mg/dL; Lp(a)¼67mg/dL.*Significant change versusbaseline.

Data from reference 133

Lower VLDL, LDL,chylomicrons, and

chylomicron remnants

Blood vessel

Intestinal epithelial cell

Cytoplasm

ER

Luman

ApoB48degraded

MTP

TG

Liver cell

Cytoplasm

ER

Luman

ApoBdegraded

MTP

FIGURE38-9f0050Au1 Effectsof microsomal triglyceride transport protein (MTP) inhibition by lomitapide. ApoB, apolipoprotein B; LDL, low-densitylipoprotein; TG, triglyceride;VLDL, very-low-density lipoprotein. (Modified fromreferences130,132,134,135.)

B978-0-323-28786-9.00038-4, 00038

Ballantyne, 978-0-323-28786-9

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38Specia

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Moriarty!P!!!&!!Santos!!RD!In!Clinical!Lipidology:!A!companion!to!Braunwald’s!Heart!DIsease!2015!

MTP inhibition lowers ApoB production

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Cuchel, M. et al. NEJM 2007; 356:148-56

Lomitapide Phase 3 Study in Patients with HoFH: LDL-C Reduction (Mean % Change) From Baseline

to Week 78

1

0

352mg/dL336mg/dL

Baseline Week 26 Week 56

50.2% reduction

40.1% reduction

Week 78

44.0% reduction38.4% reduction

(CA) 0mg(ITT)

44.6mg38.4mg 40.2mg 40.7mg0mg

Adapted from Cuchel M et al. Lancet 2013; 381:40-46

Adverse Event Category

n of subjects (%)

weeks 0-26

N=29

n of subjects (%)

weeks 26-78

N=23

Any adverse event 27 (93.1) 21 (91.3)

GI Disorders 27 (93.1) 17 (73.9)

Diarrhea 23 (79) 8 (35)

Nausea 18 (62) 7 (30)

Lab abnormalities 15 (51.7) 10 (43.5)

ALT elevation >5 x ULN 4 (13.8) 1 (4.3)

HoFH Phase 3 Study

Treatment Emergent Adverse Events

Adapted from Cuchel M et al. Lancet 2013; 381:40-46

Gastrointestinal AEs are the most frequent AEs experienced during MTP-i treatment

Adapted from Cuchel M et al. Lancet 2013; 381:40-46

Frequency of GI AEs during lomitapidetreatment tends to decrease over time

Adapted from Cuchel M et al. Lancet 2013; 381:40-46

Liver function tests and liver fat were carefully measured during lomitapide treatment

ULN for ALT: females is 33 and males is 40 U/LULN for AST: females is 36 and males is 43 U/L

Adapted from Cuchel M et al. Lancet 2013; 381:40-46

Long Term use of Lomitapide

15Blom et al. Circulation. 2017;136:332–335

Apheresis Does Not Affect Lomitapide Effects in HOFH

Stefanutti C et al. Atherosclerosis 2015; 240: 408-414

LDL-C Goal Attainment

Mipomersen

Antisense Therapy1-3

mRNA = messenger RNA.

1. Crooke RM, Graham MJ. Clin Lipidol. 2011;6,675-692.

2. Koller E, et al. Trends Pharmacol Sci. 2000;21:142-148.

3. Visser ME, et al. Eur Heart J. 2012;33:1451-1458.

• Antisense molecules are short, single-stranded, synthetic analogues of natural nucleic acids that are complementary to, and thus bind with, a specific mRNA to prevent disease-related protein synthesis

+

mRNA

mRNA

Protein synthesis Proteins

Antisense Proteinsynthesisinhibited

Fewerproteins

Rationale For Targeting Apo B-100–Containing Lipoproteins With Antisense Therapy

• Apo B-100 is an essential structural component of all atherogenic lipoproteins, including VLDL, IDL, LDL, and Lp(a)1,2

Cholesterol

Apo B-

100

VLDL

Triglyceride

VLDL IDLLDL1

LDL2LDL3 Lp(a)

VLDL = very low-density lipoprotein; IDL = intermediate-density lipoprotein; Lp(a) = lipoprotein(a).

1. Lee RG, et al. J Cardiovasc Transl Res. 2013;6:969-980.

2. Visser ME, et al. Eur Heart J. 2012;33:1451-1458.

Raal FJ, Santos RD et al. Lancet. 2010;375:998-1006

22

Pooled Population Homozygous FH

Santos RD et al. Arterioscler Thromb Vasc Biol. 2015;35:689-99.

23Santos RD et al. Eur Heart J 2015;36:566-75

Incidence of injection site reactions (ISRs) and flu-like symptom (FLS)

events occurring at least once over time.

All Subjects

Completers

ISR = 1 in 10FLS= 1 in 52

Santos R D et al. Eur Heart J 2015; ;36:566-75

Long-term Mipomersen Hepatic safety: ALT and Liver FAT

Santos R D et al. Eur Heart J 2015; ;36:566-75

ALT

Liver Fat

Duel PB, Santos RD et al J Clin Lipidol. 2016 ;10:1011-1021

Mean follow up 24 monthsLDL-C -28%

Absolute reduction 70 mg/dLor 1.8 mmol/L

Conclusions

• HoFH hard to treat

• LDL-C reduces CVD disease burden and prolongs life

• Lomitapide and mipomersen can add LDL lowering

• Caveats

– Adverse events

– Cost