Treatment of severe FHMTP Inhibitors

Dirk Blom

UCT Cape Heart Centre

Lipid Clinic - Groote Schuur Hospital

Targets for Lipid Drugs

Graphic courtesy: D. Marais

•HMG CoA-reductase•NPC1L1•Bile acids•Niacin•PPARα•apoB100•PCSK9•MTP•CETP•Thyroid hormone receptor•Squalene synthase

Extracorporeal LDLC removalLiver transplantationIleal bypassPotocaval shunt

LDLR Mediated Lipid Lowering

• Statins• Main effect via upregulation of LDLR

• Ezetimibe

• PCSK9 inhibition

• Bile acid sequestrants

Inhibiting Lipoprotein Production

• Lomitapide• Inhibition of MTP in liver and intestine

• Mipomersen• Inhibition of apoB100 production

• Lipid lowering does not require functional LDLR

Microsomal TG Transfer Protein

The Journal of Lipid ResearchJanuary 2003 vol. 44 no. 1 22-32

Abetalipoproteinaemia

• Very low/ absent apoB-containing lipoproteins

• Failure to thrive

• Diarrhoea

• Neurological dysfunction• Ataxia

• Retinitis pigmentosa

• Acanthocytosis

MTP Inhibition

• Initially explored as therapeutic strategy for all forms of hypercholesterolaemia

• Further development was abandoned• Diarrhoea

• Advent of statins

• Renewed interest in this drug class as an orphan drug for HoFH• Dan Rader at University of Pennsylvania and subsequently

Aegerion

Mechanism of Action

Proof of Concept

Cuchel M et al. N Engl J Med 2007;356:148-156.

• 6 patients• Increasing doses for 4-week periods

Lipoprotein Production

Cuchel M et al. N Engl J Med 2007;356:148-156.

Production of LDL apoB100

Lomitapide Dose Escalation

Concomitant LLTs Unchanged

Run-inPeriod

5mg

10mg

20mg

40mg

60mg

Continue Maximum Tolerated Dose

Efficacy Phase

Weeks-6

Safety Phase

0 2 6 10 14 26 7856

Maintenance Dose of LomitapideAlteration in Concomitant LLTs Allowed

Exte

nsi

on

Stu

dy

Phase 3 Study Design

Patients with clinically diagnosed HoFHPatients on apheresis were eligible (n=13)Apheresis schedule aligned to study visits

Aegerion Internal

Results

• 11 sites in USA, Canada, Italy and South Africa

• 32 patients screened

• 31 entered run-in

• 29 entered efficacy phase

• 23 completed efficacy phase (week 26)

• 23 completed safety phase (week 78)

Baseline LDLC

0

100

200

300

400

500

600

Mean 336 mg/dl8.7 mmol/L

Aegerion Internal

LDLC Reduction

Lancet. 2013 Jan 5;381(9860):40-6. doi: 10.1016/

50% reduction

Individual Responses

Aegerion Internal

Safety Phase

Aegerion Internal

Extension Study

Circulation. 2017 Jul 18;136(3):332-335

• 19 / 23 patients who completed the pivotal study entered the extension

• Patients continued on lomitapide at MTD + LLTs

• Patient exposure to lomitapide in this primary analysis ranged from ~2.5 - 5.5 years

Safety and Tolerability

Where does the fat go ?

Adverse Effects and MOA

• Most adverse effects relate to mechanism of action

• Liver• Fatty liver due to failure to export hepatic TG in VLDL

• Transaminitis

• Intestine• GIT intolerance

• Inability to tolerate fatty meals

Fatty Liver

Lancet. 2013 Jan 5;381(9860):40-6. doi: 10.1016/

Registration Study

Lancet. 2013 Jan 5;381(9860):40-6. doi: 10.1016/

Fatty Liver II

Extension Study

Circulation. 2017 Jul 18;136(3):332-335

Metabolic Effects

Circulation. 2017 Jul 18;136(3):332-335

Long Term Safety

• In the registration and extension study hepatic fat content appeared to plateau

• Will hepatic steatosis translate to fibrosis and ultimately cirrhosis? • One case of documented fibrosis in a patient with FCS

• Applicable to patients with HoFH?

• European label requires assessment of fibrosis either by biomarker panel or imaging/ elasticity • Results awaited

Transaminitis

Lancet. 2013 Jan 5;381(9860):40-6. doi: 10.1016/

Registration Study

• 10 patients >3 x ULN• 5 patients > 5 x ULN

Liver Enzymes

• Similar profile in extension study

• Registry study (187 patients)• 25 (13.7%) ALT or AST elevations ≥3× to <5× ULN

• 9 (4.9%) ALT or AST elevation ≥5× and <10× ULN

• 1 (0.5%) ALT or AST ≥10x <20× ULN.

• No cases of Hy’s law reported

• Enzymes usually return to baseline following dose interruption or reduction

• Avoid alcohol and enzyme inhibitors

• Regular monitoring is mandatory

Gastrointestinal AE

• 3 (10%) discontinuations due to GIT AE • Diarrhoea in 79.3 % of patients

• Nausea in 65.5% of patients

Dose 5 10 20 40 60 80

n29 27 26 21 13 1

DiarrhoeaN (%)

5 (17·2) 14 (51·9) 5 (19·2) 11 (52·4) 5 (38·5) 0 (0·0)

NauseaN (%)

4 (13·8) 6 (22·2) 6 (23·1) 8 (38·1) 5 (38·5) 0 (0·0)

Registration Study

Registry Study

• Diarrhoea in 33% of patients• 59% mild• 34% moderate• 7% severe

• Nausea in 12.4% of patients• 70% mild• 29% moderate• 1% severe

Adherence to a low-fat diet is crucial

Real World Data

Cohort Reports

• 15 patients from Italy with HoFH• Median dose of 19 mg/d

• LDLC reduction of 68.2%

• 8 of 10 patients receiving apheresis were able to discontinue

• Children • 11 children from 10 countries

• Mean dose of 25 mg/d

• 58.4% decrease

• Six children at target

• 3 with abnormal LFT (> 3 x ULN)

• Paediatric study awaited

Positioning

• Lomitapide is only licensed for use in patients with HoFH• Off label use for other forms of hypercholesterolaemia or severe

hypertriglyceridaemia

• Currently extremely expensive

• Requires regular monitoring of LFT and ideally also of hepatic elasticity

• Highly effective if used carefully and correctly

Positioning II

• Suggested treatment strategy• Statin

• Ezetimibe

• PCSK9 inhibitor • Stop if no response or known receptor double negative status

• Then depending on availability/ local resources• Lomitapide

• Apheresis

• Evinacumab (in the future)

Hepatic Transplantation

Conclusions

• Lomitapide is a useful therapeutic option for patients with HoFH, especially those with very little or no residual LDLR activity

• Physician effort: regular monitoring is required

• Patient effort: need to adhere to dietary restrictions• But can avoid apheresis

• Long-term hepatic safety (risk of cirrhosis) is unknown

• High price impedes access in many countries