New Therapies: Homozygous Familial Hypercholesterolemia

Pharmacy Practice in Focus: Health SystemsJanuary 2014
Volume 3
Issue 1


Familial hypercholesterolemia (FH) is an inherited genetic mutation occurring most commonly in the low-density lipoprotein receptor (LDLR) gene, resulting in extreme elevation in the concentration of low-density lipoprotein cholesterol (LDL-C).1 Less common defects in apolipoprotein B 100 (Apo B-100), proprotein convertase subtilisin/kexin 9 (PCSK9), and the autosomal recessive hypercholesterolemia (ARH) adaptor protein may also lead to elevation of LDL-C to variable levels.2

FH is among the most common inherited metabolic disorders, a well-recognized cause of premature coronary heart disease (CHD),3 and the first genetic disorder shown to cause myocardial infarction.1 The autosomal dominant transmission pattern and gene dosage effect means homozygotes are more severely affected than heterozygotes.1 Heterozygous FH (HeFH) occurs in approximately 300 to 500 individuals,butmaybeashighas1in100 in certain populations with mean total cholesterol levels of 350 to 550 mg/dL. These individuals have a nearly 20-fold increased risk of premature CHD; about 50% of males and 30% of females will experience a coronary event before their fifth and sixth decade of life, respectively.3 Those with HeFH have marked hypercholesterolemia from birth with xanthomas and arcus corneae beginning to develop in the second decade of life.1

In contrast, homozygous FH (HoFH) is estimated to occur in 1 of every 1 million persons with average cholesterol levels of 650 to 1000 mg/dL.3 Xanthomas and arcus cornea appear in early childhood.1 Affected subjects may develop CHD before age 30 years; however, death may occur as early as the first years of life from severe CHD if left untreated.3 The greatly increased lifetime risk of premature CHD in HoFH makes early initiation of cholesterol-lowering therapies paramount.

Standard Therapies

Therapeutic lifestyle changes (TLCs) are recommended for all patients with FH. These include dietary restriction of saturated fat and cholesterol. Routine physical activity and appropriate caloric intake should be encouraged to maintain a healthy body weight. Avoidance or cessation of smoking is recommended to reduce cardiovascular risk.4,5 However, TLCs are usually insufficient to achieve adequate LDL-C reduction.6

Initial pharmacologic therapy should consist of hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins. High doses of high-potency statins should be initiated to achieve >50% reduction in LDL-C from baseline.4,5 While no randomized controlled trials with atherosclerotic cardiovascular disease (ASCVD) end points have been conducted in those with FH, a meta-analysis of statin trials demonstrated a 20% reduction in CVD for each 39 mg/dL reduction in LDL-C.7 While patients with HoFH may have enough LDLR function to respond to statins, response may not be sufficient to achieve the aggressive LDL-C reduction, necessitating additional therapies.8,9

If an individual is not able to achieve sufficient reduction in LDL-C with statin therapy, it should be combined with ezetimibe, niacin, or bile acid sequestrants (BASs).5 These are the most effective non-statin agents for lowing LDL-C; however, data are not available regarding any incremental ASCVD risk reduction when added to statins.4,5 Agents such as ezetimibe may be particularly effective because they do not depend on LDLR expression (Figure).10 The decision to combine statins with these agents should be based on cardiovascular risk, risk for myopathy with high-dose statins, and the presence of other diseases or lipid abnormalities.4

When diet and 6 months of maximum drug therapy are unable to achieve adequate LDL-C reduction, not tolerated, or contraindicated, LDL apheresis may be considered.5 This process removes Apo B-containing lipoproteins such as very low density lipoproteins (VLDL), LDL, and lipoprotein (a) [Lp(a)].11 In contrast, statins do not lower Lp(a).2 While LDL-C levels decrease 70% to 80%, they rebound to baseline in about 2 weeks, producing a time-average LDL-C reduction of 40%.11 LDL apheresis is generally well tolerated with hypotension, nausea, vomiting, and flushing occurring in less than 1% of patients.11 Patients are required to have vascular access, attend frequent sessions that last 2 to 4 hours, pay $45,000 to $100,000 per year,12 and may need to travel a significant distance to find a treatment center.11,12 Other potential treatments include partial ileal bypass and liver transplantation, but are rarely used because of the risks associated with surgery. Gene therapy is currently in the investigational stage.5

New Therapies

Recent investigation into better methods to treat patients with FH has led to the approval of 2 new approaches to LDL-C lowering. Apo B-100 is the principal apolipoprotein of LDL-C and the precursor of VLDL and LDL-C. Mipomersen (Kynamro) is an antisense inhibitor of Apo B-100, targeting messenger ribonucleic acid (mRNA) of Apo B-100 leading to the inhibition of its translation and therefore protein synthesis (Figure). Blocking Apo B-100 synthesis results in decreased production of VLDL and, subsequently, LDL-C. Apo B-100 is specific to the hepatocytes, so side effects associated with blocking Apo B in enterocytes (seen with lomitapide) are not seen with mipomersen use.

Mipomersen is FDA indicated for the treatment of HoFH.13 Raal et al conducted a randomized, double-blind, placebo-controlled, parallel group, international phase III trial evaluating the use of mipomersen versus placebo for a total of 26 weeks in patients 18 to 75 years old with HoFH who were already on maximum tolerated lipid-lowering medications.14 Thirty-four patients were included in the mipomersen group versus 17 in the placebo group. Mipomersen was administered as a 200-mg subcutaneous injection once weekly, except patients <50 kg received 160 mg subcutaneously once weekly. The mean age of patients was 33 years in the mipomersen group and 30 years in the placebo group. Baseline LDL-C was 441 mg/dL (± standard deviation 139 mg/dl) in the mipomersen group and 402 mg/dL (± 143) in the placebo group. For the primary end point of percent change in LDL-C, there was a statistically significant change between groups with a -24.7 % (95% confidence interval -31.6 % to -17.7%) change from baseline in the mipomersen group compared with -3.3% (-12.1 % to 5.5%) in the placebo group (P = .003).

Mipomersen also significantly reduced Apo B, total cholesterol, non high-density lipoprotein cholesterol (HDL-C), Lp(a), triglycerides, and VLDL, and significantly increased HDL-C compared with placebo at 26 weeks. Of the 34 patients randomized to mipomersen, 26 (76%) experienced injection site reactions versus 4 (24%) in the placebo group, and 4 (12%) experienced an increase in alanine aminotransferase (ALT), ≥3 times the upper limit of normal (× ULN) versus 0 in the placebo group. Hepatic fat was not measured during this study as hepatic steatosis had not previously been reported in animal studies; however, later studies in HeFH and severe hypercholesterolemia populations did measure hepatic fat and found increased incidence of hepatic steatosis.15,16

Microsomal triglyceride protein (MTP) is a protein key to the assembly and secretion of Apo B-containing lipoproteins in enterocytes and hepatocytes. Lomitapide (Juxtapid) is an oral MTP inhibitor, resulting in decreased production of Apo B containing lipoproteins such as VLDL and subsequently LDL-C (Figure).

Lomitapide is FDA indicated for the treatment of HoFH.17 Cuchel et al conducted a single-arm, open-label, multicenter, international phase III study evaluating the use of lomitapide in patients 18 years or older with HoFH for a total of 26 weeks with a 78-week safety assessment.18 Twenty-nine patients were included in the study. There was at least a 6-week run in phase during which patients were initiated on lipid-lowering therapies, supplemented with vitamin E and essential fatty acids, and started on a low fat diet.

Lomitapide was then initiated at 5 mg by mouth daily and increased based on safety and tolerability to a maximum of 60 mg daily. The mean dosage was 40 mg daily. The primary end point was percent change in LDL-C from baseline to week 26. Lomitapide reduced LDL-C by 50% (-62% to -39%) from baseline. The mean LDL-C at baseline was 336 mg/dL (± 112), which was reduced to a mean LDL-C of 166 mg/dL (± 97) at 26 weeks. Of the 29 patients, 10 (34%) experienced elevated aspartate aminotransferase (AST) or ALT ≥3 × ULN during the study. Hepatic fat increased from a mean of 1% at baseline to 8.6% at week 26 and 8.3% at week 78. The most common adverse events were gastrointestinal (GI) in nature with 27 (93%) patients experiencing GI disturbances during the first 26 weeks and 17 (59%) experiencing them during the safety phase of the study. A total of 3 (10%) patients discontinued treatment (all by week 12) secondary to severity of GI disturbances.

Both mipomersen and lomitapide were shown to be effective in significantly reducing LDL-C in patients with HoFH. However, the high annual cost and significant side effect profiles should be taken into consideration before initiating these medications. More drug information can be found about the 2 agents in the Online Table.

Table: Mipomersen and Lomitapide Drug Information

Mipomersen (Kynamro)1

Lomitapide (Juxtapid)5

Black Box Warning

Risk of heptaotoxicity

Risk of hepatotoxicity

REMS program

- To ensure awareness of hepatotoxicity risk, need for patient monitoring, and diagnosis of HoFH

- Follow monitoring recommendations

- Prescriber training, certification, prior authorization

- Pharmacy certification

- To ensure awareness of hepatotoxicity risk, need for patient monitoring, and diagnosis of HoFH

- Follow monitoring recommendations

- Prescriber training, certification, prior authorization

- Pharmacy certification


Adjunct to lipid lowering medications and low-fat diet in patients with HoFH

Adjunct to lipid lowering medications and low-fat diet in patients with HoFH

Dosing & Administration

200 mg subcutaneously once weekly

Initially: 5 mg by mouth daily without food

Titration schedule: 5mg x 2 weeks, 10 mg daily x 4 weeks, 20 mg daily x 4 weeks, 40 mg daily x 4 weeks, 60 mg daily maximum. Increase based on safety and tolerability.

Dose Adjustments

Renal: Not recommended in severe renal impairment, significant proteinuria or undergoing dialysis

Hepatic: Contraindicated in patients with moderate or severe hepatic impairment (Child Pugh class B or C) or active liver disease

Renal: ESRD receiving dialysis maximum dose is 40 mg daily

Hepatic: Child-Pugh Class A maximum dose is 40 mg daily

If ALT or AST ≥ 3x and <5x ULN, confirm elevation with repeat measure in 1 week, if confirmed reduce dose and measure other liver related tests. Repeat tests weekly if transaminases rise ≥ 5x ULN or do not fall <3 x ULN in 4 weeks hold dosing. If ALT or AST ≥ 5x ULN, withhold dosing.

May consider restarting at lower dose and monitoring liver related tests more frequently once transaminases fall to < 3x ULN

Mechanism of Action

Antisense apolipoprotein B synthesis inhibitor

Microsomal triglyceride transfer protein inhibitor


Tmax: 3 to 4 hours

Distribution: highly protein bound (90%)

Metabolism: endonucleases

Half-life: 1 to 2 months

Tmax: 6 hours

Distribution: highly protein bound (99.8%)

Metabolism: CYP3A4

Half-life: approximately 40 hours


Child-Pugh class B or C, or active liver disease, including unexplained persistent elevations of serum transaminases

Pregnancy, concomitant use with moderate or strong CYP3A4 inhibitors, Child-Pugh class B or C, or active liver disease, including unexplained persistent elevations of serum transaminases

Adverse Events/ Precautions

Elevation of transaminases ≥ 3 x ULN (10%)

Hepatic steatosis (hepatic fat increases by a median of 10%)

Injection-site reactions (84%), Flu-like symptoms (30%)

Immunogenicity: 38% of patients tested positive for antibodies during 6-month trials, however efficacy remained the same. In extension studies 72% of patients tested positive for antibodies; presence of antibodies correlated with increased incidence of flu-like symptoms and discontinuation of mipomersen.

Elevation of transaminases ≥ 3 x ULN (34%)

Hepatic steatosis (hepatic fat increases by a mean of 8%)

Gastrointestinal: Diarrhea (79%), Nausea (65%), Dyspepsia (38%), vomiting (34%); Other GI side effects occurring in ≥ 20% of patients include constipation, flatulence, and abdominal pain, discomfort, and distension

Given the risk of fat-soluble nutrient deficiency patients should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linoleic acid, 110 mg EPA, and 80 mg DHA


Category B — not known to cause harm in animals, no data in humans

Category X — known teratogen in rats and ferrets (fetal malformation)


Baseline: ALT, AST, Alk Phos, Tbili

1st year: LFTs monthly; lipid levels every 3 months

After 1st year: LFTs every 3 months; LDL-C every 6 months

Liver related tests at baseline, prior to each dose escalation and periodically thereafter


Use of concomitant alcohol and other hepatotoxic agents (amiodarone, high dose acetaminophen, isotretinoin, methotrexate, tamoxifen, tetracyclines, etc) should be done with caution

Contraindicated with concomitant use of moderate/strong CYP3A4 inhibitors

Recommended maximum dose with weak CYP3A4 inhibitors is 30 mg daily

Should not be consumed with > 1 alcoholic beverage a day

Use caution when used concomitantly with other medications known to have potential hepatotoxicity

Reduce concomitant simvastatin by 50%

Lomitapide increases the concentration of warfarin by approximately 30%

Lomitapide is a P-gp inhibitor; consider dose reduction in concomitantly used P-gp substrates

Annual Cost27


$235,000 to $295,000

Alk Phos = alkaline phosphatase; CYP = cytochrome P450; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; ESRD = end stage renal disease; LFTs = liver function tests; P-gp = permeability glycoprotein; Tbili = total bilirubin; Tmax = time to maximum serum concentration.

Role of the Pharmacist

One area that pharmacists are increasingly asked to help with is navigating financial assistance programs for high-priced medications. There is a financial assistance program for HoFH in general that can provide $10,000 maximum assistance to qualifying patients,19 and Genzyme has a support program for mipomersen that offers payment assistance in addition to other services.20 While there is a patient support program for lomitapide through Aegerion, it does not appear to provide financial assistance.21 Further, pharmacists assist patients and providers in counseling regarding tolerability, administration, risk evaluation and mitigation strategies and treatment of women of child-bearing age.

Future Directions

Due to the high cost and significant side effect profile of mipomersen and lomitapide, new therapeutic drug targets are starting to be evaluated in patients with HoFH. One such target is PCSK9. Evolocumab (AMG 145) is a PCSK9 inhibitor that has been shown to significantly reduce LDL-C by 43% to 55% in patients with HeFH compared with placebo.22 However, PCSK9 inhibition may not be as beneficial to patients with HoFH because most of these patients have either no or minimal LDLR function.2 Despite this, a pilot study showed that evolocumab reduced LDL-C by 19% to 26% in the 6 patients with HoFH with defective LDLR function.23 The 2 LDLR negative patients in this study did not experience a reduction in LDL-C. Importantly, no serious side effects attributed to evolocumab were reported in either study.

While the prevalence of HoFH is relatively rare, you may see these agents in other patient populations in the future. Mipomersen has also been shown to reduce LDL-C by 28% in patients with HeFH,15 by 36% in patients with severe hypercholesterolemia,16 and continues to be studied. A phase I trial is recruiting to evaluate mipomersen in addition to apheresis in patients with severe LDL-hypercholesterolemia24 and a phase III trial is recruiting to evaluate various doses of mipomersen in patients with HeFH.25 Lomitapide will likely try to expand its use as well. A phase I trial is recruiting to study pharmacokinetic and pharmacodynamic differences of lomitapide in Japanese versus Caucasian patients who have elevated LDL-C.26

In conclusion, mipomersen and lomitapide are 2 agents recently approved by the FDA for the treatment of HoFH. They may serve as attractive options for patients who are on maximum tolerated doses of other lipid-lowering medications and unable to undergo LDL apheresis secondary to location, vascular access issues, or convenience. Their place in therapy may be limited by their significant side effect profiles and cost. Studies are under way evaluating these 2 agents in other patient populations as well as evaluating new therapeutic targets in patients with HoFH.

Jenna M. Siskey, PharmD, BCPS, is a cardiology pharmacy specialty resident at UNC Health Care and adjunct faculty at UNC Eshelman School of Pharmacy. Zachariah M. Deyo, PharmD, BCPS, CPP, is a clinical pharmacist practitioner at the UNC Center for Heart and Vascular Care and adjunct assistant professor at UNC Eshelman School of Pharmacy.


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