**6. New pharmacologic therapies**

Recently, three novel agents have become available—mipomersen, lomitapide, and evolocu‐ mab—each with a unique mechanism of action. Two of these agents (mipomersen and lomitapide) target very low‐density lipoprotein (VLDL) production, while the other (evolo‐ cumab) causes increased catabolism of LDL‐C via LDLR recycling (**Figure 2**) [10].

**Figure 2.** Mechanisms of action of mipomersen, lomitapide, and evolocumab. Modified from Cuchel et al. 2014 [10].

Properties of these agents are summarized in **Table 1** [28–32] and are discussed in detail in the following sections. These agents produce additive LDL‐C lowering when combined with other lipid‐lowering therapies such as statins, ezetimibe, and apheresis [10] and represent promising approaches to the treatment of HoFH for those patients who cannot achieve LDL‐C targets with conventional therapy.


a Based on phase III trials in HoFH;

b Administered as three injections consecutively within 30 minutes.

HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL‐C, low‐ density lipoprotein cholesterol; MOA, mechanisms of action; PCSK9, proprotein convertase subtilisin/kexin type 9; SC, subcutaneous.

**Table 1.** Novel agents for the treatment of HoFH.

#### **6.1. Mipomersen**

rebound in LDL‐C is seen with levels returning to baseline within 2 to 4 weeks [18, 20]. Although there are no randomized trials evaluating the effect of apheresis on clinical outcomes, there is clinical evidence that apheresis can contribute to regression and/or stabilization of atherosclerotic plaque [10]. Limitations to the use of apheresis include lack of availability in some locations, high cost, long procedure duration, and the need to maintain vascular access [4]. It is recommended that patients on apheresis undergo routine monitoring to assess carotid atherosclerosis (carotid ultrasound), progression of aortic valve/root disease (echocardiogra‐

Recently, three novel agents have become available—mipomersen, lomitapide, and evolocu‐ mab—each with a unique mechanism of action. Two of these agents (mipomersen and lomitapide) target very low‐density lipoprotein (VLDL) production, while the other (evolo‐

**Figure 2.** Mechanisms of action of mipomersen, lomitapide, and evolocumab. Modified from Cuchel et al. 2014 [10].

Properties of these agents are summarized in **Table 1** [28–32] and are discussed in detail in the following sections. These agents produce additive LDL‐C lowering when combined with other lipid‐lowering therapies such as statins, ezetimibe, and apheresis [10] and represent promising approaches to the treatment of HoFH for those patients who cannot achieve LDL‐C targets

cumab) causes increased catabolism of LDL‐C via LDLR recycling (**Figure 2**) [10].

phy), and progression of coronary atherosclerosis (stress exercise test) [6].

**6. New pharmacologic therapies**

64 Cholesterol Lowering Therapies and Drugs

with conventional therapy.

#### *6.1.1. Pharmacodynamics*

Apo B is the primary protein of VLDL, intermediate density lipoprotein, and LDL and is essential for the production and catabolism of VLDL and LDL [33, 34]. Apo B is involved in the packaging and distribution of both dietary and endogenously produced cholesterol and triglycerides by lipoproteins [35]. The atherosclerotic potential of apo B is evidenced by the observation that apo B concentrations are highly predictive for atherosclerotic disease, including patients with FH [8, 33].

Mipomersen is an antisense oligonucleotide against the mRNA of apo B‐100, the primary ligand for the LDLR [33, 34]. The drug reduces apo B mRNA translation, and thereby the synthesis of apo B by ribosomes, resulting in a reduction in the secretion of VLDL. Thus, mipomersen targets the production of LDL rather than its clearance (**Figure 2**) [34]. In animal models, species‐specific inhibition of antisense apo B leads to reductions in apo B‐100, LDL‐ C, and total cholesterol in a dose‐ and time‐dependent manner [29, 35].

Mipomersen is readily absorbed after subcutaneous administration with the highest drug concentrations in the liver and kidney. Bioavailability ranges from 54% to 78% over a dose range of 50 to 400 mg [29]. Elimination is primarily via metabolism by endonucleases and renal excretion (as parent drug and metabolites) and the half‐life ranges from 1 to 2 months [29, 35]. In the United States, mipomersen is indicated as an adjunct to lipid‐lowering medications and diet to reduce LDL‐C, apo B, total cholesterol, and non‐HDL‐C in patients with HoFH [36]. The drug is administered once weekly by subcutaneous injection [29].

#### *6.1.2. Efficacy*

Based on its mechanism of action and its demonstrated activity in patients with hypercholes‐ terolemia as either monotherapy or in combinations, it is reasonable that mipomersen would be effective in the treatment of HoFH [35]. In a phase II, open‐label, study, mipomersen was administered in a dose‐escalation fashion (50, 100, 200, and 300 mg) to nine patients with HoFH. Patients received five doses over 2 weeks followed by weekly dosing through week 6 (*n* = 5) or week 13 (*n* = 4). At week 6, LDL‐C reductions ranged from 0.5% to 36%. By week 13, the reductions ranged from 9.0% to 51.1%[29].

The phase III trial of mipomersen in patients with HoFH included 51 patients with clinical diagnosis or genetically confirmed HoFH [37]. Mean baseline LDL‐C was 402 mg/dL (10.4 mmol/L). Patients who received maximally tolerated doses of lipid‐lowering drug were randomized to receive mipomersen 200 mg subcutaneously (*n* = 34) or placebo (*n* = 17) once weekly for 26 weeks [37]. The primary endpoint was the percent change in LDL‐C concentra‐ tion from baseline. Secondary endpoints were changes from baseline in apo B, total cholesterol, and non‐HDL‐C concentrations. At 26 weeks, mipomersen‐treated patients achieved signifi‐ cant reductions in all primary and secondary endpoints versus placebo: LDL‐C (–24.7%), apo B (–26.8%), total cholesterol (–21.2%), and non‐HDLC (–24.5%). By comparison, reductions for those in the placebo group were: LDL‐C (–3.3%), apo B (–2.5%), total cholesterol (–2.0%), and non‐HDL‐C (–2.9%). In addition, mipomersen was also associated with substantial reductions in Lp(a) (–31.1%), triglycerides (–17.4%), and VLDL (–17.4%), and a significant increase in HDL‐C (+15.1%). Notably, there was substantial variability in the reduction of LDL‐C concen‐ trations among HoFH patients receiving mipomersen with values ranging from +2% to –82%. The magnitude of treatment effect was independent of baseline LDL‐C, age, race, or sex in multivariate analysis [37].

#### *6.1.3. Safety/tolerability*

In the phase III HoFH trial, the most common adverse events among patients with HoFH were injection‐site reactions (76%), flu‐like symptoms (29%), nausea (18%), headache (15%), and chest pain (12%). Injection‐site reactions included erythema (56%), hematoma (35%), pain (35%), pruritus (29%), discoloration (29%), macule (15%), papule (12%), and swelling (12%). Similar rates of injection‐site reactions were observed in pooled data from other clinical trials with rates of 84% and 33%, respectively, for those in the mipomersen and placebo groups [29]. Most reactions were of mild to moderate severity with only 5% discontinuing treatment because of an injection‐site reaction. In pooled phase III trials that included all patients with hypercholesterolemia, 30% of patients experienced flu‐like symptoms (e.g., pyrexia, chills, myalgia, arthralgia, malaise, fatigue) compared with 16% of those receiving placebo [29].

Laboratory abnormalities in the phase III HoFH trial were primarily characterized by elevated liver transaminases. Alanine aminotransferase (ALT) increases of ≥1 but ≤3 times the upper limit of normal (ULN) were observed in 50% of patients in the mipomersen groups but was similar to that seen with placebo (53%). However, increased ALT of ≥3 × ULN was seen in 12% of mipomersen‐treated patients but none of the placebo‐treated patients [37]. In the pooled phase III trials, 8.4% of patients receiving mipomersen experienced an elevated ALT >3 × ULN on two consecutive occasions at least 7 days apart compared to 0.0% of placebo‐treated patients [29]. These ALT changes were generally associated with lesser elevations of aspartate aminotransferase (AST). Mipomersen was also associated with an increase in hepatic fat in 9.6% of patients compared with 0.02% of placebo‐treated patients. However, this increase was not accompanied by changes in patient weight, plasma glucose, or HbA1c, suggesting that there is no associated increased risk of metabolic syndrome. It is suggested that the hepatic steatosis and elevated transaminase concentrations are inherent consequences of attenuating apo B production. Nevertheless, mipomersen carries a black box warning for the risk of hepatotoxicity (i.e., increased transaminases and hepatic steatosis) and the drug is only available in the United States via a Risk Evaluation and Mitigation Strategy program [29].

#### **6.2. Lomitapide**

models, species‐specific inhibition of antisense apo B leads to reductions in apo B‐100, LDL‐

Mipomersen is readily absorbed after subcutaneous administration with the highest drug concentrations in the liver and kidney. Bioavailability ranges from 54% to 78% over a dose range of 50 to 400 mg [29]. Elimination is primarily via metabolism by endonucleases and renal excretion (as parent drug and metabolites) and the half‐life ranges from 1 to 2 months [29, 35]. In the United States, mipomersen is indicated as an adjunct to lipid‐lowering medications and diet to reduce LDL‐C, apo B, total cholesterol, and non‐HDL‐C in patients with HoFH [36].

Based on its mechanism of action and its demonstrated activity in patients with hypercholes‐ terolemia as either monotherapy or in combinations, it is reasonable that mipomersen would be effective in the treatment of HoFH [35]. In a phase II, open‐label, study, mipomersen was administered in a dose‐escalation fashion (50, 100, 200, and 300 mg) to nine patients with HoFH. Patients received five doses over 2 weeks followed by weekly dosing through week 6 (*n* = 5) or week 13 (*n* = 4). At week 6, LDL‐C reductions ranged from 0.5% to 36%. By week 13,

The phase III trial of mipomersen in patients with HoFH included 51 patients with clinical diagnosis or genetically confirmed HoFH [37]. Mean baseline LDL‐C was 402 mg/dL (10.4 mmol/L). Patients who received maximally tolerated doses of lipid‐lowering drug were randomized to receive mipomersen 200 mg subcutaneously (*n* = 34) or placebo (*n* = 17) once weekly for 26 weeks [37]. The primary endpoint was the percent change in LDL‐C concentra‐ tion from baseline. Secondary endpoints were changes from baseline in apo B, total cholesterol, and non‐HDL‐C concentrations. At 26 weeks, mipomersen‐treated patients achieved signifi‐ cant reductions in all primary and secondary endpoints versus placebo: LDL‐C (–24.7%), apo B (–26.8%), total cholesterol (–21.2%), and non‐HDLC (–24.5%). By comparison, reductions for those in the placebo group were: LDL‐C (–3.3%), apo B (–2.5%), total cholesterol (–2.0%), and non‐HDL‐C (–2.9%). In addition, mipomersen was also associated with substantial reductions in Lp(a) (–31.1%), triglycerides (–17.4%), and VLDL (–17.4%), and a significant increase in HDL‐C (+15.1%). Notably, there was substantial variability in the reduction of LDL‐C concen‐ trations among HoFH patients receiving mipomersen with values ranging from +2% to –82%. The magnitude of treatment effect was independent of baseline LDL‐C, age, race, or sex in

In the phase III HoFH trial, the most common adverse events among patients with HoFH were injection‐site reactions (76%), flu‐like symptoms (29%), nausea (18%), headache (15%), and chest pain (12%). Injection‐site reactions included erythema (56%), hematoma (35%), pain (35%), pruritus (29%), discoloration (29%), macule (15%), papule (12%), and swelling (12%). Similar rates of injection‐site reactions were observed in pooled data from other clinical trials

C, and total cholesterol in a dose‐ and time‐dependent manner [29, 35].

The drug is administered once weekly by subcutaneous injection [29].

the reductions ranged from 9.0% to 51.1%[29].

multivariate analysis [37].

*6.1.3. Safety/tolerability*

*6.1.2. Efficacy*

66 Cholesterol Lowering Therapies and Drugs

#### *6.2.1. Pharmacodynamics*

The microsomal triglyceride transfer protein (MTP) is an intracellular lipid‐transfer protein located in the lumen of the endoplasmic reticulum. It is responsible for binding and moving individual lipid molecules between membranes. MTP is a major mediator of the assembly and secretion of apo B‐containing lipoproteins such as VLDL from the liver, which is converted into LDL‐C, and chylomicrons, which contain dietary cholesterol and triglycerides, from the intestine [30, 31, 38]. The rare genetic condition abetalipoproteinemia provides insight into the importance of MTP in lipid handling and transport. Abetalipoproteinemia is characterized by loss‐of‐function mutations in the gene encoding MTP (i.e., *MTTP*) and is associated with marked hypocholesterolemia and an absence of apo B‐containing lipoproteins in the plasma [35]. Lack of functional MTP in abetalipoproteinemia results in the inability to load apo B with lipoproteins and the targeted proteasomal degradation of apo B. This leads to a loss of intestinal secretion of chylomicrons and liver secretion of VLDL and a consequent lack of LDL‐C in the plasma [35]. Thus, inhibition of MTP is a potentially powerful therapeutic target to reduce the production of apo B‐containing lipoproteins, particularly VLDL (the precursor of LDL‐C) [30].

Lomitapide is a small molecule that inhibits MTP action. By binding directly to MTP, lomita‐ pide inhibits the synthesis of triglyceride‐rich chylomicrons in the intestine and VLDL in the liver, with a resulting reduction in plasma LDL‐C [39]. The mechanism of action of lomitapide in inhibiting MTP is illustrated in **Figure 2**.

Oral absorption of lomitapide is poor with an absolute bioavailability of 7%, thought to be due to a first‐pass effect. Lomitapide pharmacokinetics is approximately dose proportional after single oral doses of 10–100 mg. The drug is extensively metabolized in the liver and has a terminal half‐life of 39.7 hours [28, 30]. Lomitapide is indicated in the United States and the European Union as an adjunct to a low‐fat diet and other lipid‐lowering treatments, including LDL apheresis where available, to reduce LDL‐C, total cholesterol, apo B, and non‐HDL‐C in patients with HoFH [28, 39].

#### *6.2.2. Efficacy*

An initial study in 18 patients with HoFH evaluated the addition of lomitapide to usual lipid‐ lowering therapy, including apheresis [40]. The dose of lomitapide was gradually titrated during the first 14–18 weeks to a target dose of 60 mg/day (80 mg/day if LDL and safety criteria were met). The mean overall LDL‐C reduction was 44% at 6 months compared with baseline but the individual values ranged from an increase in LDL‐C of 19% to a reduction of 93%, indicating a wide variability of effect. Four patients achieved an LDL‐C <100 mg/dL (<2.6 mmol/L) and another two achieved levels <170 mg/dL (<4.4 mmol/L) [40].

The pivotal phase III open‐label trial included 29 patients with HoFH based on clinical criteria or documented genetic mutations [41]. Upon enrollment, patients were required to enter a 6‐ week run‐in phase in which patients were initiated on concomitant lipid‐lowering therapy (including apheresis), vitamin E, essential fatty acids, and a low‐fat diet. Patients then entered a 26‐week efficacy phase where lomitapide was initiated at 5 mg/day and titrated (at 4‐week intervals) up to a maximum of 60 mg/day. Following the efficacy phase, patients continued lomitapide therapy in a 52‐week safety phase. Mean baseline total cholesterol and LDL‐C levels were 429 mg/dL (11.1 mmol/L) and 336 mg/dL (8.7 mmol/L), respectively [41]. Twenty‐three of 29 patients completed both the efficacy phase (26 weeks) and safety phase (52 weeks). At the end of 26 weeks, patients achieved statistically significant mean reductions from baseline in total cholesterol (–46%; *P* < 0.0001) and LDL‐C (–50%; *P* < 0.0001) [41]. The large majority of patients (*n* = 19/23 [83%]) achieved LDL‐C reductions >25% and one‐half (*n* = 12/23) had a >50% reduction [41]. Furthermore, 8 patients achieved LDL‐C concentrations <100 mg/dL (<2.6 mmol/L). Based on these LDL‐C reductions, three patients permanently discontinued aphe‐ resis and three permanently increased the time interval between apheresis treatments. Significant reductions from baseline were also seen for VLDL cholesterol (–45%), non‐HDL‐C (–50%), triglycerides (–45%), and apo B (–49%). Lipid lowering was independent of the use of apheresis, suggesting that apheresis does not affect the lipid‐lowering efficacy of lomitapide [42]. These reductions were maintained throughout the 52‐week safety phase with reductions of 35% and 38%, respectively, for total cholesterol and LDL‐C despite changes in concomitant lipid‐lowering therapy [41]. Nineteen of the 23 patients who competed the efficacy and safety phases entered a long‐term extension study [43, 44]. As of 2015, the median duration of treatment was 5.1 years [43]. At 126 weeks, mean LDL‐C levels were reduced by 46%. Similar reductions were also observed in apo B (–54%), non‐HDL‐C (–47%), VLDL cholesterol (–37%), and triglycerides (–38%) [43, 44].

Additional evidence of the efficacy of lomitapide in HoFH comes from a Japanese trial [45] and the Lomitapide Observational Worldwide Evaluation Registry (LOWER) [45, 46]. The Japanese trial included nine patients with a mean baseline LDL‐C of 199 mg/dL (5.2 mmol/L), which was reduced to 118 mg/dL (3.1 mmol/L) at week 26 (–42%) [45]. Significant reductions were also seen for total cholesterol (–32%), non‐HDL‐C (–40%), VLDL (–42%), apo B (–45%), and triglycerides (–42%) [45]. LOWER is a noninterventional registry open to lomitapide‐ treated patients that is designed to evaluate the long‐term safety and efficacy of lomitapide in clinical practice and is eventually expected to enroll at least 300 patients and follow them for at least 10 years [47]. As of March 2015, 84 patients had enrolled in LOWER, with all but one from the United States [46]. Titration of lomitapide occurred slower than in the pivotal phase III trial, with a mean dose of 10 mg reached only after 12 months. The mean reduction in LDL‐ C at month 4 was 42%, with 38% of patients achieving a reduction of at least 50% at 6 months [46, 47].

#### *6.2.3. Safety/tolerability*

liver, with a resulting reduction in plasma LDL‐C [39]. The mechanism of action of lomitapide

Oral absorption of lomitapide is poor with an absolute bioavailability of 7%, thought to be due to a first‐pass effect. Lomitapide pharmacokinetics is approximately dose proportional after single oral doses of 10–100 mg. The drug is extensively metabolized in the liver and has a terminal half‐life of 39.7 hours [28, 30]. Lomitapide is indicated in the United States and the European Union as an adjunct to a low‐fat diet and other lipid‐lowering treatments, including LDL apheresis where available, to reduce LDL‐C, total cholesterol, apo B, and non‐HDL‐C in

An initial study in 18 patients with HoFH evaluated the addition of lomitapide to usual lipid‐ lowering therapy, including apheresis [40]. The dose of lomitapide was gradually titrated during the first 14–18 weeks to a target dose of 60 mg/day (80 mg/day if LDL and safety criteria were met). The mean overall LDL‐C reduction was 44% at 6 months compared with baseline but the individual values ranged from an increase in LDL‐C of 19% to a reduction of 93%, indicating a wide variability of effect. Four patients achieved an LDL‐C <100 mg/dL (<2.6

The pivotal phase III open‐label trial included 29 patients with HoFH based on clinical criteria or documented genetic mutations [41]. Upon enrollment, patients were required to enter a 6‐ week run‐in phase in which patients were initiated on concomitant lipid‐lowering therapy (including apheresis), vitamin E, essential fatty acids, and a low‐fat diet. Patients then entered a 26‐week efficacy phase where lomitapide was initiated at 5 mg/day and titrated (at 4‐week intervals) up to a maximum of 60 mg/day. Following the efficacy phase, patients continued lomitapide therapy in a 52‐week safety phase. Mean baseline total cholesterol and LDL‐C levels were 429 mg/dL (11.1 mmol/L) and 336 mg/dL (8.7 mmol/L), respectively [41]. Twenty‐three of 29 patients completed both the efficacy phase (26 weeks) and safety phase (52 weeks). At the end of 26 weeks, patients achieved statistically significant mean reductions from baseline in total cholesterol (–46%; *P* < 0.0001) and LDL‐C (–50%; *P* < 0.0001) [41]. The large majority of patients (*n* = 19/23 [83%]) achieved LDL‐C reductions >25% and one‐half (*n* = 12/23) had a >50% reduction [41]. Furthermore, 8 patients achieved LDL‐C concentrations <100 mg/dL (<2.6 mmol/L). Based on these LDL‐C reductions, three patients permanently discontinued aphe‐ resis and three permanently increased the time interval between apheresis treatments. Significant reductions from baseline were also seen for VLDL cholesterol (–45%), non‐HDL‐C (–50%), triglycerides (–45%), and apo B (–49%). Lipid lowering was independent of the use of apheresis, suggesting that apheresis does not affect the lipid‐lowering efficacy of lomitapide [42]. These reductions were maintained throughout the 52‐week safety phase with reductions of 35% and 38%, respectively, for total cholesterol and LDL‐C despite changes in concomitant lipid‐lowering therapy [41]. Nineteen of the 23 patients who competed the efficacy and safety phases entered a long‐term extension study [43, 44]. As of 2015, the median duration of treatment was 5.1 years [43]. At 126 weeks, mean LDL‐C levels were reduced by 46%. Similar

mmol/L) and another two achieved levels <170 mg/dL (<4.4 mmol/L) [40].

in inhibiting MTP is illustrated in **Figure 2**.

patients with HoFH [28, 39].

68 Cholesterol Lowering Therapies and Drugs

*6.2.2. Efficacy*

Oral lomitapide was generally well tolerated in patients with HoFH. Although the majority of patients experienced an adverse event in the phase III trial (*n* = 27/29 [93%] in the efficacy phase; *n* = 21/23 [91%] in the safety phase), most events were mild to moderate in intensity [41]. The most common adverse events were gastrointestinal in nature, with 27/29 patients in the efficacy phase and 21/23 patients in the safety phase experiencing a gastrointestinal event [41]. The most common events in the phase III trial were gastrointestinal in nature (27 patients during the efficacy phase and 17 during the safety phase), most commonly manifested as diarrhea, nausea, dyspepsia, and vomiting [41, 43]. Three patients discontinued treatment due to a gastrointestinal event [41]. The incidence of gastrointestinal events decreased during the extension phase: diarrhea (42%), nausea (32%), vomiting (26%), and dyspepsia (11%) [43].

Ten patients in the phase III trial had elevated levels of ALT, AST, or both >3 × ULN at least once during the trial, and four patients had elevations at least 5 × ULN [41]. No patient discontinued treatment permanently because of these elevations and all were managed by either dose reduction or temporary interruption of lomitapide [41, 43]. In the LOWER registry, elevated transaminase levels ≥3 × ULN were observed in only 16 patients (19%) [46].

Among the 20 patients from the phase III trials with evaluable nuclear magnetic resonance spectroscopy data, hepatic fat increased from 1% at baseline to 8.6% at the end of week 26 and 8.3% at week 78 [41]. Hepatic fat continued to increase through the extension trial [43], although the accumulation of fat appears to be reversible after discontinuation of lomitapide [39]. Whether this fat accumulation is a risk factor for the development of steatohepatitis and cirrhosis is currently unknown. No cases of cirrhosis or late‐stage liver disease have been identified in the long‐term extension studies [43].

#### **6.3. Evolocumab**

#### *6.3.1. Pharmacodynamics*

PCSK9 is a key regulator of LDLR function. When PCSK9 binds to the LDLR, LDLR degrada‐ tion is enhanced in the liver, thereby increasing LDL‐C plasma concentrations [4].Although some patients with HoFH have no LDLR function, up to 75% have residual activity (between 2% and 25%) [2]. Patients with HoFH also have increased PCSK9 function. Among patients with residual LDLR function, PCSK9 inhibition may be useful for lowering LDL‐C [2]. Evolocumab is a human immunoglobulin G2 monoclonal antibody directed against human PCSK9. By binding to PCSK9, evolocumab inhibits circulating PCSK9 from binding to the LDLR, preventing PCSK9‐mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. This increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL‐C level (**Figure 2**) [32, 48, 49].

#### *6.3.2. Efficacy*

The addition of evolocumab to stable lipid‐lowering therapy was evaluated in an open‐label pilot trial in eight patients with LDLR‐negative or LDLR‐defective HoFH [32]. Patients received subcutaneous evolocumab 420 mg every 4 weeks for 12 weeks, maintained for an additional 12 weeks at 4‐week intervals, and then 420 mg of evolocumab every 2 weeks for an additional 12 weeks [32]. All eight patients had LDLR mutations, with six patients having defective receptor status (i.e., residual LDLR function) and two having negative LDLR function. Mean baseline LDL‐C was 441 mg/dL (11.4 mmol/L) [32]. After 12 weeks of every 4‐week dosing, mean LDL‐C decreased by a mean of 17% (range, +5% to –44%). The two patients with negative LDLR activity did not achieve reductions in LDL‐C [32]. After 12 weeks of every 2‐week dosing, mean LDL‐C was reduced by 14%, again with no reductions in the two patients that were LDLR‐negative. Apo B was reduced by 14.9% and 12.5% by the 4‐week and 2‐week dosing schedules and Lp(a) was reduced by 11.7% and 18.6%, respectively, by the two schedules. However, there was little change in triglycerides, HDL‐C, or apolipoprotein A1 with either schedule [32].

The pivotal randomized, phase III, double‐blind, placebo‐controlled trial included 49 patients with HoFH on stable lipid‐lowering therapy (but not apheresis) for at least 4 weeks. Patients were randomized in a 2:1 ratio to receive evolocumab 420 mg or placebo every 4 weeks [48]. LDLR mutations in both alleles were present in 45 of 48 patients (94%), with 22 of these having the same mutation in both alleles (true HoFH) and 23 having different mutations in each LDLR allele (i.e., compound heterozygous FH) [48]. One patient receiving evolocumab had LDLR receptor‐negative mutations in both alleles and another had autosomal recessive hypercho‐ lesterolemia. The mean decrease in ultracentrifugation LDL‐C was 23.1% for those receiving evolocumab compared with a 7.9% increase for the placebo group (primary endpoint) [48]. Evolocumab was also associated with a 19.2% reduction in apo B at week 12, although changes in Lp(a), HDL‐C, and triglycerides were not significantly different relative to placebo [48]. Response to evolocumab correlated with the underlying genetic cause of HoFH, with a greater reduction in LDL‐C among those with two LDLR‐defective mutations than in those with even a single LDLR‐negative mutation. However, among the 20 patients receiving evolocumab who had defects in either one or both alleles, a 29.5% reduction in ultracentrifugation LDL‐C was achieved [48]. The patient with LDLR‐negative mutations in both alleles and the one with autosomal recessive hypercholesterolemia did not respond to evolocumab (LDL‐C levels increased by 3–10%) [48].

The efficacy of evolocumab in combination with apheresis is under evaluation in the Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects with Genetic LDL Disorders (TAUSSIG) in patients with severe FH not controlled with current lipid therapy [50]. Patients received evolocumab 420 mg and apheresis every 2 weeks. An interim analysis found that evolocumab was associated with a mean reduction of 17% in LDL‐C at week 12 (*n* = 24) and 20% at week 24 (*n* = 12) [50]. Four patients were able to stop or decrease the frequency of apheresis. The three patients with LDLR‐negative mutations in both alleles did not respond to evolocumab. Evolocumab is indicated in the United States and EU as an adjunct to diet and other LDL‐lowering therapies for the treatment of patients with HoFH who require additional lowering of LDL‐C.

#### *6.3.3. Safety/tolerability*

**6.3. Evolocumab**

*6.3.2. Efficacy*

schedule [32].

*6.3.1. Pharmacodynamics*

70 Cholesterol Lowering Therapies and Drugs

PCSK9 is a key regulator of LDLR function. When PCSK9 binds to the LDLR, LDLR degrada‐ tion is enhanced in the liver, thereby increasing LDL‐C plasma concentrations [4].Although some patients with HoFH have no LDLR function, up to 75% have residual activity (between 2% and 25%) [2]. Patients with HoFH also have increased PCSK9 function. Among patients with residual LDLR function, PCSK9 inhibition may be useful for lowering LDL‐C [2]. Evolocumab is a human immunoglobulin G2 monoclonal antibody directed against human PCSK9. By binding to PCSK9, evolocumab inhibits circulating PCSK9 from binding to the LDLR, preventing PCSK9‐mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. This increases the number of LDLRs available to clear LDL from the

The addition of evolocumab to stable lipid‐lowering therapy was evaluated in an open‐label pilot trial in eight patients with LDLR‐negative or LDLR‐defective HoFH [32]. Patients received subcutaneous evolocumab 420 mg every 4 weeks for 12 weeks, maintained for an additional 12 weeks at 4‐week intervals, and then 420 mg of evolocumab every 2 weeks for an additional 12 weeks [32]. All eight patients had LDLR mutations, with six patients having defective receptor status (i.e., residual LDLR function) and two having negative LDLR function. Mean baseline LDL‐C was 441 mg/dL (11.4 mmol/L) [32]. After 12 weeks of every 4‐week dosing, mean LDL‐C decreased by a mean of 17% (range, +5% to –44%). The two patients with negative LDLR activity did not achieve reductions in LDL‐C [32]. After 12 weeks of every 2‐week dosing, mean LDL‐C was reduced by 14%, again with no reductions in the two patients that were LDLR‐negative. Apo B was reduced by 14.9% and 12.5% by the 4‐week and 2‐week dosing schedules and Lp(a) was reduced by 11.7% and 18.6%, respectively, by the two schedules. However, there was little change in triglycerides, HDL‐C, or apolipoprotein A1 with either

The pivotal randomized, phase III, double‐blind, placebo‐controlled trial included 49 patients with HoFH on stable lipid‐lowering therapy (but not apheresis) for at least 4 weeks. Patients were randomized in a 2:1 ratio to receive evolocumab 420 mg or placebo every 4 weeks [48]. LDLR mutations in both alleles were present in 45 of 48 patients (94%), with 22 of these having the same mutation in both alleles (true HoFH) and 23 having different mutations in each LDLR allele (i.e., compound heterozygous FH) [48]. One patient receiving evolocumab had LDLR receptor‐negative mutations in both alleles and another had autosomal recessive hypercho‐ lesterolemia. The mean decrease in ultracentrifugation LDL‐C was 23.1% for those receiving evolocumab compared with a 7.9% increase for the placebo group (primary endpoint) [48]. Evolocumab was also associated with a 19.2% reduction in apo B at week 12, although changes in Lp(a), HDL‐C, and triglycerides were not significantly different relative to placebo [48]. Response to evolocumab correlated with the underlying genetic cause of HoFH, with a greater reduction in LDL‐C among those with two LDLR‐defective mutations than in those with even

blood, thereby lowering LDL‐C level (**Figure 2**) [32, 48, 49].

In the phase III trial in patients with HoFH, the most common adverse events among those receiving evolocumab were upper respiratory tract infection (9%), influenza (9%), gastroenteritis (6%), nasopharyngitis (6%), and increased ALT or AST ≥3 × ULN [48]. There were no adverse event‐related treatment discontinuations. These rates of adverse events are generally consistent with those seen in other large randomized trials evaluating evolocumab in the treatment of hypercholesterolemia [49]. Immunogenicity appears to be uncommon, with only 0.1% of patients in pooled clinical trials testing positive for binding antibody development. There was no evidence of neutralizing antibodies and no evidence that the presence of antidrug antibodies impacted the pharmacokinetic profile, clinical response, or safety of evolocumab [49].
