Clinical Therapeutics/Volume 37, Number 12, 2015

Review Article Non-statin Treatments for Managing LDL Cholesterol and Their Outcomes

Traci Turner, MD; and Evan A. Stein, MD, PhD Metabolic & Atherosclerosis Research Center, Cincinnati, Ohio

ABSTRACT agents are being developed as orphan indications ex- Purpose: Over the past 3 decades reducing LDL-C pressly for patients with homozygous familial hyper- has proven to be the most reliable and easily achiev- cholesterolemia, including peroxisome proliferator able modifiable risk factor to decrease the rate of activated receptor-δ agonists, angiopoietin-like protein 3 cardiovascular morbidity and mortality. Statins are inhibitors, and gene therapy. effective, but problems with their side effects, adher- Implications: Monoclonal antibodies that inhibit ence, or LDL-C efficacy in some patient groups PCSK9 were shown to be very effective reducers of remain. Most currently available alternative lipid- LDL-C and well tolerated despite subcutaneous ad- modifying therapies have limited efficacy or tolerabil- ministration, and no significant safety issues have yet ity, and additional effective pharmacologic modalities emerged during large Phase II and III trials. They have to reduce LDL-C are needed. the potential to substantially impact further the risk of Methods: Recent literature on new and evolving cardiovascular disease. A number of additional new, LDL-C–lowering modalities in preclinical and clinical but less effective, oral LDL-C–lowering agents are development was reviewed. also in various stages of development, including Findings: Several new therapies targeting LDL-C are some which are targeted only to patients with homo- in development. Inhibition of proprotein convertase sub- zygous familial hypercholesterolemia. (Clin Ther. tilisin/kexin type 9 (PCSK9), a recently elucidated key 2015;37:2751–2769) & 2015 Elsevier HS Journals, regulator of plasma LDL-C, is the most promising and Inc. All rights reserved. effective, with a number of approaches aimed at this Key words: CETP inhibitors, LDL cholesterol, target. The most advanced are monoclonal antibodies, PCSK9 inhibitors, Familial hypercholesterolemia. which have demonstrated LDL-C reductions of 60%, whether given alone or added to statins. Other PCSK9- targeted therapies in clinical development include adnec- tins and gene silencing techniques. Preclinical approaches INTRODUCTION involve vaccines, whereas a search remains for small Reducing LDL-C concentrations was well established molecule inhibitors. Other new pharmacologic ap- in large, prospective clinical trials as a primary modal- proaches in Phase III clinical trials include a refocusing ity for decreasing the risk of cardiovascular morbidity – of cholesterol ester transfer protein inhibitors from and mortality.1 3 Although hydroxymethylglutaryl primarily agents to increase HDL-C to their off-target coenzyme A reductase inhibitors, or statins, are the effect on LDL-C and adenosine triphosphate citrate lyase mainstay of LDL-C reduction, there are patient popu- inhibition. In earlier clinical development is new delivery lations that either are intolerant or have contraindi- of nicotinic acid-containing compounds. Additional cations to statins or are unable to achieve consensus

Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Accepted for publication August 12, 2015. Clinical Therapeutics topical updates or text http://dx.doi.org/10.1016/j.clinthera.2015.09.004 GS2C65 to 64842. To scan QR Codes your 0149-2918/$ - see front matter phone must have a QR Code reader installed. & 2015 Elsevier HS Journals, Inc. All rights reserved.

December 2015 2751 Clinical Therapeutics based ‘optimal’ or ‘target’ LDL-C levels despite side effects, further restricting their use even in these adequate response to statins and other currently populations.11 Thus, there remains an important need available LDL-C reducing drugs.4 The recent, still for efficacious agents to robustly and safely decrease controversial and even in the United States not LDL-C, and several compounds currently in clinical widely accepted, American Heart Association/ development are included in this review and are American College of Cardiology guidelines recom- classified into those for widespread use in the mend consideration of non-statin therapies that general population and those specifically for patients have demonstrated favorable benefit, compared with HoFH (Table I). with adverse effects, for reduction of atherosclerotic cardiovascular disease (CVD).5,6 Currently available EVOLVING THERAPIES FOR REDUCING LDL-C non-statin therapies for lowering LDL-C include bile IN THE GENERAL POPULATION acid sequestrants, cholesterol absorption transport PCSK9 Inhibitors inhibitors, niacin, and fibrates. However, with the Since its discovery in 2003 proprotein convertase exception of ezetimibe, these modalities are not well subtilisin/kexin type 9 (PCSK9) was found to play tolerated and often result in inadequate additional a key role in the metabolism of LDL-C via its interaction LDL-C reduction, and the benefit when added to with, and subsequent degradation of, the LDL re- statins has not shown to improve cardiovascular ceptor (LDLR).12 The elucidation of the patho- – outcomes.7 10 More recently, in specific and rare physiologic role of PCSK9 via gain-of-function and populations with homozygous familial hypercholes- loss-of-function (LOF) mutations has been extensively terolemia (HoFH), agents that target apolipoprotein B reviewed in the past few years and is not repeated – (apoB)-containing lipoprotein formation, mipomersen here.13 15 However, it was mostly the studies document- and lomitapide, have gained limited approval and ing that LOF mutations resulted in small but lifelong have encountered significant postmarketing adverse reductions in LDL-C which were associated with a 40%

Table I. LDL cholesterol-lowering therapies: new drugs in development.

General or widespread use (non-FH, HeFH, and HoFH) PCSK9 inhibitors Monoclonal antibodies Approved (alirocumab, evolocumab) Phase III (bococizumab) Phase II (LY3015014, RG7652) Adnectins: Phase I (BMS-962476) siRNA: Phase I (ALN-PCS) CETP inhibitors: Phase III (anacetrapib, evacetrapib, TA-8995) Adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase modulator: Phase II (ETC-1002/ bempedoic acid) New niacin-related agents: Phase I (CAT-2054); ARI-3037MO Specific or orphan use (HoFH only) PPAR-δ agonist (MBX-8025): Phase II ACC inhibitor (gemcabene): Phase II ANGPTL3 inhibition: monoclonal antibody (REGN1500) Phase I; antisense (ISIS-ANGPTL3Rx); siRNA (ALN-ANG)

ACC, acetyl coenzyme A carboxylase; ANGPTL3, angiopoietin-like protein 3; CETP, cholesterol ester transfer protein; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; PCSK9, proprotein convertase subtilisin/kexin type 9; PPAR, peroxisome proliferator-activated receptor; siRNA, small interfering RNA.

2752 Volume 37 Number 12 T. Turner and E.A. Stein to 60% reduction in CVD risk that led to the search for, (Eli Lilly) and RG7652 (Genentech/Roche), reportedly and development of, compounds that target PCSK9. The awaiting a commercial decision to proceed after com- – critical finding, by Legace et al16 in 2006, that pleting Phase II.21 23 circulating PCSK9 was responsible for interaction with The first published study in humans with a PCSK9 the LDLR resulted in the rapid development of highly mAb, alirocumab,17 clearly demonstrated PCSK9 targeted therapy to inhibit PCSK9 with the use of inhibition to be a powerful modality for reducing monoclonal antibodies (mAbs). Alternative mechanisms LDL-C. Large and statistically significant dose that reduce intrahepatic PCSK9 production such as gene response reductions in LDL-C, from 28% to 65%, silencing techniques are also in development, whereas the were reported in 2 single ascending dose (SAD) trials search still continues for small molecules. conducted in healthy volunteers with baseline LDL-C concentrations 4100 mg/dL. Although doses up to mAbs to PCSK9 ~800 mg (12 mg/kg) were tested the study found a The most promising and advanced current therapeu- plateau of effect at a dose of ~150 mg. A multiple tic approach to PCSK9 inhibition is mAbs. In 2009 to ascending dose (MAD) trial with alirocumab 50, 100, 2010, 2 mAbs targeting PCSK9, alirocumab and evolo- and 150 mg given at 2- and 4-week intervals was cumab, entered clinical trials in humans.17,18 Since that conducted in 3 cohorts (heterozygous familial hyper- time, development has progressed rapidly (Figure 1), cholesterolemia [HeFH] and non–familial hypercho- and both compounds were recently approved by the lesterolemia on stable dose atorvastatin, and subjects Food and Drug Administration by the Endocrinologic without FH on diet alone) assessed both safety and and Metabolic Drugs Advisory Committee and the efficacy, confirming a moderate dose response that European Medicines Agency with marketing having ranged from 39% to 61%. Maximum LDL-C low- started in the United States in August 2015.19,20 Other ering occurred rapidly and was stable for 2 weeks mAbs in clinical development include bococizumab, after dosing in all 3 cohorts. Single and multiple dose currently in Phase III, and 2 agents, LY3015014 data were reported later in 2012 for evolocumab18

1st MAD phase 1b trials with PCSK9 mAb started including FH, Phase 3 trials complete nonFH, statin Rx Phase 2 trials in-progress for 2 mAbs, BLA* filed Published for REGN727 and CVD outcome including FH, Q2W/Q4W trials started dosing

First subjects treated Phase 2 trials puplished Early data with PCSK9 mAb in for AMG145 including on CVD SAD studies 1st publications MAD HoFH, Statin Intol, benefit Marketing POC in FH, nonFH on Q2W/Q4W approval statin or diet USA/Europe

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

*BLA-Biologics licensing application

Stein: PCSK9 Clinical Development Timeline 2015

Figure 1. PCSK9: rapid progress in humans from proof of concept to CVD data. BLA, biological licensing application; CVD, cardiovascular disease; FH, familiar hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; Intol, intolerant; mAb, monoclonal antibody; MAD, multiple ascending dose; PCSK9, proprotein convertase subtilisin/kexin type 9; POC, point of care; Q2W, every 2 weeks; Q4W, every 4 weeks; Rx, therapy; SAD, single ascending dose.

December 2015 2753 Clinical Therapeutics

Over the past 3 years a large number of random- Table II. Key clinical information from Phase II ized, mostly double-blind, placebo-controlled, Phase II and III trials of alirocumab and – and III trials with alirocumab24 26 and evolocu- evolocumab. – mab,27 34 have been published involving over 8000 Pharmacokinetic and pharmacodynamic patients with various lipid phenotypes and genotypes properties and on a variety of background therapies. This review LDL-C efficacy in various phenotypes and focuses on what we have learned from these trials, genotypes particularly trials that address specific clinical ques- Non-familial hypercholesterolemia tions listed in Table II. Monotherapy Combination with statins PK and Pharmacodynamic Properties of mAbs to Long-term adherence PCSK9 Statin adverse patients As the concentration of the mAb, total and free Heterozygous familial hypercholesterolemia PCSK9, and LDL-C are measurable in plasma/serum, it Homozygous familial hypercholesterolemia provides a unique opportunity to be able to study both Effect on Lp(a) and other lipids and lipoproteins the pharmacokinetic (PK) and pharmacodynamic param- Safety and tolerability eters of this therapy. As shown in Figure 2,using Emerging CVD data and Outcomes trials evolocumab as the example, the mAb is rapidly absorbed after subcutaneous injection, peaks within a CVD, cardiovascular disease. few hours in the circulation, and after binding to its target, PCSK9, is gradually cleared via the reticular endothelial system over the ensuing weeks.18 Although with similar patient populations and results. The total PCSK9 in plasma increases because of binding by safety and tolerability profile of both alirocumab the mAb, free PCSK9 rapidly decreases and at effective and evolocumab in these early short-term trials were doses of mAb within a few hours is reduced by 499% similar to that of placebo, and development of both (Figure 2). This is followed within days by a reduction in drugs progressed rapidly to Phase II. LDL-C which plateaus at roughly 60% and remains

500 Total AMG 145 (evolocumab) 160 Free PCSK9 450 LDL–C 140

400 LDL–C Mean Change (%) 120 350 100 300

250 80 200 60 150 40 100

Free PCSK9 concentration (ng/mL) 50 20

Free AMG 145 concentration (ng/mL × 0.01) 0 0 0 14 28 48 56 70 84 Study Day

Stein EA & Raal FJ Annu. Rev. Med. 2014. 65:417−31.

Figure 2. Pharmacokinetic and pharmacodynamic properties of evolocumab: changes in PCSK9 and LDL-C levels in response to evolocumab. Reproduced with permission.15 PCSK9, proprotein convertase subtilisin/kexin type 9.

2754 Volume 37 Number 12 T. Turner and E.A. Stein stable as long as there is sufficient mAb to keep free all have shown a consistent response irrespective of PCSK9 suppressed. It became apparent from the early the background treatment. Perhaps the Durable Effect SAD and MAD trials that the LDL-C dose response tailed of PCSK9 Antibody Compared with Placebo Study off soon after a dose of 140 to 150 mg and that the (DESCARTES) best exemplifies the effect of various duration of effect on LDL-C appeared related to the dose background therapy in a single trial because patients of mAb administered. In the SAD trial of alirocumab at a with hyperlipidemia were stratified according to risk dose of 12 mg/kg, 800 mg in a 70-kg human, reduced categories from the National Cholesterol Education LDL-C to no greater extent than doses of 3 or 6 mg/kg; Program Adult Treatment Panel III.34 They were then however, the duration of LDL-C reduction was ex- started on background lipid-lowering therapy with tended to nearly 60 days.17 To robustly confirm these 2 diet alone or diet plus atorvastatin 10 mg daily, aspects further, larger numbers of patients in various atorvastatin 80 mg daily, or atorvastatin 80 mg plus dose groups were required, and is thus best assessed by 10 mg ezetimibe for a run-in period of 4 to 12 weeks. the pooled Phase II data published on evolocumab Patients with an LDL-C Z75 mg/dL were then which compared placebo, 70, 105, 140, 280, 350, and randomized in a 2:1 ratio to receive either evolocumab 420 mg in cohorts of 125 to 210 per group.27 To assess (420 mg) or placebo every 4 weeks for 52 weeks. The maximal reduction in LDL-C for any dose a time point overall LDL-C reduction with evolocumab compared 2 weeks after mAb administration is optimal, and it can with placebo was 57% with the reductions in each of be seen from this pooled analysis that a maximal the different background groups, diet alone, atorvas- decrease of 60% was achieved with the 140-mg dose tatin 10 mg, atorvastatin 80 mg, and atorvastatin 80 and despite a 3-fold increase to 420 mg essentially no mg plus ezetimibe 56%, 62%, 57%, and 49%, additional LDL-C reduction occurred. This is consistent respectively. Thus, there appears to be little impact of with the biology of PCSK9 in that once all free PCSK9 background therapy with the addition of mAb to reduce is bound no additional upregulation of LDLR will be LDL-C an additional 55% to 60%. These results were attained. To assess the duration of effect it can also be also consistent with LDL-C reductions of 60% found seen from the pooled data that the larger the dose of with every-2-week treatment with 150 mg alirocumab mAb the greater the duration of LDL-C reduction, and or 140 mg evolocumab in trials in which patients were when the drug is administered at 420 mg every 4 weeks, on various background therapies.30,31,35 almost identical LDL-C reductions occur compared with the 140-mg dose given every 2 weeks. This rule of thumb Long-Term Tolerability and Adherence that it takes 3 times the every-2-weeks dose to achieve the Alirocumab and evolocumab were well tolerated in sameresultsasanevery-2-weeksdoseisconsistentwith the Phase II trials that were of 8 to 12 weeks in nonlinear PK properties for evolocumab and may reflect duration, and concern remained as to longer term non-target mediated clearance of unbound mAb and/or adherence, given that this was the first mainstream reduced clearance of free PCSK9 because it no longer subcutaneous therapy for LDL-C. A number of trials binds to and is cleared by the LDLR. Although reduced in Phase III of Z52 weeks were thus considered frequency of administration is desirable, it does require pivotal for this reason alone. DESCARTES, the Open larger injection volumes, and the current physical limi- Label Study of Long-Term Evaluation against LDL-C tation of 150 mg mAb in 1 mL, an optimal volume for Trial (OSLER), and the ODYSSEY trials FH I, an autoinjector, means that 3 mL is required for a 420- FH II36,37 and LONGTERM all demonstrated adher- mg every-4-week dose. This entails 3 1 mL auto- ence as good as trials of similar duration with statins, injectors or more optimally the use of a slow subcuta- ezetimibe, and other oral lipid-altering agents, with neous infusion device. 88% of patients in DESCARTES and 93% in the open label OSLER trial completing the 52-week trial and LDL-C Efficacy in Patients without FH 72% completing the 78-week ODYSSEY LONG Influences of Background Therapy; Diet Alone, Low- TERM study.38,39 or High-Dose Statin Therapy, or Statin with Ezetimibe A number of trials were done in patients on Addition to Statin; Synergy or Additive? diet alone and others in patients on existing statin Two issues related to statins were addressed. First, therapy or randomized to various doses of statins, and if inhibition of PCSK9 would be synergistic, additive,

December 2015 2755 Clinical Therapeutics or less than additive, and second, if patients who GAUSS-2 nearly 20% of the patients had more severe could not tolerate statins, or effective doses of statins, and objective adverse effects, including myositis or would respond to and tolerate mAbs. The first ques- rhabdomyolysis. In both GAUSS trials most patients tion related to an initial hypothesis after the finding were at high or very high risk of CVD, and the that statins caused upregulation of PCSK9 synthesis, baseline LDL-C was 4190 mg/dL, concentrations not in addition to synthesis of LDLRs.34 It was postulated seen in such patients since before the advent of statins. that this may be the reason for the log linear dose The ODYSSEY ALTERNATIVE trial had a different response curve with statins, also known as the rule of design with patients enrolled only if they consented to 6or7.40 On the basis of this it was suggested that the potential of being exposed to atorvastatin 20 mg inhibition of PCSK9 would therefore be synergistic in the double-blind phase. This in essence likely and lead to enhanced LDL-C reduction with statins, excluded patients with the most significant and serious especially higher doses of statins. Although no trial SAMSs especially myositis and rhabdomyolysis and addressed this specifically, the trial by Roth et al24 patients previously exposed to multiple statins.41 comes closest. In this trial patients were on stable There was also a single-blind double placebo (oral treatment with atorvastatin 10 mg daily before being medication and subcutaneous injection) lead-in during randomized to receive either continued atorvastatin which time 6% of patients were excluded from the 10 mg plus alirocumab 150 mg every 2 weeks or randomized phase. The trial excluded patients in the increased to 80 mg plus alirocumab 150 mg every 2 atorvastatin arm from the efficacy analysis a priori weeks or placebo injections. The increase from 10 to because the purpose was to compare statin re- 80 mg atorvastatin resulted in the expected additional exposure for tolerability. In the efficacy arm ezetimibe 17% reduction in LDL-C, whereas continuing on was used as in the GAUSS trials. The patient pop- atorvastatin 10 mg and adding alirocumab decreased ulation in terms of CVD risk and baseline LDL-C was LDL-C 66%. Thus, if PCSK9 inhibition was additive, similar to that in the GAUSS trials, emphasizing the increasing atorvastatin to 80 mg and adding alirocu- significant unmet need for additional effective LDL-C mab would be expected to reduce LDL-C by 66% þ lowering in this population. In the first GAUSS trial,29 17% or 83% and even more if the inhibition of dose-dependent reductions in LDL-C concentrations PCSK9 was synergistic. However, the LDL-C reduc- of 41% to 63% in patients on evolocumab, compared tion in the atorvastatin 80 mg þ alirocumab group with 15% in the ezetimibe group, were observed. was 73%, only 7% more than in the atorvastatin 10 There was no significant difference in tolerability seen mg þ alirocumab arm. This study clearly showed no between evolocumab- and ezetimibe-treated patients. synergy exists and suggested that at the highest doses GAUSS-232 showed LDL-C reductions of up to 56%, of statins there may be a limit to the upregulation of and 475% achieved LDL-C concentrations of o100 LDLR activity. mg/dL. Based on a questionnaire, muscle adverse events (AEs) were reported in 12% of evolocumab- Statin-adverse Patients treated patients and 23% of ezetimibe-treated For PCSK9 mAbs in patients with statin-associated patients. In ODYSSEY ALTERNATIVE41 LDL-C muscle side effects (SAMSs),4 three trials were was reduced 45% from baseline compared with published or presented, 2 with evolocumab (GAUSS 15% in the ezetimibe group. Tolerability was better [Goal Achievement after Utilizing an anti-PCSK9 and discontinuations fewer in the alirocumab group, antibody in Statin Intolerant Subjects] and GAUSS- followed by the ezetimibe arm with nearly 50% of 2)29,32 and 1 with alirocumab (ODYSSEY ALTER- patients exposed to atorvastatin reporting SAMSs. NATIVE).41,42 GAUSS and GAUSS-2 required patients have documented intolerance to at least 1 Patients with HeFH and 2 statins, respectively, and both studies showed The Phase I MAD studies for both alirocumab and that physicians and patients in fact attempt different evolocumab included cohorts of patients with HeFH statins more frequently than previously thought. For who demonstrated LDL-C reductions similar to that example, in GAUSS-2 75% to 80% of patients in the seen in patients without FH. However, most of these trial had been treated with 3 statins and 20% to 25% patients were from a single clinical site and thus likely had been exposed to a fourth statin. In addition in carried similar genetic mutations. It is known that

2756 Volume 37 Number 12 T. Turner and E.A. Stein there are 41600 mutations in the LDLR alone that weeks. The LDL-C reductions in both evolocumab cause FH, so it was important to assess the response in groups were virtually identical at 59% and 61%, large and global trials in which patients with greater respectively, versus placebo. The unique aspect of diversity of LDLR, apoB, and potentially PCSK9 RUTHERFORD-2 was that in the 80% of patients gain-of-function mutations would be found. In addi- who consented to genetic analysis of their mutation tion, it was of potential clinical importance to assess if that caused FH it was unequivocally demonstrated the the LDL-C response would be related to the under- LDL-C reduction was not related to underlying defect lying defect because this could lead to more tailored with equal reductions seen in those with LDLR use of what are likely to be expensive medications. To defective and negative mutations. address the first issue the HeFH population was expanded in Phase II trial to patients from North Patients with HoFH America in a 77-patient alirocumab trial that also Some initial skepticism that PCSK9 inhibition assessed higher doses of 200 and 300 mg every 4 would not be effective in lowering LDL-C in patients weeks compared with 150 mg given both every 2 with HoFH was dispelled by a small pilot proof-of- weeks and every 4 weeks in patients with LDL-C concept trial with evolocumab (TESLA part A).44 4100 mg/dL on stable maximal statin therapy and Eight LDLR-negative or -defective patients with many with ezetimibe.25 The evolocumab trial, HoFH on maximal stable drug therapy were treated RUTHERFORD (Reduction of LDL-C with PCSK9 with evolocumab 420 mg every 4 weeks for Z12 Inhibition in Heterozygous Familial Hypercholester- weeks, followed by 420 mg every 2 weeks for an olemia Disorder),28 was global with 168 patients, additional 12 weeks. No reduction was seen in the 2 90% of whom were on intensive statin therapy, LDLR-negative patients but in the 6 with LDLR- randomized to receive evolocumab 350 mg or 420 defective mutations reductions of 19.3% and 26.3% mg subcutaneously every 4 weeks or placebo for 12 were found with 4- and 2-week dosing, respectively, weeks. Maximal reductions in LDL-C of 60% Ϯ 5% and ranged from 4% to 48%. On the basis of these were seen in both the alirocumab 150-mg every-2- results a larger more definitive randomized placebo- week dose group and the evolocumab 420 mg dose controlled, double-blind trial, TESLA part B, was group with lesser reductions in the lower dose every-4- undertaken. Forty-nine patients, including patients week arms, again confirming that the response in aged Z12 years on maximal statin Ϯ ezetimibe but HeFH even on maximal statin, with or without not apheresis with mean baseline LDL-C of 348 mg/dL ezetimibe, was no different from patients without were randomized 2:1 to receive evolocumab 420 mg FH. Even larger numbers and greater global diversity every 4 weeks or placebo for 12 weeks.33 Compared of patients with HeFH along with longer duration of to placebo, LDL-C was reduced by 31%, and the therapy were achieved in the Phase III trials for absolute decrease in LDL-C was 93 mg/dL. The trial alirocumab and evolocumab. Alirocumab enrolled also assessed response based on the underlying genetic 1150 patients in the ODYSSEY FH1, FH2, and mutation, and, although few patients had defects LONG TERM trials, all of which lasted 452 weeks associated with no receptor activity, it confirmed they and with a 2:1 randomization to alirocumab or did not respond. However, in the majority of patients, placebo, resulted in 4750 receiving the PCSK9 who had at least 1 LDLR defective mutation, the – mAb.36 38 The reductions in LDL-C were different LDL-C reduction was 41% and in patients with 2 because of the incorporation of a lower starting dose LDLR defective genes it was 46%. of 75 mg every 2 weeks in FH1 and FH2, which was increased to the full 150-mg dose if LDL-C goal was Effect on Lp(a) and Other Lipid and Lipoproteins not achieved after 12 weeks of therapy. This resulted Similar to statins that upregulate LDLR synthesis in LDL-C reductions that ranged from 51% to 61% and activity, PCSK9 mAbs reduce apoB and related compared with placebo. The evolocumab lipids and lipoproteins such as total cholesterol, non– RUTHERFORD-243 trial enrolled 331 patients with HDL-C, and VLDL in parallel to LDL-C. In addition, HeFH on maximal statin with or without ezetimibe mild-to-moderate reductions in triglycerides (TGs) and randomized assigned them 2:1 to 140 mg every 2 were reported. Small increases in HDL-C and its weeks, 420 mg every 4 weeks, or placebo for 24 associated apoA1 were seen in most trials, which is,

December 2015 2757 Clinical Therapeutics again, consistent with the effect seen with statins human genetic studies in populations with LOF whereby clearance of atherogenic lipoproteins is en- mutations in which no adverse effects have been hanced. However, a completely unexpected effect was reported and even in the rare patient with dual PCSK9 the robust and consistent reductions in Lp(a) which LOF where no plasma PCSK9 is detectable, LDL-C was first noted in the MAD trials.17,18 The reduction concentrations are o20 mg/dL, but no physical, was confirmed in the larger Phase II and III trials, and, psychological, endocrine, or reproductive abnormal- – while dose dependent, at the doses most frequently ities are found.47 50 used and likely to be marketed of 150 mg every The other area of potential concern has been the 2 weeks for alirocumab and 140 mg every very low LDL-C levels attained in many patients, 2 weeks and 420 mg every 4 weeks for evolocumab, especially those in whom pre-PCSK9 mAb treatment respectively, Lp(a) is reduced 25% to 30%.45,46 LDL-C is just above 70 mg/dL, and the large Although a number of theories exist for the reduction, treatment-associated decreases result in LDL-C o25 which is not seen with other drugs that lower LDL-C or even 15 mg/dL. However, recently reported results by increased clearance, the mechanism is yet to be from both the ODYSSEY LONG TERM trial and elucidated. OSLER extension trials examined the incidence of clinical and laboratory AEs in these patient subgroups Safety Profile and found no differences in mAb-treated patients with Despite exposure to 48000 patients for durations higher LDL-C or those in the placebo or standard of up to 2 years no specific or serious clinical or care (SOC) alone groups (Tables III and IV).38,39 One – laboratory AEs have emerged so far.24 34 The sub- potential area that requires additional monitoring and cutaneous injections have been well tolerated with few assessment is neurocognitive events that in both injection site reactions, and, because both alirocumab OSLER and ODYSSEY LONG TERM trials showed and evolocumab are fully human mAbs, few and low slight excess in the groups treated with mAbs. These titer anti-mAb antibodies were seen. It thus appears events were not assessed or adjudicated in a systematic fortuitous that circulating PCSK9 has no other role manner in either study and appeared to vary in the other than to bind to and regulate LDLR recycling; same patient from visit to visit. However, to address thus, removal of PCSK9 via binding to mAbs results in the issue in greater detail and more systematically a no off target effects. This is also supported by the substudy, EBBINGHAUS (Evaluating PCSK9 Binding

Table III. OSLER: adverse events by achieved LDL-C.39

Evolocumab subjects stratified by minimum achieved LDL-C o25 mg/dL 25 to o40 mg/dL o40 mg/dL Z40 mg/dL All EvoMab SOC Alone (n ¼ 773) (n ¼ 759) (n ¼ 1532) (n ¼ 1426) (n ¼ 2976) (n ¼ 1489)

Adverse events (%) Any 70.0 68.1 69.1 70.1 69.2 64.8 Serious 7.6 6.9 7.2 7.8 7.5 7.5 Muscle related 4.9 7.1 6.0 6.9 6.4 6.0 Neurocognitive 0.5 1.2 0.8 1.0 0.9 0.3 Laboratory results (%) ALT/AST 0.9 0.8 0.8 1.3 1.0 1.2 43 ULN CK 45 ULN 0.4 0.9 0.7 0.5 0.6 1.2

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; EvoMab, evolocumab; OSLER, Open Label Study of Long-Term Evaluation against LDL-C Trial; ULN, upper limit of normal; SOC, standard of care.

2758 Volume 37 Number 12 T. Turner and E.A. Stein

Table IV. ODYSSEY outcomes: summary of adverse events (AEs) by achieved LDL-C.38

Alirocumab Alirocumab with 2 consecutive (n ¼ 1550) LDL-C o25 mg/dL (n ¼ 575) Placebo (n ¼ 788)

Any AE 1255 (81.0) 435 (75.7) 650 (82.5) Serious AE 290 (18.7) 98 (17.0) 154 (19.5) AE leading to death 8 (0.5) 4 (0.7) 10 (1.3) AE leading to study drug discontinuation 111 (7.2) 26 (4.5) 46 (5.8)

AE, adverse event. Values are n (%).

Antibody Influence on Cognitive Health in High double-blind ODYSSEY LONG TERM trial, where Cardiovascular Risk Subjects; ClinicalTrials.gov LDL-C was decreased 62% with alirocumab 150 mg identifier NCT02207634) was incorporated in the every 2 weeks, showed a 48% reduction in CVD evolocumab, CVD outcome trial FOURIER (Further events at 78 weeks (1.7% with alirocumab vs 3.3% Cardiovascular Outcomes Research with PCSK9 In- with placebo; hazard ratio, 0.52; 95% CI, 0.31–0.90; hibition in Subjects with Elevated Risk). P = 0.02). Although CVD events were not the primary However, just as with statins, decades of therapy or even secondary end points for these 2 trials and the with these agents in many hundreds of thousands of number of events was relatively small in both trials, patients may be necessary to detect more subtle side both were statistically significant and demonstrated effects not readily apparent in short-term trials. almost identical reductions of nearly 50% relative to either placebo or SOC. These studies are encouraging Cardiovascular Events and Outcome Trials and also in direct contrast to smaller short-term trials Unlike the development of statins 3 decades ago for example, with torcetrapib. In Rating Atheroscler- when no impact on CVD events were discernable otic Disease by Imaging with a new CETP inhibitor before regulatory approval and marketing, and it took (RADIANCE) I and II, in which the primary end point nearly a decade after initial approval until the results was carotid intimal media change, CVD events in both of the 4S trial were reported,3 2 Phase III trials with trials showed an increase with torcetrapib added to both alirocumab and evolocumab showing a atorvastatin, reaching statistical significance (P o reduction in CVD have been published.38,39 In the 0.05) in RADIANCE I.51 OSLER trial, evolocumab was studied in 4465 pa- The definitive CVD outcome trials for evolocumab, tients who enrolled into an open-label trial after alirocumab, and bococizumab are already under way completing 1 of the Phase II or III parent trials. (Table V) and should also address the long-term safety Patients were re-randomized 2:1 to receive standard profile of the drugs and low and very low LDL-C of care (SOC) plus evolocumab 140 mg every 2 weeks levels. The FOURIER (NCT01764633) trial that or 420 mg every 4 weeks for 12 months or SOC alone. compares evolocumab 150 mg every 2 weeks or 420 A prespecified exploratory analysis included CVD mg every 4 weeks added to statin versus statin alone is events, which were adjudicated blinded without already fully enrolled with 27,500 patients with knowledge of treatment group. LDL-C was reduced results expected no later than 2017.52 The with evolocumab, 61%, to a median LDL-C of 48 mg/dL ODYSSEY OUTCOMES trial is projected to from a baseline median of 120 mg/dL, and at 11 complete planned enrollment of 18,000 patients by months CVD event estimates by Kaplan-Meier anal- the end of 2015 and will compare addition to statin of ysis were 0.95% and 2.18%, with SOC þ evolocu- alirocumab 75 mg every 2 weeks, with up titration to mab and SOC alone, respectively (hazard ratio, 0.47; 150 mg every 2 weeks if LDL-C o70 mg is not 95% CI, 0.28–0.78; P = 0.003). A blinded post hoc achieved, to statin alone, and results are anticipated analysis of CVD events in the 2341 high-risk patient by late 2017 or early 2018.53

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Table V. PCSK9 inhibitor CVD outcomes trials in progress.

Alirocumab (SAR236553/ Evolocumab (AMG 145) REGN727) Bococizumab (RN 3160

Sponsor Amgen Sanofi/Regeneron Pfizer Trial FOURIER ODYSSEY Outcomes SPIRE I SPIRE II Sample size 27,500 18,000 17,000 9000 Patients MI, stroke, or PAD 4–25 wk after ACS High risk or CV event Statin Atorva Z20 mg or equiv Evidence-based medical Rx Lipid-lowering Rx LDL-C mg/dL Z70 (Z1.8) Z70 (Z1.8) 70–99 (1.8–2.6) Z100 (Z2.6) (mmol/L) PCSK9i dosing Q2W or Q4W Q2W Q2W End point 11: CV death, MI, stroke, CHD death, MI, ischemic CV death, MI, stroke, or urgent revasc or hosp for UA stroke, or hosp for UA revasc Key 21: CV death, MI, or stroke Recruitment status Completed June 2015 Projected for December 2015 ? Completion December 2017 January 2015 August 2017

ACS, acute coronary syndrome; Atorva, atorvastatin; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; equiv, equivalent; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; hosp, hospital; MI, myocardial infarction; PAD, peripheral artery disease; Q2W, every 2 weeks; Q4W, every 4 weeks; revasc, revascularization; Rx, therapy; SPIRE, Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects; UA, unstable angina.

Regulatory Status, Marketing Approval, and Annual though these drugs are by far the most efficacious Cost LDL-C agents yet developed and have excellent toler- The development progress from first in human ability and early safety profiles, it is important that trials through to completion of Phase III, filing bio- they be used only when appropriate and always only logical licensing application, regulatory review, and after maximal tolerable doses of the most efficacious final marketing approval for alirocumab and evolo- statins, atorvastatin and rosuvastatin, plus ezetimibe cumab was remarkably rapid (Figure 1) in both have been fully implemented. Europe and the United States.19,20 Alirocumab be- came available in the United States in early August ADNECTINS: BINDING PROTEINS TO PCSK9 2015, with a recommended starting dose of 75 mg Although mAbs to PCSK9 have shown to be effective every 2 weeks, for use as an adjunct to diet and and well tolerated, they are expensive to manufacture maximally tolerated statin therapy for the treatment because they require production in mammalian cell of adults with HeFH or clinical atherosclerotic CVD, lines and have physical limitations in terms of injec- who require additional lowering of LDL-C. Evolocu- tion volumes as previously described. Alternative mab became available in early September with similar smaller binding proteins that like mAbs bind circulat- indications plus the additional indication for patients ing PCSK9 may therefore offer potential advantages. with HoFH aged 13 or older. The list price for Adnectins are proprietary fusion proteins derived alirocumab, 75 mg or 150 mg doses, was recently from the tenth type III domain of human fibronectin, announced by the manufacturers at $14,600 per year, designed to bind with high affinity and specificity to a although it is likely that actual costs to health therapeutic target, analogous to mAbs, and are pro- insurance payers will be less. The price of evolocumab duced via an Escherichia coli–based manufacturing is approximately $500 per year less. However, even process.54 BMS-962476 is an 11-kDa polypeptide

2760 Volume 37 Number 12 T. Turner and E.A. Stein

first-generation PCSK9-targeted adnectin conjugated 95% and mean LDL-C decreased 69% at the highest to polyethylene glycol to provide extended circulating dose, with effective reductions maintained 450 days time and to extend its PK properties. In a phase I SAD after the last dose, raising the possibility of monthly or study55 of 64 otherwise healthy patients with elevated longer dosing intervals. ALN-PCSsc is currently in Phase LDL-C treated with statins or diet alone, SC doses I clinical development (clinicaltrials.gov identifier of BMS-962476 showed a dose-related effect with NCT02314442) in a SAD/MAD trial in healthy volun- 0.3 mg/kg, reducing free PCSK9 490% and LDL-C teers with LDL-C Z100 mg/dL; ALN-PCSsc combined 48% from baseline. While an attractive alternative to with statins will be assessed in the multiple dose phase. mAbs, given the lower potential cost of production It is anticipated this agent will enter Phase II in late 2015 and smaller injection volumes, it remains to be seen if or early 2016. adnectins provide the same tolerability, safety profile, and reductions in LDL-C as mAbs. Vaccines Targeting PCSK9 Peptide-based anti-PCSK9 vaccines being developed by Gene Silencing Approaches to PCSK9 Inhibition: AffiRiS AG (Vienna, Austria) have shown LDL-C reduc- RNA Interference and Antisense Oligonucleotides tion up to 55% for 1 year in preclinical studies. Generated Gene-silencing techniques, such as RNA interfer- PCSK9-specific antibodies efficiently blocked PCSK9 pro- ence and antisense oligonucleotides impede the intra- tein in animals, upregulated LDLRs, and also recognized cellular production of target proteins through nucleic human PCSK9.59 Pfizer has announced a vaccine to acid–based therapies that interfere with RNA function. PCSK9 will begin clinical development in 2016. RNA interference occurs at the post-transcriptional level and is a mechanism by which double-stranded CETP Inhibitors RNA is processed by an endonuclease to small inter- Cholesterol ester transfer protein (CETP) inhibition fering RNA (siRNA), 15 to 30 nucleotides in length, may be anticipated to reduce the risk of CVD, sup- which is then bound to a nuclease complex that triggers ported by epidemiologic studies showing genetic unwinding of the siRNA, the antisense siRNA strand is mutations that result in CETP deficiency and associa- then directed to a complementary target mRNA, ted increases in HDL-C.60,61 The background on the resulting in degradation of mRNA, preventing trans- epidemiology, physiology, and pharmacology of lation of the target protein, potently silencing gene CETP inhibitors (CETPis) was recently reviewed.62,63 expression.56 ALN-PCS (Alnylam Pharmaceuticals, Over the past decade several CETPis have entered Cambridge, Mass), a siRNA inhibitor of PCSK9 clinical development with the primary goal of reduc- administered intravenously, was studied in a Phase I ing CVD events through their ability to increase SAD study in 32 healthy subjects with LDL-C 4115 HDL-C concentrations and enhance reverse choles- mg/dL and reduced mean PCSK9 protein and LDL-C terol transport. The effect on HDL-C has ranged from concentrations by 70% and 40% 3 days after infusion, 35% with dalcetrapib to 4150% with TA-8995, respectively, in the highest dosed, 0.400 mg/kg, cohort. whereas reductions in LDL-C concentrations have Treatment-emergent AEs were similar in the ALN-PCS varied from minimal with dalcetrapib to 45% with andplacebogroups;however, subjects required pre- TA-8995. Because there is no regulatory pathway for medication with dexamethasone and antihistamines to approval on the basis of HDL-C as a surrogate mitigate the potential for infusion-related reactions that biomarker, trials demonstrating reduction in CVD can occur with lipid-formulated drugs.57 Subsequently, are required. Two agents, torcetrapib and dalcetrapib, siRNA paired with triantennary N-acetylgalactosamine were terminated during large CVD outcome trials (GalNAc) resulted in a GalNAc-siRNA conjugate, after an increase in CVD events of 25% in patients comprised of a sugar moiety that acts as a ligand to taking torcetrapib,64 whereas the trial with dalce- the asialoglycoprotein receptor, resulting in a 5-fold trapib was terminated because of futility as dalce- improvement in efficacy and enabling targeted delivery trapib did not improve CVD events compared to directly to the liver, inducing marked gene silencing with placebo at a planned interim analysis.65 subcutaneous administration.58 In a preclinical study of Three CETPis remain in clinical development, ALN-PCSsc conjugate given as a single dose in cyn- anacetrapib, evacetrapib, and TA-8995. Anacetrapib omolgous monkeys, PCSK9 protein was lowered by 100 mg daily has been evaluated in patients with

December 2015 2761 Clinical Therapeutics

HeFH and without FH, with reported increases in concentrations and to target dyslipidemia and other HDL-C of 100% and LDL-C reductions when cardiometabolic risk factors associated with the meta- measured accurately of 25% to 35%. Adverse events bolic syndrome and atherosclerosis.71 A dual mecha- appear similar in the anacetrapib and placebo groups; nism of action has been demonstrated in preclinical however, the drug has an extremely long half-life, studies, consisting of adenosine monophosphate– measured in months, because it accumulates in adi- activated protein kinase activation and direct inhibition pose tissue, which is a concern.66 Prespecified CVD of the enzyme adenosine triphosphate citrate lyase by end points in two 1- to 2-year trials with patients with bempedoic acid-coenzyme A, a thioester coenzyme rap- HeFH and without FH have not shown significant idly formed in the liver. This was linked to beneficial increased or decreased events compared with pla- effects on lipid and carbohydrate metabolism, including cebo.67,68 The large CVD outcome trial with anace- inhibition of both sterol and fatty acid synthesis, im- trapib, REVEAL (Randomized Evaluation of the proved glycemic control, and increased fatty acid Effects of Anacetrapib through Lipid-Modification; oxidation.72 clinical trials.gov identifier NCT01252953), which is In completed Phase I and II clinical trials nearly 1000 recruiting 30,000 patients with established CVD, is patients were studied, two-thirds were treated with expected to complete in 2017. ETC-1002 at doses of 60, 120, 180, and 240 mg daily, Evacetrapib has been shown to increase HDL-C by either as monotherapy or in combination with ezeti- 120% and reduce LDL-C 20% to 25% when added mibe or low-dose statins. Dose-dependent reductions in to statin therapy and is currently undergoing a large LDL-C were seen and the percentage of decreases with CVD outcome trial, ACCELERATE (A Study of monotherapy versus placebo or baseline have varied Evacetrapib in High-Risk Vascular Disease; clinical- from the low 20s to as high as 45% in a trial in diabetic trials.gov Identifier NCT01687998), which will eval- patients.71 The occurrence of treatment emergent AEs uate an estimated 11,000 patients to determine was similar in patients receiving ETC-1002 and pla- whether evacetrapib added to statins provides addi- cebo, and there were no discontinuations of ETC-1002 tional risk reduction in major adverse cardiovascular because of muscle-related complaints.73,74 events compared with statins alone in patients with In the initial exploratory 6-week study LDL-C was CVD; results are expected in 2016. The sponsors reduced 24% compared with placebo with ETC-1002 recently announced that after an interim analysis for 180 mg in patients on diet-only therapy. A subsequent futility the data safety and monitoring committee had 12-week trial, 008, in which patients on diet only recommended continuation of the trial.69 were treated with ETC-1002 120 mg or 180 mg as Recently, TULIP (TA-8995: Its Use in Patients with monotherapy had reductions in LDL-C from baseline Mild Dyslipidaemia), reported a Phase II dose-ranging of 27% and 30%, respectively. In study 009, treat- study of the CETPi TA-8995 in patients with LDL-C ment with 120 and 180 mg daily of ETC-1002 between 100 and 175 mg/dL, HDL-C between added to stable statin background therapy resulted 30 and 70 mg/dL, doses of 1, 2.5, 5, or 10 mg daily in a 17% and 24% reduction in LDL-cholesterol, as monotherapy, 10 mg TA-8995 plus 20 mg ator- respectively, compared with patients on statin therapy vastatin or 10 mg rosuvastatin, or placebo. LDL-C alone.71 reductions after 12 weeks were significant at all TA- ETC-1002 has also shown a consistent reduction of 8995 doses, with a decrease of 45.3% in the 10-mg 25% to 40% in high-sensitivity C-reactive protein and dose monotherapy group and 50.2% reduction in a neutral effect on blood pressure, with good safety LDL-C when combined with statin compared with profile and tolerability even in patient subgroups with statin alone.70 prior SAMSs.71 No increased muscle-related AEs or elevated liver Dual Adenosine Triphosphate Citrate Lyase function test results relative to placebo were reported Inhibitor/Adenosine Monophosphate–Activated in these trials. Thus, ETC-1002 appears to offer an Protein Kinase Activator oral agent with promising, if moderate, additional Bempedoic acid, ETC-1002 (Esperion Therapeutics LDL-C reduction with good tolerability and is pro- Inc, Ann Arbor, Mich), is a novel, oral, once daily ceeding into large Phase III trials that are primarily to therapeutic agent in development to reduce LDL-C assess long-term safety.

2762 Volume 37 Number 12 T. Turner and E.A. Stein

NEW NIACIN (NICOTINIC ACID)-RELATED reported by study patients.81 The results of a recently COMPOUNDS completed MAD trial showed that tolerability Niacin (nicotinic acid) is one of the oldest lipid- remained good, LDL-C reductions of up to 20% were altering drugs in use, having been used therapeutically seen, and the drug is planned to enter Phase II.82 since the mid-1950s. It has well-documented favorable ARI-3037MO (Arisaph Pharmaceuticals, Boston, effect on lipid parameters, including TG and LDL-C Mass) is a new, synthetic derivative of nicotinic acid83 reductions of 20% to 50% and 10% to 25%, that does not interact with the GPR109A receptor, respectively, and HDL-C increases of 15% to and a healthy volunteer SAD trial of 0.5 to 6 g daily 35%.75,76 Reduced rates of cardiovascular morbidity found statistically significant mean decreases in TGs of and mortality with monotherapy were seen in the 56.7% and increases in HDL-C of 7.7% in the 6-g Coronary Drug Project,77,78 where doses of immediate cohort. A MAD trial, dose range 0.5 to 3.5 g daily, release nicotinic acid 42 g/d in patients with prior demonstrated significant reductions in TG concentra- myocardial infarction were associated with a 27% tions, and a trend toward reduction in LDL-C in the reduction in nonfatal recurrent myocardial infarctions 2-g cohort. In both trials, at all dosing regimens, ARI- (P o 0.004) and long-term 15-year follow up showed 3037MO was well tolerated without flushing, itching, 11% fewer deaths in the treatment group than in the or other skin changes; in addition, no liver enzyme or placebo group. Side effects with niacin treatment, in glucose abnormalities were observed. Future trials will part because of niacin-mediated GPR109A receptor determine whether the trends toward LDL-C reduc- agonist activity, have resulted in difficulty with toler- tion seen in early studies will be efficacious in a ability, mainly because of flushing, consisting of skin dyslipidemic population. symptoms that include warmth, redness, itching, or tingling, and increased insulin resistance.79 However, EVOLVING THERAPIES FOR REDUCING LDL-C 2 large CVD outcome trials, both with the use of IN SPECIFIC OR ORPHAN HOFH extended release niacin formulations added to statins, POPULATIONS AIM-HIGH (Atherothrombosis Intervention in Meta- Two orphan drugs were approved in the past 2 years bolic Syndrome with Low HDL/High Triglycerides: only for use for HoFH and under stringent require- Impact on Global Health Outcome)8,9 and HPS2- ments because of the significant potential toxicity THRIVE (Heart Protection Study 2-Treatment of associated with both drugs.11 The 2 agents have HDL to Reduce the Incidence of Vascular Events),8 similar mechanism of action in that they decrease failed to show clinical benefit. Despite these setbacks, formation of apoB-containing lipoproteins and thus research into niacin and its derivatives continues. entry of VLDL and LDL into the circulation. Lomita- With the use of a proprietary technology, SMART pide inhibits the enzyme microsomal TG transfer linker, approach to target and deliver niacin in higher protein which is present in both the intestine and liver concentrations directly to the liver CAT-2054 (Cata- and is essential for the addition of lipid to apoB (B48 in basis Pharmaceuticals Inc, Cambridge, Mass) is an the gut and B100 in the liver) to allow chylomicron and oral novel small molecule compound designed to VLDL formation, respectively. Mipomersen is an reduce sterol regulatory-element binding protein, a apoB antisense agent that works in the liver to family of membrane-bound transcription factors that downregulate synthesis of apoB, the apolipoprotein activate genes encoding enzymes involved in choles- essential for VLDL production and its subsequent terol and fatty acid synthetic pathways, the LDLR, down-stream product LDL.11 Although effective at and PCSK9.80 CAT-2054, consisting of eicosapen- reducing plasma LDL-C, especially because no LDLR taenoic acid conjugated to niacin, does not activate activity is involved, both drugs result in hepatic fat the GPR109A receptor, thus mitigating the potential accumulation with unknown long-term consequences, for flushing and via the eicosapentaenoic acid ensures in addition to significant and limiting side effects such direct delivery to the hepatocyte. Preclinical studies as diarrhea and fat-soluble vitamin reductions with have shown reductions in both LDL-C and PCSK9 lomitapide and injection site reactions and flu-like concentrations, and in a Phase I SAD trial in healthy symptoms with mipomersen. Both drugs are also volunteers, CAT-2054 was well tolerated, and AEs extremely expensive with list price in the United States were similar at doses r500 mg/dL, flushing was not of $300,000 per year for lomitapide and close to

December 2015 2763 Clinical Therapeutics

$200,000 for mipomersen. Excellent recent reviews on Acetyl Coenzyme A Carboxylase Inhibitors the pharmacology, lipid altering, side effects and Gemcabene, a dialkyl ether (dicarboxylic acid), restrictions for use are available; thus, this review part of a class of lipid-modifying compounds that focuses on novel agents in development for this possess a gem-dimethyl carboxylate moiety, has been difficult to treat severe disease.11 shown in preclinical studies to act as a PPAR ligand.88 Originally discovered in the 1990s it entered clinical PPAR Agonists development as a drug for broad use in all patients to Peroxisome proliferator-activated receptors (PPARs) reduce LDL-C, and thus was studied in nearly 1000 are nuclear hormone receptors that are comprised of 3 patients in Phase I and II trials.89 Moderate LDL-C receptors PPAR-α,PPAR-δ,andPPAR-γ, and function lowering of 15% to 25% was demonstrated along as ligand-activated transcription factors to regulate with good safety. The drug has recently been licensed multiple metabolic processes such as glucose and lipid to a start-up biotech company, orphan designation for metabolism, fatty acid oxidation, adipogenesis, and use in HoFH obtained, and gemcabene is now being insulin sensitivity. Drugs with PPAR-α activity, such developed for HoFH, and a Phase II proof-of-concept as clofibrate, gemfibrozil, and fenofibrate, have been trial is planned. used for decades to treat lipid disorders, predominantly to reduce TGs and to increase HDL-C. PPAR-δ ANGPTL3 Inhibitors activation affects lipid transport, storage, and metabo- Angiopoietin-like protein 3 (ANGPTL3) is a glyco- lism in liver and muscle, resulting in decreased concen- protein, secreted by the liver, with modulating effects trations of TGs and LDL-C, decreased HDL-C on lipoprotein and glucose metabolism, mainly concentrations, and improved insulin sensitivity, and through inhibition of lipoprotein lipase activity. has been identified as a therapeutic target.84 Genome-wide association studies have linked the MBX-8025 (Cymabay Therapeutics, Newark, ANGPTL3 gene to levels of circulating lipids; multiple Calif), a novel, potent PPAR-δ agonist with 4750- single-nucleotide polymorphisms have been associated fold and 42500-fold activity compared with PPAR-α with decreased TGs. A unique lipid phenotype related or PPAR-γ receptors, respectively, was previously to LOF mutations in the ANGPTL3 gene, familial evaluated in a double-blind, placebo-controlled, combined hypolipidemia (FHBL2), comprised of low proof-of-concept study of 181 patients with mixed concentrations of all plasma lipoproteins (VLDL, dyslipidemia who were randomized to receive MBX- LDL, and HDL), was initially described in 4 siblings 8025 50 or 100 mg daily with or without atorvastatin subsequently found to be compound heterozygotes 20 mg daily, atorvastatin alone, or placebo and with 2 inactivating mutations in ANGPTL3 reduced apoB85,86 compared with baseline, 20% to (p.E129X/p.S17X). To date, 9 distinct mutations in 38% (P o 0.0001). In addition, LDL-C decreased ANGPTL3-producing FHBL2 have been identified, 18% to 43%. No differences were reported in AEs with LDL-C concentrations as low as 35 mg/dL between treatment groups, and the drug was well reported.90 These findings suggest that inhibiting tolerated. ANGPTL3 may be an attractive target to treat The drug has been repositioned, and MBX-8025 has hyperlipidemia. received an orphan drug designation for HoFH whereby REGN1500 (Regeneron Pharmaceuticals, Tarry- clinical development is being undertaken. Part of the town, New York) is a fully humanized mAb with premise for efficacy in HoFH is that in Watanabe- high-binding affinity to ANGPTL3. In preclinical stud- heritable hyperlipidemic rabbits, with low (o5%) ies in dyslipidemic mice, administration of REGN1500 hepatic LDLR activity and markedly elevated LDL-C was associated with 2.5-fold increased concentrations concentrations (360–592 mg/dL) characteristic of HoFH, of post-heparin LPL activity, and statistically significant subcutaneous administration of MBX-8025 30 mg/kg reductions in TGs, total cholesterol, and LDL-C levels daily for 3 weeks resulted in mean LDL-C reduction up to 53%, 35%, and 45%, respectively, were ob- from baseline of 42%.87 A Phase II open-label, dose- served after 8 weeks of treatment with REGN1500 escalation, proof of concept trial in HoFH (clinicaltrials. compared to controls. Subsequent studies in dyslipi- gov identifier NCT02472535) has commenced, and, demic monkeys given either 3 or 10 mg/kg in a if successful, a larger phase 3 trial will follow. single dose again showed robust reductions in TG

2764 Volume 37 Number 12 T. Turner and E.A. Stein concentrations of 89% at days 1 and 2 with sustained has rapidly changed the climate within academia and reductions in TGs maintained for 33 days before industry so that LDL-C is once again a major focus. returning to baseline concentrations; LDL-C levels did The encouraging results with PCSK9 mAbs, including not change, possibly because of a low mean baseline the early but promising impact on CVD events, have level of 58 mg/dL.91 Currently, REGN1500 is in created an environment in the clinical and cardiovas- clinical development with 3 active trials, 2 Phase I cular community which is likely to surpass even the SAD and MAD studies, and a proof-of-concept trial statin era as the large-scale CVD outcome trials come to evaluate the safety and efficacy of both single to fruition in the next 2 years. and multiple doses of REGN1500 in patients with HoFH (clinicaltrials.gov identifiers NCT01749878, NCT02107872, and NCT02265952, respectively). ACKNOWLEDGMENTS Isis Pharmaceuticals (Carlsbad, Calif) and its sub- The authors were solely responsible for the writing sidiary, Akcea Therapeutics, are pursuing clinical and submission of the manuscript. development of an antisense oligonucleotide, ISIS- ANGPTL3Rx, and recently reported results from a CONFLICTS OF INTEREST Phase I SAD/MAD study in healthy volunteers. In this Dr Turner has no personal conflicts; her institution study, ISIS-ANGPTL3Rx was generally well tolerated has received funds related to clinical trials and central and demonstrated reductions of up to 93% in laboratory analysis from Amgen, Regeneron, Sanofi, o ANGPTL3 from baseline (P 0.001). In addition, Genentech, Roche, ISIS, Genzyme, Catabasis and fi statistically signi cant reductions from baseline in BMS. Dr Stein has received consulting fees from lipid markers were observed, with mean TG and Amgen, Regeneron, Sanofi, Genentech, Roche, ISIS, total cholesterol concentrations decreased by 49% Catabasis, AstraZeneca, CymaBay, and BMS. and 28%, respectively.92 ALN-ANG is a novel GalNAc-RNA interference conjugate in preclinical development by Alnylam Pharmaceuticals (Cam- REFERENCES bridge, Mass). In an ob/ob mouse model of hyper- 1. The Lipid Research Clinics Coronary Primary Prevention lipidemia, ALN-ANG 3 mg/kg given subcutaneously Trial results. I. Reduction in incidence of coronary heart daily for 5 weeks reduced ANGPTL3 protein concen- disease. JAMA. 1984;251:351–364. fi trations by 495%; TG, total cholesterol, and LDL-C 2. Baigent C, Keech A, Kearney PM, et al. Ef cacy and concentrations were decreased by 495%, 460%, safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in and 485%, respectively.93 14 randomised trials of statins. Lancet. 2005;366:1267– 1278. CONCLUSION 3. Randomised trial of cholesterol lowering in 4444 patients fi It has been 30 years since the rst statins entered with coronary heart disease: the Scandinavian Simvastatin general use, and, despite development of slightly Survival Study (4S). Lancet. 1994;344:1383–1389. more efficacious statins during this period, the only 4. Stroes ES, Thompson PD, Corsini A, et al. Statin- additional safe and well-tolerated LDL-C–reducing associated muscle symptoms: impact on statin therapy- drug has been ezetimibe which provided an addi- European Atherosclerosis Society Consensus Panel tional 18% decrease in LDL-C. In fact, interest in Statement on Assessment, Aetiology and Management. developing new LDL-C–lowering agents had waned Eur Heart J. 2015;36:1012–1022. within the pharmaceutical industry along with 5. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/ reduced research as focus moved to what was felt AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a to be more interesting and presumably more profitable report of the American College of Cardiology/American targets such as CETPis for HDL-C and ω3 fatty acids Heart Association Task Force on Practice Guidelines. for TGs. Circulation. 2014;129:S1–45. However, the development of apoB antisense and 6. Shrank WH, Barlow JF, Brennan TA. New therapies in the microsomal triglyceride transfer protein inhibitors, treatment of high cholesterol: an argument to return to both initially in development for general use, as goal-based lipid guidelines. JAMA. 2015. [Epub ahead of orphan drugs for HoFH and the discovery of PCSK9 print].

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7. Cannon CP, Blazing MA, Giugliano 17. Stein EA, Mellis S, Yancopoulos hypercholesterolemia: a random- RP, et al. Ezetimibe added to statin GD, et al. Effect of a monoclonal ized, placebo-controlled, dose- therapy after acute coronary syn- antibody to PCSK9 on LDL choles- ranging, phase 2 study. J Am Coll dromes. N Engl J Med. 2015;372: terol. N Engl J Med. 2012;366:1108– Cardiol. 2015;65:A1591. Abstract. 2387–2397. 1118. 24. Roth EM, McKenney JM, Hanotin 8. HPS2-THRIVE Colaborative Group, 18. Dias CS, Shaywitz AJ, Wasserman C, et al. Atorvastatin with or with- Landray MJ, Haynes R, et al. Effects SM, et al. Effects of AMG 145 on out an antibody to PCSK9 in pri- of extended-release niacin with laro- low-density lipoprotein cholesterol mary hypercholesterolemia. N Engl piprant in high-risk patients. NEngl levels: results from 2 randomized, J Med. 2012;367:1891–1900. JMed. 2014;371:203–212. double-blind, placebo-controlled, 25. Stein EA, Gipe D, Bergeron J, et al. 9. AIM-HIGH Investigators, Boden WE, ascending-dose phase 1 studies in Effect of a monoclonal antibody to Probstfield JL, et al. Niacin in pa- healthy volunteers and hypercho- PCSK9, REGN727/SAR236553, to tients with low HDL cholesterol levels lesterolemic subjects on statins. reduce low-density lipoprotein receiving intensive statin therapy. J Am Coll Cardiol. 2012;60:1888– cholesterol in patients with hetero- NEnglJMed. 2011;365:2255–2267. 1898. zygous familial hypercholesterolae- 10. ACCORD Study Group, Ginsberg 19. European Commission Approves mia on stable statin dose with or HN, Elam MB, et al. Effects of Amgenʼs New Cholesterol-Lowe- without ezetimibe therapy: a phase combination lipid therapy in type ring Medication Repatha™ (evolocu- 2 randomised controlled trial. Lancet. 2 diabetes mellitus. N Engl J Med. mab), the First PCSK9 Inhibitor To 2012;380:29–36. 2010;362:1563–1574. Be Approved in the World, for Treat- 26. McKenney JM, Koren MJ, Kereiakes 11. Rader DJ, Kastelein JJ. Lomitapide ment of High Cholesterol. http:// DJ, et al. Safety and efficacy of a and mipomersen: two first-in-class www.amgen.com/media/media_pr_ monoclonal antibody to propro- drugs for reducing low-density lip- detail.jsp?releaseID=2069405&.Ac- tein convertase subtilisin/kexin type oprotein cholesterol in patients cessed 2015. 9 serine protease, SAR236553/ with homozygous familial hyper- 20. FDA approves Praluent to treat REGN727, in patients with primary cholesterolemia. Circulation.2014; certain patients with high choles- hypercholesterolemia receiving on- 129:1022–1032. terol. http://www.fda.gov/newse going stable atorvastatin therapy. 12. Abifadel M, Varret M, Rabes J-P, vents/newsroom/pressannounce J Am Coll Cardiol. 2012;59:2344– et al. Mutations in PCSK9 cause ments/ucm455883.htm. Accessed 2353. autosomal dominant hypercholes- 2015. 27. Stein EA, Giugliano RP, Koren MJ, terolemia. Nat Genet. 2003;34:154– 21. Ballantyne CM, Neutel J, Cropp A, et al. Efficacy and safety of evolo- 156. et al. Results of bococizumab, a cumab (AMG 145), a fully human 13. Turner TA, Raal FJ, Stein EA. Evolv- monoclonal antibody against pro- monoclonal antibody to PCSK9, in ing targets of therapy: proprotein protein convertase subtilisin/kexin hyperlipidaemic patients on vari- convertase subtilisin/kexin 9 inhib- type 9, from a randomized, placebo- ous background lipid therapies: ition. In: Ballantyne C, ed. Clinical controlled, dose-ranging study in pooled analysis of 1359 patients Lipidology: A Companion to Braun- statin-treated subjects with hyper- in four phase 2 trials. Eur Heart J. wald’s Heart Disease. 2nd ed. New cholesterolemia. Am J Cardiol.2015; 2014;35:2249–2259. York: Elsevier; 2014:346–357. 115:1212–1221. 28. Raal F, Scott R, Somaratne R, et al. 14. Lambert G, Sjouke B, Choque B, 22. Budha NR, Leabman M, Jin JY, Low-density lipoprotein cholesterol- et al. The PCSK9 decade. J Lipid et al. Modeling and simulation to lowering effects of AMG 145, a Res. 2012;53:2515–2524. support phase 2 dose selection for monoclonal antibody to proprotein 15. Stein EA, Raal F. Reduction of low- RG7652, a fully human monoclo- convertase subtilisin/kexin type 9 density lipoprotein cholesterol by nal antibody against proprotein serine protease in patients with monoclonal antibody inhibition of convertase subtilisin/kexin type 9. heterozygous familial hypercholes- PCSK9. Annu Rev Med. 2014;65: Aaps J. 2015;17:881–890. terolemia: the Reduction of LDL-C 417–431. 23. Kastelein J, Nissen S, Rader D, with PCSK9 Inhibition in Heterozy- 16. Lagace TA, Curtis DE, Garuti R, et al. Safety and efficacy of gous Familial Hypercholesterolemia et al. Secreted PCSK9 decreases the Ly3015014, a new monoclonal Disorder (RUTHERFORD) random- number of LDL receptors in hepa- antibody to proprotein convertase ized trial. 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PCSK9 on low-density lipoprotein heterozygous familial hypercholes- (RUTHERFORD-2): a randomised, cholesterol levels in statin-intolerant terolaemia (heFH) not adequately double-blind, placebo-controlled patients: the GAUSS randomized controlled with current lipid- trial. Lancet. 2015;385:331–340. trial. JAMA. 2012;308:2497–2506. lowering therapy: Results of ODYS- 44. Stein EA, Honarpour N, Wasserman 30. Giugliano RP, Desai NR, Kohli P, SEY FH I and FH II studies. SM, et al. Effect of the proprotein et al. Efficacy, safety, and tolerabil- Presented at European Society of Car- convertase subtilisin/kexin 9 mono- ity of a monoclonal antibody to diology Congress. Spain: Barcelona; clonal antibody, AMG 145, in proprotein convertase subtilisin/ 2014. homozygous familial hypercholes- kexin type 9 in combination with 37. Kastelein JJ, Robinson JG, Farnier terolemia. Circulation. 2013;128: a statin in patients with hypercho- M, et al. Efficacy and safety of 2113–2120. lesterolaemia (LAPLACE-TIMI 57): alirocumab in patients with heter- 45. Raal FJ, Giugliano RP, Sabatine a randomised, placebo-controlled, ozygous familial hypercholesterole- MS, et al. Reduction in lipopro- dose-ranging, phase 2 study. Lancet. mia not adequately controlled with tein(a) with PCSK9 monoclonal 2012;380:2007–2017. current lipid-lowering therapy: de- antibody evolocumab (AMG 145): 31. Koren MJ, Scott R, Kim JB, et al. sign and rationale of the ODYSSEY a pooled analysis of more than Efficacy, safety, and tolerability of a FH studies. Cardiovasc Drugs Ther. 1,300 patients in 4 phase II trials. monoclonal antibody to propro- 2014;28:281–289. J Am Coll Cardiol. 2014;63:1278– tein convertase subtilisin/kexin type 38. Robinson JG, Farnier M, Krempf 1288. 9 as monotherapy in patients with M, et al. Efficacy and safety of 46. Gaudet D, Kereiakes DJ, McKenney hypercholesterolaemia (MENDEL): alirocumab in reducing lipids and JM, et al. 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The C679X trolled trial of evolocumab in hy- TIVE: efficacy and safety of the mutation in PCSK9 is present and perlipidemia. N Engl J Med.2014; proprotein convertase subtilisin/ lowers blood cholesterol in a 370:1809–1819. kexin type 9 monoclonal antibody, Southern African population. Athe- 35. Robinson JG, Nedergaard BS, alirocumab, versus ezetimibe, in rosclerosis. 2007;193:445–448. Rogers WJ, et al. Effect of evolocu- patients with statin intolerance as 50. Cariou B, Ouguerram K, Zair Y, maborezetimibeaddedtomoder- defined by a placebo run-in and et al. PCSK9 dominant negative ate- or high-intensity statin therapy statin rechallenge arm. Presented mutant results in increased LDL on ldl-c lowering in patients with at AHA Scientific Sessions; 2014; catabolic rate and familial hypo- hypercholesterolemia: the LAPLACE- Chicago, Ill. betalipoproteinemia. Arterioscler 2 randomized clinical trial. JAMA. 43. Raal FJ, Stein EA, Dufour R, et al. Thromb Vasc Biol. 2009;29:2191– 2014;311:1870–1883. PCSK9 inhibition with evolocu- 2197. 36. Kastelein JJ. Efficacy and safety mab (AMG 145) in heterozy- 51. Kastelein JJ, van Leuven SI, Burgess of alirocumab in patients with gous familial hypercholesterolaemia L, et al. Effect of torcetrapib on

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