PCSK9 inhibitors – past, present and future

Abstract

Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular disease (CVD) morbidity and mortality. Statins are the treatment of choice for lowering LDL-C but a considerable number of patients treated with statins are unable to achieve LDL-C target values and many are statin-intolerant. New LDL-C-lowering drugs – antibodies to PCSK9 (alirocumab, evolocumab and bococizumab) – have been developed and are being tested in large clinical trials. They further reduce LDL-C above maximally tolerated statin therapy by up to > 70%; they also reduce Lp(a), non-HDL-C, apolipoprotein-B, and modestly increase HDL-C. These drugs are well tolerated and even patients who achieved very low LDL-C ≤ 0.65 mmol/l (∼ 25 mg/dl) did not have any significant adverse effects. Treatment with PCSK9 inhibitors resulted in LDL-C target values in 70 – 90% of patients according to the guidelines. However, although PCSK9 inhibitors seem to be the most promising emerging therapeutic option for LDL-C lowering today, outcome data with endpoints on their effects are still lacking. Another important open question is their long-term safety. Their use in statin-intolerant patients also raises questions, as the criteria for statin-intolerance are neither clear nor generally accepted. The presumed high cost of PCSK9 inhibitors might be an obstacle for their broader use.

Keywords:

• alirocumab
• bococizumab
• cardiovascular disease prevention
• evolocumab
• low-density lipoprotein-cholesterol
• PCSK9 inhibitors
• statins

1. Introduction

Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular disease (CVD) morbidity and mortality, both in primary and in secondary prevention [1,2]. Although statins are the treatment of choice for lowering LDL-C, a considerable number of patients treated with statins is unable to achieve the LDL-C target values as recommended by the guidelines, no matter whether the US guidelines recommending LDL-C lowering ≥ 50% are followed or the European guidelines recommending LDL-C goals of LDL-C ≤ 2.6 and ≤ 1.8 mmol/l [3-6]. This happens most often in patients with familial hypercholesterolaemia (FH) and in statin-intolerant patients who are unable to tolerate statin therapy at all or to tolerate a full therapeutic statin dose because of adverse effects, mostly myopathy, their number reaching up to 10 – 20% [7,8]. However, it is very difficult to define what statin intolerance really is – although statin myopathy is most often accompanied with an increase of CK (> 10 times the upper limit of normal), individuals can have muscle pains as an adverse effect of statin treatment without it [9,10]. Many other subjects with high- and very-high CVD risk on statin therapy also do not reach the treatment goals [11]. Therefore, additional LDL-C lowering treatment is needed and PSCK9 inhibitors seem nowadays to be the most promising emerging treatment option.

2. Past

The story with PCSK9 inhibitors started in 2003 when two gain-of-function mutations in the gene encoding PCSK9 (a secretory protease that is the last member of the PCSK convertase family which is produced in the liver, secreted into the plasma, binds to the LDL-receptor and promotes their degradation) which regulates the surface expression of hepatic LDL-receptors were found to cause a form of FH [12]. The idea was further developed in 2006 when a young women of African descend was found to have (because of loss-of function mutations of PCSK9) very low LDL-C – 14 mg/dl, a level unheard-of in healthy adults [13]. The Atherosclerosis Risk in Communities study found over a 15-year follow-up period that 2.6% (n = 3363) of African Americans were heterozygous for the PCSK9^Y142X or PCSK9^C679X nonsense mutation, which was associated with a 28% reduction in plasma LDL-C and an 88% reduction in coronary heart disease (CHD) whereas 3.2% (n = 9524) of white subjects had the PCSK9^R46L sequence variant, which was associated with a 15% reduction in mean LDL-C and a 47% reduction in CHD [14]. These experiments of nature based on the genetic variants of PCSK9 have led to an improved understanding of the role of this substance in regulating LDL-C levels and realizing that PCSK9 mutations are associated with hypocholesterolemia and hypercholesterolemia through loss-of-function and gain-of-function mechanisms, respectively. They have also suggested that partial abrogation of PCSK9 function and interrupting the interaction between PCSK9 and LDL-receptor may lead to increased concentrations of LDL-receptors on the cell surface causing lowering of LDL-C levels accompanied by lower CVD risk, and that complete abrogation of PCSK9 function might result in very low LDL-C levels without any apparent adverse consequences. It has been also established that statins increase LDL-receptor expression and density on cell surface whereas PCSK9 levels increase as a feedback response to statin (and ezetimibe) treatment, rising by 10 – 50%. Therefore it has been proposed that upregulation of PCSK9 in response to statin therapy may attenuate the LDL-C reduction induced by statins whereas PCSK9 inhibition with an anti-PCSK9 monoclonal antibody could potentially modify this barrier which limits efficacy of statins and other LDL-C-lowering therapies. The view that the increase in PCSK9 with statins explains ‘the rule of 6’ has been challenged as it appears that the LDL-receptor can only be upregulated with statins by a certain amount [15]. Soon three antibodies to PCSK9 were developed and they are used in clinical trials – alirocumab or formally SAR236553/REGN727, evolocumab or formally AMG 145 and bococizumab or formally PF-04950615/RN316.

3. Present

Inhibiting PCSK9 binding to LDLR with monoclonal antibodies developed against PSCK9 has been shown to be effective in further reducing LDL-C by 40 – 72% in hypercholestrolaemic patients with LDL-C ≥ 100 mg/dl (∼ 2.6 mmol/l) on stable statin therapy in a dose- and dosing frequency-dependent manner [16]. An extensive clinical study with alirocumab called ODYSSEY is ongoing consisting of 14 global Phase III trials, including > 23,500 patients across > 2000 study centers. Some of these trials are performed in heterozygous FH patients, some in patients with high- and very-high CVD risk and some in statin-intolerant patients. This drug is well tolerated and no significant increases were reported for hepatic transaminases or CK. The most common adverse event of alirocumab is a mild transient injection-site reaction [17]. Not even patients who achieved very low LDL-C ≤ 0.65 mmol/l (∼ 25 mg/dl) did have any significant adverse effects. A significant reduction in Lp(a) is an additional beneficial effect of alirocumab that contrasts with other lipid-lowering drugs, especially statins. Alirocumab decreases non-high-density lipoprotein-cholesterol (non-HDL-C), apolipoprotein B, and modestly increases HDL-C as well. It is important to stress that treatment with alirocumab injected subcutaneously 150 mg every 2 weeks, which is an usual dosage regimen (although there is a choice between two dosage regimes – 75 and 150 mg), in > 90% of patients achieved an LDL-C target of < 70 mg/dl (1.8 mmol/l) [18]. In a post hoc analysis of a 78-week randomized trial with alirocumab involving 2341 patients at high risk for cardiovascular events who had LDL-C of 70 mg/dl (∼ 1.8 mmol/l) or more and were receiving statins at the maximum tolerated dose, there was an indication of a reduction in the rate of cardiovascular events [19].

An extensive clinical study with evolocumab named OSLER including 4465 patients is also ongoing consisting of 12 Phase II and III trials, comparing patients treated with evolocumab plus standard LDL-C-lowering treatment with those on standard LDL-C-lowering treatment alone. PROFICIO is a large clinical trial program with evolocumab consisting of 22 clinical trials, with a combined planned enrollment of ∼ 35,000 patients. Evolocumab significantly reduces serum LDL-C (> 50%) in hypercholesterolaemic subjects, including those with heterozygous FH taking the highest doses of atorvastatin or rosuvastatin, with an overall adverse effect profile similar to placebo. Like alirocumab, evolocumab is also quite a safe drug and not even patients who achieved very low LDL-C of ≤ 0.65 mmol/l (∼ 25 mg/dl) did have significant adverse effects. However, in OSLER (as in ODYSSEY) more patients on the PCSK9 inhibitor reported some neurocognitive effects [19,20]. Evolocumab, similarly to alirocumab, also reduces Lp(a) up to 30%, it decreases non-HDL-C, apolipoprotein B, triglycerides and modestly increases HDL-C. Treatment with evolocumab in > 90% of patients achieved LDL-C target of < 100 mg/dl (∼ 2.5 mmol/l), and in > 70% of patients a target of < 70 mg/dl (∼ 1.8 mmol/l). A lack of efficacy in homozygous null LDL-receptor mutations was noted [21]. There are some indications that evolocumab can also reduce the incidence of cardiovascular events based upon a prespecified but exploratory analysis [20]. The dosage of this drug is 140 mg injected subcutaneously every 2 weeks or 420 mg every 4 weeks.

The first Phase III studies with bococizumab, which is a humanized antibody, were initiated in October 2013 – much later than those with alirocumab and evolocumab, which are fully human antibodies. In the first publication of bococizumab, a 24-week, multicentre, double-blind, placebo-controlled, dose-ranging study of 351 patients with LDL-C levels ≥ 2.0 mmol/l (∼ 80 mg/dl) who were on stable statin therapy, the doses of the drug were lowered if LDL-C levels were persistently decreased ≤ 0.65 mmol/l (∼ 25 mg/dl). The results showed that bococizumab like other PCSK9 inhibitors reduced LDL-C levels significantly across all doses despite dose lowering in several patients, and the treatment was generally well tolerated [22].

At the moment the position of PCSK9 inhibitors resembles very much the one of statins at the end of 1980s and the beginning of the 1990s, that is, before the 4S trial. Namely, it has been proven that they significantly decrease LDL-C and that there is potentially a large number of patients to whom they might be beneficial but there is still no hard evidence that they can really prevent cardiovascular events and mortality and it is evident that they will be very expensive.

4. Future

The European Medicines Agency (EMA) has very recently (in July 2015) approved evolocumab as the first PCSK9 inhibitor in Europe for the treatment of adults and adolescents (> 12 years old) with homozygous FH, as well as adult patients with heterozygous FH and mixed dyslipidemia. The drug is approved for patients currently taking a maximally tolerated statin dose or other lipid-lowering therapies but unable to achieve LDL-C target values. It also received an indication for use in statin-intolerant patients or in whom a statin is contraindicated. The FDA approved most recently (also in July 2015) alirocumab for heterozygous FH and for patients with clinical atherosclerotic of CVD, such as a prior myocardial infarction or stroke, as the first PCSK9 inhibitor in the US. The drug is recommended in addition to diet and maximally-tolerated statin treatment in adults who require additional lowering of LDL-C. However, patients who are statin-intolerant without established clinical atherosclerotic CVD are at the moment left out of the indications. FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended also to FDA approval of evolocumab.

Nevertheless, it has to be pointed out that despite very promising LDL-C-lowering results of the trials with PCSK9 inhibitors and enormous enthusiasm concerning these drugs, data with hard endpoints on their effects are still lacking. Namely, neither OSLER/PROFICIO nor ODYSSEY trials published until now were powered to look at outcomes. It is, however, expected that as a 22% reduction in major cardiovascular events for each 1 mmol/l (37.8 mg/dl) reduction of LDL-C in statin trials that was constant across a broad range of LDL-C values, the LDL-C reduction from PCSK9 inhibitors might result in about a 40% reduction in major cardiovascular events. Exactly therefore, the results of a large trial named ODYSSEY OUTCOMES which has just completed enrolment of ∼ 18,000 subjects looking into the effects of alirocumab on the occurrence of cardiovascular events (composite endpoint of CHD death, non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization) are eagerly awaited. Similarly, the results of a trial with evolocumab – further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) – which has completed enrolment of ∼ 27,000 subjects (the results are expected in 2017) testing this drug versus statin therapy for the reduction of the primary composite end point of CVD death, MI, hospitalization for unstable angina, stroke, or coronary revascularization, will also be very important. SPIRE-1 and 2 are two other ongoing outcome trials to test bococizumab versus placebo for the reduction of major cardiovascular events (death due to CVD, MI, stroke, and unstable angina requiring urgent revascularization) in high-risk patients who are receiving background lipid-lowering therapy. Therefore, until completion of these trials the question concerning PCSK9 inhibitors capability of reducing CVD morbidity and mortality will still remain open. Particularly interesting would be to see the long-term results of treatment with PCSK9 inhibitors of children with FH.

Another important open question is long-term safety. Follow-up in OSLER was only 11 months and in ODYSSEY it was 78 weeks which is too short for medications supposed to be used as a life-long treatment. It must not be forgotten that with statins it took 16 years and millions of treated patients before it was established that they are, besides causing other adverse effects, associated with a significant increase in the incidence of incident type 2 diabetes. Potential broader use of PCSK9 inhibitors, such as in statin-intolerant patients, also raises questions as the criteria for statin-intolerance are not clear and there is no generally accepted definition of this condition.

Although parenteral application was at the beginning considered as a potential obstacle, this has not been confirmed so far in clinical trials. However, the presumed high cost of PCSK9 inhibitors might have an impact on their use. Nevertheless, similarly to what happened with statins some 10 years ago, it can be expected that the cost of treatment with PCSK9 inhibitors will go down as the time passes by and with their more extensive use.

It has to be mentioned that, apart from alirocumab, evolocumab and bococizumab, two other injectable monoclonal antibodies are in Phase II testing and some pharmaceutical companies are working on an anti-PCSK9 vaccine that might be given annually as they have shown on animal models a LCL-C-lowering effect lasting up to 10 months. Two companies have small molecule PCSK9 inhibitors administered orally which have entered Phase I human trials in 2015.

Declaration of interest

Ž Reiner has received honoraria for lectures and advisory boards from Sanofi. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.