PCSK9 Inhibitors for Lowering Cholesterol: Ready for Prime Time?

Article Citation:

Thomas Knickelbine (2017) PCSK9 Inhibitors for Lowering Cholesterol: Ready for Prime Time?. Journal of the Minneapolis Heart Institute Foundation: January 2017, Vol. 1, No. 1, pp. 30-37.

Original Article

Thomas Knickelbine, MD, FACC, FSCCT, FSCAI

Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, MN

Address for correspondence:
Thomas Knickelbine, MD, FACC, FSCCT, FSCAI
Minneapolis Heart Institute
920 E 28th Street #300
Minneapolis, Minnesota 55407
Tel: 612-863-3900

E-mail: thomas.knickelbine@allina.com

ABSTRACT

Proprotein convertase subtilisin/kexin type 9 inhibitors are newly introduced medications in the treatment of hypercholesterolemia. These medications, in addition to other existing treatments, offer the clinician the opportunity to address patients who do not achieve adequate low-density lipoprotein reduction or have developed intolerance to statin therapy. While statin therapy remains the mainstay for treating hyperlipidemia, these new agents show early indications of not only reducing low-density lipoprotein cholesterol, but potentially reducing cardiovascular events in the long term. This article reviews the current state of non-statin therapy including Niacin, Ezetimibe, fibrates, bile acid sequestrants and the new PCSK9 inhibitors and offers insight into how these medications may be applied in clinical practice.

Keywords: PCSK9 inhibitor, hyperlipidemia, treatment guidelines

INTRODUCTION

Statin therapy remains the mainstay in the treatment of hyperlipidemia in clinical practice. Non-statin therapy has been studied extensively as a means to address the residual risk identified in patients treated with statin therapy. Efforts around high-density lipoprotein (HDL)-raising or triglyceride-lowering (cholesterylester transfer protein [CTEP] inhibitors, niacin, fibrates) and low-density lipoprotein (LDL)-lowering (ezetimibe, bile acid sequestrants) have demonstrated limited or no incremental benefit beyond maximal tolerated statin therapy. Inhibitors of PCSK9 are newly introduced medications in the treatment of hypercholesterolemia. These new agents show early indications of not only markedly reducing LDL cholesterol, but also potentially reducing cardiovascular (CV) events in the long term.

This article reviews the current state of non-statin therapy including the new PCSK9 inhibitors and offers insight into how these medications may be applied in clinical practice.

TREATMENT OF HYPERLIPIDEMIA WITH STATIN THERAPY

The initial clinical approach to the treatment of hyperlipidemia should involve consideration of the patients overall risk status. In 2013, the American College of Cardiology (ACC) and American Heart Association (AHA) updated the guidelines provided to practitioners to serve as a template of discussion regarding the benefits of statin therapy.1 After thorough review of lifestyle factors including dietary measures, exercise, weight management and smoking cessation, the document provides guidance for the consideration of statin therapy. These guidelines recognized a predominately “dose intensity” approach as most existing studies had not titrated statins to a target LDL but were dose leveraged. In addition, these guidelines de-emphasized the use of non-statin add-on therapy in recognition of the limited information regarding any clinical benefit of these medications.

The physicians of the Minneapolis Heart Institute have reviewed the guidelines and provided primary care physicians with a 1-page review for more rapid decision making (Figure 1). This document broadly separates patients into 3 categories: (1) secondary prevention (known coronary artery disease [CAD]); (2) primary prevention (with or without diabetes), and (3) LDL >190 mg/dL. It is notable that the LDL level of >190 mg/dL leads to the recommendation of high-intensity statin therapy regardless of risk. This represents an effort to identify and treat patients with familial hypercholesterolemia (FH) or type IIa hyperlipidemia in recognition of the very high-risk status of this group.

FIGURE 1
Selection of patients for statin therapy based on risk.

The benefits of statin therapy are widely published: The Cholesterol Treatment Trialist data in over 60,000 patients have shown statin therapy yields an average 27% reduction in combined fatal/nonfatal CV events.2 This effect was equivalent in high- and low-risk individuals with absolute event reduction highest in high-risk individuals, but only a small overall reduction in mortality. Many patients, however, are unable to take statin therapy at high doses or at all. Intolerance to statin therapy has been recognized clinically in up to 20% of patients taking statins and clinicians often look for alternative therapy to provide these patients.

NON-STATIN THERAPY

Prior to 2015, efforts to address residual risk in patients treated with maximal tolerated statin therapy have shown minimal benefit.

Inhibitors of CTEP markedly raise HDL cholesterol and were thoroughly studied in the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE, torcetrapib) and dal-OUTCOMES (dalcetrapib) trials. When added to maximally tolerated statin therapy, these agents dramatically increased HDL cholesterol but had no or even a negative impact on CV outcome.

Niacin, which raises HDL, lowers triglyceride and LDL cholesterol, showed early promise when used as monotherapy in the Coronary Drug Project reducing coronary heart disease (CHD) events by 19%. When combined with statin therapy, however, no benefit was demonstrated in the atherothrombosis intervention in metabolic syndrome with low HDL/high triglycerides: impact on global health outcomes (AIM HIGH) trial and higher adverse events (more myalgias, bleeding, gastrointestinal symptoms, rashes with 1.8% excess new diabetes) in the larger heart protection study 2-treatment of HDL to reduce the incidence of vascular events (HPS2-THRIVE) study. Similarly, the action to control cardiovascular risk in diabetes (ACCORD) study demonstrated no net benefit when fenofibrate was added to simvastatin therapy. The use of niacin, therefore, is now limited to certain clinical scenarios of either markedly elevated triglycerides (fibrates) or possibly in patients with markedly elevated lipoprotein (a).

Ezetimibe inhibits Niemann-Pick like 1 protein and reduces LDL modestly (15%–17% range) when added to statin therapy. In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), CAD patients on statin therapy achieved an LDL of 69 mg/dL in the simvastatin alone group versus 53 mg/dL in simvastatin plus ezetimibe group. An absolute 2% risk reduction and 6% relative risk reduction in composite endpoint of CV death, myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), or stroke was noted at 7 years. Therefore, the additional costs of ezetimibe need to be weighed against this relatively small benefit when considering additional therapy in CAD patients. This trial, however, demonstrated that achieving LDL levels to new lower thresholds may produce significant reductions in CV events and has promoted the interest in further LDL lowering by newer agents including PCSK9 inhibitors.

PCSK9 INHIBITORS

In 2002, French researchers identified gain of function (GOF) mutations in FH families of a protein to become known as PCSK9. This protein was noted to play a critical role in the regulation of LDL liver receptor density. Similar GOF mutations were identified in Portugal, Norway, and New Zealand populations. These mutations of GOF were associated with low LDL receptor density and very high LDL and total cholesterol levels. In contradistinction, genetic analysis of the atherosclerosis risk in communities (ARIC) database showed that mutations in PCSK9 lead to reduced LDL cholesterol and importantly, a markedly lower prevalence of CHD. It was these initial discoveries that prompted contemporary drug manufactures to examine ways to inhibit PCSK9 in an attempt to lower LDL cholesterol and possibly reduce CV events.

In less than a decade since the discovery of PCSK9 GOF mutations, clinical trials have led to the FDA approval of two current PCSK9 Inhibitor drugs. The refinements of the antibody to PCSK9, with human monoclonal components yield a low immunogenicity and make these agents suitable for human injection. By inhibiting the bioavailability of PCSK9, these agents dramatically increase LDL receptor density and reduce LDL cholesterol (Figure 2). The two currently FDA-approved agents are alirocumab from Sanofi/Regeneron and evolocumab from Amgen. Since these agents are not metabolized by the liver or renal systems, the FDA requires or requires no ongoing laboratory surveillance of liver function or other tests while being treated with PCSK9 inhibitors.

FIGURE 2
Monoclonal antibodies to PCSK9 decrease the lysosomal degradation of LDL receptors resulting in higher LDL receptor density and lower LDL levels due to enhanced removal by the liver. Reproduced and modified with permission from: Lambert G, Sjouke B, Choque B, Kastelein JJP, Hovingh GK. The PCSK9 decade: thematic review series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases. J Lipid Res. 2012;53:2515–2524.

Clinical trials of alirocumab and evolocumab have been directed at examining the degree of LDL lowering versus ezetimibe, overall safety and optimal dosing in various populations. Patient with FH, as add-on therapy to maximally tolerated statins and statin-intolerant patients have all been included in these trials. Most importantly, large outcome data trials with these agents will soon be available.PCSK9 Inhibitors: LDL Lowering

Alirocumab has been studied in multiple clinical settings in the outcomes: Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome during Treatment with Alirocumab (ODYSSEY) trials. This program includes over 14 clinical trials in over 23,000 patients in greater than 4,000 centers. In trials ODYSSEY FH 1 and 2, LDL was reduced 49% compared with placebo over maximally tolerated statin. This effect was maintained over 78 weeks with >70% patients achieving goal LDL in the alirocumab group versus <11% in the placebo arm. In trials ODYSSEY OPTIONS 1 and 2, patients with atherosclerotic cardiovascular disease (ASCVD) or high risk for CVD not at goal on statin showed a 44% to 54% reduction in LDL-C compared with placebo. When compared with ezetimibe in the ODYSSEY COMBO 1 and 2 trials in those with high risk on maximum tolerated statin, LDL was reduced 46% versus 21% for ezetimibe and 77% achieved goal LDL cholesterol versus 45% for ezetimibe. Similarly, statin-intolerant patients in the study of alirocumab (REGN727/SAR236553) in patients with primary hypercholesterolemia and moderate, high, or very high cardiovascular (CV) risk, who are intolerant to statins (ODYSSEY ALTERNATIVE) trial demonstrated an LDL reduction of 45% versus 15% for ezetimibe the long-term safety and tolerability of alirocumab in high cardiovascular risk patients with hypercholesterolemia not adequately controlled with their lipid modifying therapy (ODYSSEY LONG TERM) study looked at patients on maximum tolerated statin, FH or high CV risk including diabetics. LDL was reduced 48% and the effect was similar for those with and without diabetes. Importantly, this study showed LDL reductions occur quickly with LDL reduction of 61% by week 4 and was maintained over 78 weeks.

Evolocumab has been studied similarly in the program to reduce LDL-C and CV outcome following inhibition of PCSK9 in different populations (PROFICIO) trials. This series includes over 20 trials, 30,000 patients of various levels of risk. Goal achievement after utilizing an anti-PCSK9 antibody in statin intolerant subjects (GAUSS-2) examined statin-intolerant patients showing an LDL reduction of 56% with a dose of 140 mg every 2 weeks and LDL reduction of 53% with the 420 mg monthly dose. Monoclonal antibody against PCSK9 to reduce elevated LDL-C in subjects currently not receiving drug therapy for easing lipid levels-2 (MENDEL 2) studied evolocumab monotherapy versus ezetimibe in hyperlipidemia patients showing LDL reductions of 57% with the 150 mg dose versus 39% compared with ezetimibe. Durable effect of PCSK9 antibody compared with placebo study (DESCARTES) examined evolocumab versus diet or atorvastatin at varied doses from 10 to 80 mg versus 80 mg atorvastatin plus ezetimibe. Overall, there was a 57% reduction in LDL with the highest effect noted in patients treated with atorvastatin plus evolocumab of 61% reduction. In reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder study-2 (RUTHERFORD-2), heterozygous FH patients (HeFH) on maximal statin showed an LDL reduction of 57% at the 150 mg dose and 61% with monthly dosing. Only one study has examined homozygous FH patients (HoFH): the continuous transcutaneous electrical stimulation in sleep apnoea (TESLA) trial. Patients were on maximally tolerated statin and ezetimibe. Patients on 420 mg evolocumab monthly showed an LDL reduction of 31%. Therefore, HoFH patients that are LDL receptor negative may have a decreased ability to upregulate LDL receptors and lower LDL with PCSK9 inhibitors.

Collectively, these trials have shown PCSK9 inhibitors afford an average additional LDL reduction of 50% beyond maximally tolerated statin, regardless of population type treated. This reduction appears sustained with minimal loss of effect over a year of follow up.Effects of PCSK9 Inhibitors on Other Lipid Parameters

Inhibitors of PCSK9 affect serum lipoproteins other than LDL cholesterol alone. In trials ODYSSEY FH 1 and 2, titrated alirocumab 75 to 150 mg reduced lipoprotein (a) 20%, triglycerides down 16%, and increased HDL by 8%. In the trial GAUSS-2, 150 mg evolocumab subcutaneously every 2 weeks reduced lipoprotein (a) by 25%, apolipoprotein B by 33%, and raised HDL 6%. Similarly, DESCARTES yielded a 28% reduction in lipoprotein (a), 9% triglycerides, and increased HDL by 6% compared with placebo. Similar consistent findings have been reported with multiple other trials showing reductions in lipoprotein (a), triglycerides, apolipoprotein B, very (V)-low lipoprotein (VLDL) while modestly increasing HDL cholesterol.PCSK9 Inhibitors: Adverse Effects

Adverse effects to PCSK9 inhibitors have been reported with variable frequency in the above clinical trials. In the trial ODYSSEY FH, there were 2 to 3 times more injection site reactions with alirocumab. Nasopharyngitis was more common in the PCSK9 group in 2 trials (11.5% versus 3.9% in the efficacy and safety of alirocumab [SAR236553/REGN727] versus ezetimibe in patients with hypercholesterolemia [ODYSSEY MONO] trial). In the trial DESCARTES, there was a slight increase in nasopharyngitis, influenza, and back pain and in TESLA there was more nasopharyngitis, influenza, and gastroenteritis in evolocumab group.

Since PCSK9 is found in brain tissue, neurocognitive events have been a concern with these agents. Neurocognitive issues were more common in two ODYSSEY trials: ODYSSEY ALTERNATIVE (2.4% versus 1.6%) and ODYSSEY LONG TERM (1.2% versus 0.5%). These events include self-reported delirium, cognition and attention disorders, dementia, disturbed thinking and perceptive disorders, and memory impairment. Similarly, in the open label study of long term evaluation against LDL-C trial (OSLER 1 and 2), neurocognitive effects were reported in 0.9% evolocumab group versus 0.3% standard care arm. The self-reported nature of these events makes it difficult to further characterize as some of these trials were open label and the treatment arm received more frequent follow up. Importantly, an ongoing trial is evaluating this issue: evaluating PCSK9 binding antibody influence on cognitive health in high cardiovascular risk subjects (EBBINGHAUS). Participants without dementia or mild cognitive impairment at baseline will be randomized in a double blind, placebo-controlled, multicenter study to evaluate evolocumab + background statin therapy versus statin therapy alone. The primary outcome will be the spatial working memory test, an assessment of executive function. Results are expected in September 2017 with an enrollment of 4,000 subjects.

Three meta-analyses have examined potential side effects across the entire existing PCSK9 trials.3–5 One of these noted increased injection site reactions; another increased neurocognitive events but similar overall rates of abnormal liver tests, myalgia, and serious adverse events. Taken collectively, meta-analysis of both the ODYSSEY and PROFICO trials have shown the overall treatment emergent adverse effect rates to be similar in treatment versus placebo groups of these trials. The larger outcome trials with high enrollment numbers will add to the knowledge of potential side effects of these agents.PCSK9 Inhibitors: Outcome

While not designed specifically as outcome studies, several LDL-lowering trials have evaluated cardiovascular outcome in a post-HOC or continuation type study. In 2015, the ODYSSEY LONG TERM study enrolled 2,341 patients at high risk for CV events to 150 mg alirocumab every 2 weeks for 78 weeks.6 Low density lipoprotein was reduced 62% compared with placebo and after 84 weeks, there were 1.7% events in the PCSK9 arm versus 3.3% events in the placebo group (P = 0.02, hazard ratio 0.52).

Similarly, evolocumab was evaluated for CV outcome as a combined long-term follow-up of 4,465 patients who had completed 1 of 12 phase 2 or 3 studies (“parent trials”) of evolocumab: the OSLER trials 1 and 2.7 Eligible patients were randomly assigned in a 2:1 ratio to receive evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Baseline LDL was reduced from 120 mg/dL to a median of 48 mg/dL (61% reduction). The majority (74%) of patients achieved an LDL <70 mg/dL. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio 0.47; 95% confidence interval, 0.28–0.78; P = 0.003).

Three meta-analyses have examined the clinical outcome collectively of the entire existing PCSK9 trials and reported in the literature.3–5 A consistent reduction in total mortality has been reported (odds ratio 0.43–0.45, P = 05) and reduced CV mortality and CV events. These meta-analyses, however, were driven largely by the ODYSSEY LONG TERM and OSLER studies.

Currently, there are 2 ongoing large-scale outcome studies evaluating multiple population types: the evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab (ODYSSEY OUTCOMES, 600 patients) and further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER; Table 1). A third set of trials, the Pfizer-sponsored the evaluation of bococizumab (PF-04950615;RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE 1 and 2) trials were halted in November 2016. These trials studied high-risk or CVD patients with bococizumab. The manufacturer stated the drug was “not likely to provide value to patients, physicians, or shareholders.” In remains unclear whether these trials were discontinued for lack of efficacy or based on business concerns. Data from the SPIRE trials are expected in 2017. Combined, these trials will address whether the LDL lowering translates into improved long-term cardiovascular outcome.

TABLE 1
Outcome trials of PCSK9.

Safety: LDL too Low?

Prior to the PCSK9 data, there was limited information to identify the value and risks of VLDL. In trials OSLER 1 and 2, the rates of overall adverse events, serious adverse events, and elevations in aminotransferase or creatinine kinase levels were similar among patients in the evolocumab group who had LDL cholesterol levels of <40 mg/dL or <25 mg/dL. In the trial ODYSSEY LONG TERM, there were no difference in adverse events in 575 points achieving LDL <25 mg/dL on 2 occasions. Similarly, compound heterozygotes for PCSK9 mutations, including a 21-year-old female with LDL of 15 mg/dL, have been noted to have normal cognition and development. The ongoing outcome studies will evaluate this concept further as they have enrolled a significant number of patients with LDL <50 mg/dL.ACC 2016 Update

In 2016, the ACC released an update for clinicians regarding non-statin therapy to help incorporate the new agents and existing data into treatment guidelines.8 Emphasis was placed on shared decision-making given the complexities of these agents and high costs. This guideline does reintroduce the concept of LDL goals targets largely abandoned in the 2013 AHA/ACC document.

Their suggested approach is shown in Figure 3. In summary, these agents are FDA approved and should be considered in patients with known ASCVD with LDL >70 mg/dL (if comorbidities present) or LDL >100 mg (if no comorbidities) on maximally tolerated statin and ezetimibe or a bile acid sequestrant (BAS) has been utilized first (Figure 3a). Inhibitors of PCSK9 are also approved for use in FH patients. In patients with FH without ASCVD, a PCSK9 inhibitor can be considered when LDL reductions are <50% from baseline or >100 mg/dL on maximal statin and BAS or if LDL >70 mg/dL with ASCVD present (Figure 3b,c). Importantly, these agents are not recommended for patients with a baseline LDL <190 mg/dL without ASCVD (Figure 3b).

FIGURE 3
a. Non-statin therapy in secondary prevention. *Diabetes mellitus, myocardial infarction while on statin, chronic kidney disease, elevated lipoprotein (a). Adapted from: Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL cholesterol lowering. J Am Coll Cardiol. 2016;68:92–125. b. Primary prevention: non-statin therapy. Adapted from: Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL cholesterol lowering. J Am Coll Cardiol. 2016;68:92–125. c. Atherosclerotic cardiovascular disease and baseline LDL >190 mg/dL (FH patients) on statin therapy. Adapted from: Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL cholesterol lowering. J Am Coll Cardiol. 2016;68:92–125.

PCSK9 Costs

The costs of additional therapy are a strong consideration in treatment approach. A 2016 study examined the incremental cost effectiveness ratio of both PCSK9 inhibitors and ezetimibe in all potentially eligible US patients.9 Using a wholesale costs of approximately 14,000 USD annually, the effectives was evaluated in the FH and ASCVD populations: In familial hypercholesterolemia, ezetimibe led to 214,000 fewer events at $152,000 per quality adjusted life year saved (QUALY) and PCSK9 inhibitors 316,000 fewer CV events at a cost of $503,000 per QUALY. In patients with ASCVD, ezetimibe would result in 2.7 million fewer CV events at $154,000 per QUALY and PCSK9 showed 4.3 million fewer events at $414,000 per QUALY. As a reference, a cost of $100,000 per QUALY is considered the accepted threshold of cost effectiveness.

Full implementation of PCSK9 inhibitors in the United States was therefore estimated to result in $120 billion in net costs. An annual PCSK9 cost of $4,536 was estimated to results in a cost of 100,000 per QUALY. Therefore, this study argues PCSK9 inhibitors need to be reduced in cost substantially before large-scale implementation would be cost effective and underscores the importance of careful patient selection.

MINNEAPOLIS HEART INSTITUTE AND NON-STATIN THERAPY

The Minneapolis Heart Institute is actively treating appropriate patients with PCSK9 inhibitors and in certain cases, other non-statin therapy. Approval of the FDA currently supports use in HeFH, HoFH, and for existing CAD patients “not achieving adequate LDL reductions” including those with statin intolerance. Our practice follows the 2016 ACC treatment guidelines regarding non-statin treatment.

The Minneapolis Heart Institute also offers cholesterol apheresis to FH patients. Our experience has been reported with this therapy with excellent results.10 However, this therapy is costly and inconvenient with bimonthly trips to our infusion center. The trial ODYSSEY ESCAPE showed that the institution of PCSK9 inhibitors allowed 63% of patients undergoing apheresis to discontinue therapy.11 We have begun to implement this strategy in our apheresis population successfully changing to PCSK9 therapy. In addition, we have reported our experience with the use the electronic medical record in finding potential FH patients who may benefit from additional therapies.12 The institution of two new diagnosis codes in the 2016 International Classification of Diseases, Tenth Revision will also help in the screening and identification for this condition within the electronic health record.

We are further identifying potential FH patients and enrolling them in the CASCADE FH registry, a national registry for FH patients. This registry aims to collect comprehensive data on individuals with confirmed or suspected FH on a longitudinal basis. The registry, CASCADE FH, will serve as a key instrument to support health service planning; increase knowledge on the disorder; and pool data for epidemiologic, clinical, and outcomes research, as well as for surveillance of therapy effectiveness.

Given the costs and complexities of administration, the prior authorization procedure for PCSK9 prescription is difficult. Approval is only initiated in the indicated populations: FH and ASCVD with persistent LDL elevation. Rigorous documentation regarding the FH diagnosis (using Simone Broome or Dutch Lipid criteria) leading to a “definite HeFH” diagnosis is required for FH approval. Statin intolerance should be documented with at least two prior statin therapies in differing lipophilicity, metabolic pathway classes with reproducible symptoms. We employ a team of practitioners in our clinic including a physician, physician assistant, dedicated nursing support, a dietician, and our research nurse team in order to ensure the patient is afforded all opportunities in their treatment.

SUMMARY

The inhibitors PCSK9, as additional therapy to maximally tolerated statin treatment, are showing early promise as a powerful tool to lower cholesterol in patients unable to achieve adequate LDL lowering with statin therapy. While very costly, early data are encouraging showing reduced cardiovascular events and overall mortality. We eagerly await the long-term event trials currently underway.

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