Looking back at 2015: what made the news
21 December 2015
2015 has been an eventful year for atherosclerosis activities. Here, we discuss some of the highlights.
Familial hypercholesterolaemia (FH)
FH has gained much needed focus with a raft of new initiatives. Building on the momentum generated by the European Atherosclerosis Society (EAS) Consensus Panel statements on FH,1-3 the EAS launched the FH Studies Collaboration (FHSC) at EAS Congress in Glasgow, involving over 50 countries world-wide, with the mission to improve FH care. As a benchmark, there is a need for robust data on how FH is currently managed, and therefore one of the initial priorities of the FHSC is to establish a consortium of major FH registries across Europe, Asia-Pacific, Africa and South America. Such information will be critical for leveraging public policy to improve FH care. As a follow-up, over 40 experts signed up to a global call to action statement on FH, published in September this year.4
Opportunities for change in FH care were highlighted in recent studies. A report from EUROASPIRE IV,5 a survey of secondary prevention care across Europe, showed that one in five patients with a coronary event before age 50 years may have FH. However, it is not just increased coronary risk that is specific to FH. Recent data from the University of São Paulo also show that one in six FH patients have evidence of peripheral arterial disease, suggesting that clinicians should also consider screening for peripheral vascular disease even in asymptomatic patients.6 By far the most important action is to identify children with FH, so as to initiate lifestyle intervention and treatment early and therefore avoid the consequences of an elevated burden of low-density lipoprotein cholesterol (LDL-C) from birth. As summed up so succinctly by Wiegman and colleagues3: the aim is to gain decades of healthy life in children and adolescents.
Much of this much-needed emphasis on FH care has been driven the advent of novel therapies – PCSK9 monoclonal antibody therapy - that now allow clinicians to attain LDL-C goal in the majority of patients with heterozygous FH. In the most recent report, long-term follow-up data from ODYSSEY FH I and FH II, showed sustained LDL-C lowering with alirocumab, on top of statins ± other lipid-lowering therapy, over 78 weeks (>50% reduction), with the majority of patients (63%) attaining an LDL-C goal of <1.8 mmol/L.7 These data are consistent with findings with evolocumab, reported previously in RUTHERFORD-2.8 With both alirocumab and evolocumab now licensed in Europe and the USA, clinicians now have an effective tool for managing these difficult-to-treat patients. The key determinant of access will undoubtedly be cost, as indicated by a recent preliminary decision from the UK National Institute for Health and Care Excellence (NICE) on the use of PCSK9 monoclonal antibody therapy in the National Health Service.9 Patient advocacy will undoubtedly play an important part in arguing the case for access in this important patient group.
New treatments: good news...
Lipoprotein(a) [Lp(a)] has also been a key focus in 2015. Since the EAS Consensus Panel identified Lp(a) as a cardiovascular risk factor,10 there has been accumulating data from observational, mechanistic and genetic studies reaffirming that Lp(a) is causal for cardiovascular disease, calcific aortic valve stenosis and most recently, heart failure.11,12 The underlying mechanism(s) have been debated, but current evidence implicates Lp(a) both in promotion of atherosclerosis as well as promotion of thrombosis/inhibition of fibrinolysis.13 Emerging data also indicate that oxidised phospholipids that are associated with Lp(a) may mediate progression of, calcific aortic valve stenosis, as well as stimulate proinflammatory intracellular signalling pathways.14
Given that elevated Lp(a) (>50 mg/dl) is not uncommon, affecting about one in 5 of the general population, and that there is a causal association with cardiovascular disease, treatment targeting this lipoprotein abnormality is clearly warranted. The lack of a specific treatment targeting Lp(a) has been a key stumbling block. However, this may be about to change with encouraging results from a phase I trial for a second generation antisense oligonucleotide that inhibits hepatic apolipoprotein (apo)(a) mRNA translation (ISIS-APO(a)Rx). Following multiple doses of ISIS-APO(a)Rx, there was dose-dependent reduction in Lp(a), by up to 80% at 300 mg (6 injections over 4 weeks).15 Moreover, the advent of novel treatments that specifically target Lp(a) indicate a need for reconsideration in treatment guidelines. We await the next chapter in the evolving Lp(a) story.
Genetic insights have also been the driver for developments targeting apoCIII, which is a key player in the regulation of triglyceride metabolism. In 2014, two Mendelian randomisation studies showed that carriage of loss of function APOC3 variants was associated with lower triglycerides and a reduced risk of ischaemic and coronary heart disease,16,17 thus providing a pivotal rationale for the development of antisense technology aimed at inhibiting apoCIII production. A phase II study reported earlier this year, with ISIS 304801, a second-generation antisense inhibitor of apoCIII synthesis, provided exciting support for this strategy.18 In individuals with baseline triglycerides 4-22.6 mmol/L (350-2000 mg/dl), treatment with ISIS 304801 (either alone or with a fibrate) led to dose-dependent and prolonged reduction in plasma apoCIII levels (by up to 80% at the 200 mg dose), with a similar magnitude decrease in plasma triglycerides. Given a favourable safety profile to date, the continued development of this agent may offer new potential.
And PCSK9 again….
Finally, while PCSK9 monoclonal antibody therapy led the field in PCSK9-targeted therapy, it would be remiss not to mention other approaches which are attracting attention. Phase I data reported at this year’s European Society of Cardiology Congress, London19 and the American Heart Association Scientific Sessions20 suggest potential for a reformulated small interference RNA (siRNA) therapeutic targeting PCSK9 mRNA, ALN-PCSsc. This agent was initially formulated for intravenous administration (ALN-PCS), but was subsequently reformulated for subcutaneous administration (ALN-PCSsc). LDL-C lowering with ALN-PCSsc was comparable to that achieved with PCSK9 monoclonal antibody therapy. Multiple subcutaneous dosing with 300 or 500 mg ALN-PCSsc every 2 months lowered LDL-C levels by up to 83%, either alone or against a background of statin treatment. Additionally, there was also benefit on other lipoproteins, including reduction in Lp(a) by up to 45% with a single 300 mg dose. As the response to single administration of ALN PCSsc was sustained for up to 208 days, dosing every 6 months could be a possibility. Phase II development will be initiated in 2016.
And not so good news...
However, there were also some pitfalls in 2015, most notably, discontinuation of another CETP inhibitor, evacetrapib. On the basis of interim data from the phase III cardiovascular outcomes study ACCELERATE, the independent data monitoring committee recommended termination of the study due to insufficient efficacy, prompting the closure of other studies with this investigational agent. Incidentally, findings from a recent meta-analysis indicated significant LDL-C lowering (by 21% on average) and elevation in high-density lipoprotein cholesterol (HDL-C, by 86% on average), but no significant impact on plasma triglycerides.21 We await full publication of the results of ACCELERATE for answers. On a more favourable front, following a recent planned review of unblinded data from REVEAL, the cardiovascular outcomes study with anacetrapib, the Data Monitoring Committee recommended the study continue with no changes. This decision was based on review of both safety and efficacy data from the study, and included an assessment of futility.22
The CETP inhibitors have had a chequered history to date, with two agents (dalcetrapib and evacetrapib) now terminated due to lack of efficacy, and one (torcetrapib) terminated due to (most likely off-target) safety issues. We await the results of REVEAL with anacetrapib in 2017.
No doubt, 2016 will continue this exciting new dawn in atherosclerosis and cardiovascular research. The Society looks forward to welcoming all members to next year’s Congress in Innsbruck in May, to hear the latest in developments with these and other novel lipid-modifying therapies.
- Nordestgaard BG, Chapman MJ, Humphries SE et al; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90a.
- Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57.
- Wiegman A, Gidding SS, Watts GF et al; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-37.
- Vallejo-Vaz AJ, Kondapally Seshasai SR, Cole D et al. Familial hypercholesterolaemia: A global call to arms. Atherosclerosis 2015; 243:257-9.
- De Backer G, Besseling J, Chapman J et al. Prevalence and management of familial hypercholesterolaemia in coronary patients: An analysis of EUROASPIRE IV, a study of the European Society of Cardiology. Atherosclerosis 2015;241:169-75.
- Pereira C, Miname MH, Makdisse MR et al. Peripheral arterial disease in heterozygous familial hypercholesterolemia. Atherosclerosis 2015;242:174-8.
- Kastelein JJ, Ginsberg HN, Langslet G et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;36:2996-3003.
- Raal FJ, Stein EA, Dufour R et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331-40.
- NICE issues draft guidance on evolocumab for lipid disorder. Draft guidance available at: http://www.nice.org.uk/guidance/indevelopment/gid-tag498
- Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010; 31:2844-53.
- Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2011;63:470–7.
- Kamstrup PR, Nordestgaard BG. Elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population. JACC Heart Fail 2015; [Epub ahead of print].
- Boffa MB, Koschinsky ML. Lipoprotein(a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res 2015 [Epub ahead of print]
- Capoulade R, Chan KL, Yeang C et al. Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis. J Am Coll Cardiol 2015;66:1236-46.
- Tsimikas S, Viney NJ, Hughes SG et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 2015;386:1472-83.
- Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.
- TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, Crosby J, Peloso GM et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.
- Gaudet D, Alexander VJ, Baker BF et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med 2015;373:438-47.
- Fitzgerald K, Kallend D, White S et al. A phase 1, randomized, placebo-controlled, single ascending and multiple dose study of subcutaneously administered ALN-PCSSC in subjects with elevated low density lipoprotein cholesterol. Eur Heart J 2015;36(Abstract Supplement):309. Abstract P1761.
- Fitzgerald K, Simon A, White S et al. ALN-PCSsc, an RNAi investigational agent that inhibits PCSK9 with potential for effective quarterly or possibly bi-annual dosing: results of a single-blind, placebo-controlled, Phase I single-ascending dose (SAD) and multi-dose (MD) trial in adults with elevated LDL-C, on and off statins. Latebreaking Clinical Trials 4, Abstract, AHA Scientific Sessions, Orlando, USA.
- Sahebkar A, Simental-Mendía LE, Guerrero-Romero F et al. Efficacy and Safety of Evacetrapib for Modifying Plasma Lipids: A systematic Review and Meta-Analysis of Randomized Controlled Trials. Curr Pharm Des 2015 Nov 24. [Epub ahead of print].
- Merck Provides Update on REVEAL Outcomes Study. Available at http://www.mercknewsroom.com/news-release/research-and-development-news/merck-provides-update-reveal-outcomes-study