ESC 2014: the buzz is back in cardiology

After a long, barren spell, cardiology is once again a dynamic therapy area because of novel medicines which promise to advance treatment of heart disease.

Recent years have seen oncology and other therapy areas dominate the industry’s new launches, with pharma struggling to find new and improved ways to tackle cardiovascular disease (CVD), still the world’s biggest killer.

Now several late-stage drugs are being hailed as potentially major advances, and the excitement is back. This was evident at the European Society of Cardiology’s (ESC) annual meeting held in Barcelona from 30 August to 3 September.

Chief among these new agents showcased at the congress were Novartis’ new heart failure treatment LCZ696 and Sanofi and Regeneron’s hypercholesterolemia candidate alirocumab.

Photo: ESC

The ESC picked out the following studies as their own official highlights, as shown below. The six studies cover a wide range of themes in cardiology, and not all demonstrated success – most notably Servier’s disappointment with its drug ivabradine.

• PARADIGM-HF: Investigational new heart failure drug LCZ696 could be poised to change the face of cardiology

• ODYSSEY studies: Investigational lipid-lowering agent alirocumab produced superior results compared to placebo

• SIGNIFY: Adding ivabradine (used for the treatment of heart failure and stable angina) to standard therapy has no effect on cardiovascular (CV) events in patients with stable coronary artery disease (CAD) and should be used with caution in patients with severe forms of angina

• CONFIRM: Intravenous doses of an iron supplement improves functional capacity and quality of life in heart failure patients with iron deficiency

• EUROECO: First financial assessment of the impact of home monitored follow-up estimates the cost to physicians, hospitals and insurance providers is the same as traditional in-office monitoring, according to a new study, but reimbursement is lagging behind

• FOCUS: Patients were more likely to take their medication to prevent a heart attack when it was given as a polypill, rather than as three separate pills.

LCZ696: too early to call it a paradigm shift?

The star of the show at ESC was undoubtedly Novartis’ heart failure treatment LCZ696.

The potential of the drug first became clear in March when its phase III trial was stopped early, but full data unveiled in Barcelona suggested it could help advance survival significantly in one of the most hard-to-treat cardiac conditions.

The drug showed exceptional results in heart failure patients with reduced ejection fraction (HF-REF): reducing the risk of death from CV causes by 20 per cent; reducing heart failure hospitalisations by 21 per cent; and reducing the risk of all-cause mortality by 16 per cent.

Overall, LCZ696 produced a 20 per cent risk reduction on the primary endpoint, a composite measure of CV death or heart failure hospitalisation.

“Once approved, Novartis almost certainly has a blockbuster drug on its hands”

These results have been acclaimed as a major step forward in treating the disease, and means that, once approved, Novartis almost certainly has a blockbuster drug on its hands.

The Swiss firm plans to file the drug with the US FDA by the end of 2014 and in the EU in early 2015. A further advantage for Novartis is that the drug has no immediate rivals, giving it a clear run at developing the market.

There is no consensus yet among market analysts on how much the drug could generate in peak sales, but Bernstein’s Tim Anderson forecasts that LCZ696 could reach as much as $8 billion.

LCZ696 is a twice-a-day tablet combining the older angiotensin receptor blocker valsartan with a new agent, sacubitril. The combination has a unique mode of action which is thought to reduce the strain on the failing heart. It acts to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful system (the RAAS).

Existing medicines for HF-REF work only to block the detrimental effects. The mortality rate remains very high, with up to 50 per cent of patients dying within five years of a diagnosis of heart failure. Approximately half of patients with heart failure have HF-REF.

Scepticism

Some cardiologists are not quite so convinced by the data, however, and numerous queries and challenges to the PARADIGM-HF trial have been raised in Barcelona and via online discussions. For example, why, with such a dramatic impact on congestive heart failure, did LCZ696 not manage to reduce atrial fibrillation (AF), a key characteristic of worsening heart failure? The investigators say the number of AF patients in the trial was not sufficient to provide insight into this question.

Other questions raised about the trial included that the target dose of enalapril deployed – 10mg twice-daily – was lower than the maximal dose (10mg-20mg twice daily) recommended in guidelines, while the valsartan portion of LCZ696 could be pushed to its maximum of 160mg twice-daily.

Another point raised by cardiologists at the ESC meeting was how a run-in period in the trial – designed to weed out patients who could not tolerate therapies – could skew the safety outcomes data.

The possibility of the novel compound sacubitril also having unintended effects in other metabolic pathways was also raised. Sacubitril inhibits the neprilysin enzyme – which plays a role in heart failure, but is also known to have a function in the brain.

Specifically, neprilysin is also elevated in Alzheimer’s, and seems to play a role in processing beta-amyloid, which clumps to form the plaques that are characteristic of the disease.

And finally, as with all new major drugs emerging this year, the cost implications of the drug were also seen by some as a potential problem, though of course Novartis will only disclose its pricing strategy once it has gained approval.

PCSK9 inhibitors – the next generation of cholesterol busters

The other major trial of the congress was from Sanofi and Regeneron who announced positive results for alirocumab, one of a new class of drugs which targets PCSK9, in people with hypercholesterolemia. These new drugs are being tested first in patients whose LDL cholesterol levels are resistant to statins or are otherwise hard to treat; but, if they prove significantly more effective, their use could eventually be widened.

The results of the four phase III ODYSSEY trials were showcased at the event, and followed hot on the heels of news that Amgen has just filed its rival PCSK9 inhibitor drug evolocumab with the US FDA.

One of the four studies, the ODYSSEY Long Term trial, evaluated the long-term safety and efficacy of alirocumab in patients with hypercholesterolemia who are at high or very-high CV risk, including patients with heterozygous familial hypercholesterolemia (HeFH). Both study groups were treated with statins and some received additional lipid-lowering therapies. At 24 weeks, there was a significant 61 per cent reduction from baseline in LDL-C levels in the alirocumab group compared to a 1 per cent increase in the placebo group.

At 52 weeks the trend continued, with a 57 per cent reduction from baseline in LDL-C levels in the alirocumab group compared to a 4 per cent increase in the placebo group.

In a post hoc safety analysis, there was a lower rate of adjudicated major CV events in the alirocumab group compared to placebo (1.4 per cent compared to 3.0 per cent). This suggests a significant CV benefit, but the trial was not set up to demonstrate this endpoint.

Regulatory submissions are anticipated by the end of 2014 in the EU and US, with priority review status likely to be sought in the US.

Alirocumab is one of Sanofi’s best drug prospects, but the drug will face stiff competition. In addition to Amgen’s evolocumab, there are further rivals in the pipeline: Pfizer’s bococizumab, Roche’s Genentech’s RG7652 and Lilly’s LY3015014.

Brilinta/Brilique in STEMI

AstraZeneca has an early opportunity to trumpet its antiplatelet drug Brilinta/Brilique (ticagrelor), which has only just emerged from a US Department of Justice (DoJ) investigation into the PLATO trial which underpinned its approval in 2011.

The results of the ATLANTIC study show the drug is equally effective when given before hospital admission to heart attack patients as it is when given in hospital, in line with new ESC guidelines, with no adverse impact on bleeding rates. The results of the trial, which involved patients with ST segment elevation myocardial infarction (STEMI), suggest Brilinta can be given to patients at first medical contact as well as in hospital, making it a flexible option for patients undergoing life-saving percutaneous coronary interventions (PCIs) such as angioplasty.

Moreover, there was a hint in the results that early treatment with Brilinta in the ambulance could actually improve outcomes after PCI, which “warrants further investigation”, according to the company.

Disappointing results for ivabradine

There was disappointment in the SIGNIFY trial of Servier and Amgen’s chronic heart failure drug ivabradine, however, after it failed to have any impact on CV events in patients with stable coronary artery disease (CAD).

As the drug acts mainly by lowering heart rate, the results call into question the idea that this is an effective treatment target in CAD patients without heart failure, say the researchers behind the trial. Ivabradine was able to reduce the heart rate by around 10 beats per minute in the 19,000-patient study, but there was no difference in the rate of CV death or nonfatal heart attack when compared to placebo.

The results also suggested worsening outcomes in patients with severe angina, a previously-reported finding that prompted the European Medicines Agency (EMA) to launch a re-assessment of the drug earlier this year. The dose used in SIGNIFY is, however, higher than that approved for marketing in the EU.

Meanwhile, cardiologists got some insight into the failure of GlaxoSmithKline’s acute coronary syndrome (ACS) therapy darapladib with the first public discussion of the results of the SOLID-TIMI-52 trial.

ACS patients treated with darapladib alongside standard medical therapy did no better than those on medical therapy alone in the two-and-a-half-year study, which measured the combined rate of CV death, myocardial infarction and urgent CV revascularisation, according to the researchers behind the study.

Biotech company Trophos also got some disappointing news after its experimental agent to prevent reperfusion injury in STEMI patients – TRO40303 – proved ineffective in the phase I/IIb MITOCARE trial.

TRO40303 is designed to prevent tissue damage when impaired blood flow is corrected via percutaneous coronary intervention procedures but – like many other drugs developed for this use – was unable to show any positive effect on the size of the infarct.

Principal investigator Dan Atar of the University of Oslo in Norway described the findings as “yet another nail in the coffin” of reperfusion injury prevention.

Novel oral anticoagulants (NOACs)

The field of novel oral anticoagulants is hotly contested, with three established drugs vying for market share in a number of indications, and a fourth expected to reach the US and European markets soon.

Pfizer and Bristol-Myers Squibb reported new data from the AMPLIFY-Extension trial of their oral anticoagulant Eliquis (apixaban), which indicate the drug significantly reduced hospitalisation rates compared to placebo over one year in patients with venous thromboembolism (VTE).

AMPLIFY-Ext was first unveiled at the end of 2012 and suggested that an extra year of treatment with the drug cuts the risk of recurrence of VTE, and the new data reinforces the value of that additional treatment duration, according to study investigator Alexander Cohen of King’s College London.

Eliquis benefits in reducing hospitalisation were independent of other factors such as renal function, which was the only other significant predictor of hospitalisation in the trial.

Meanwhile Boehringer Ingelheim presented new data for its drug Pradaxa (dabigatran etexilate). A sub-analysis of its RE-LY trial showed that kidney function decline is less pronounced in patients with an irregular heartbeat (non-valvular atrial fibrillation, NVAF) who are treated with the drug compared to warfarin. Boehringer has had to fight to maintain Pradaxa’s reputation as a safe medicine in the face of concerns about the raised risk of bleeding. Regulators have confirmed the drug’s overall favourable safety profile, but the drug may struggle to convince doctors.

Meanwhile, Bayer and Janssen presented new data on Xarelto which showed the drug can be used in place of warfarin in AF patients undergoing cardioversion to restore normal heart rhythm.

Xarelto (rivaroxaban) is the first of the NOACs to show a benefit in this setting and – in addition to being more practical to administer to patients – also seemed to have an advantage over vitamin K antagonists (VKAs) such as warfarin, according to the results of the X-VErT study. Read more here.

Finally, Daiichi Sankyo has its own Factor Xa antagonist called Lixiana (edoxaban) waiting in the wings: already on the market in Japan, the drug is currently under regulatory review in Europe and the US.

In preparation for its launch, the company released market research which found that NOACs use is rising dramatically in Europe, but uncovered major differences in use across Europe. Read more here.

Lifestyle changes

Finally, lest one forget that managing CVD is not all about medical interventions, the ESC also provided interesting updates on the lifestyle changes we can all make to improve our health.

Studies reported in Barcelona indicated that drinking tea can cut blood pressure and reduce non-CV mortality (there was a trend towards reducing CV mortality as well), while it appears drinking wine only has a protective effect in those who exercise.

Avoiding energy drinks is probably a good idea though; a French study uncovered 257 cases in which the caffeine-laden drinks were linked to side effects, of which 95 involved cardiovascular symptoms.

 


About the author:

Andrew McConaghie is pharmaphorum’s managing editor, feature media.

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