ESC preview – Medicines Company hopes for a starring role

Novartis has been reduced to a Paragon data dredge, but results with The Medicines Company’s inclisiran, Astrazeneca’s Brilinta and Cellaegis’ AutoRIC device should pique interest.

Conferences

With Novartis falling short with Entresto, other groups will have the chance to seize the spotlight at this year’s European Society of Cardiology meeting. And The Medicines Company, which is due to present the first phase III data with its long-acting PCSK9 inhibitor inclisiran, will hope to be at the centre of attention. 

Astrazeneca’s blood thinner Brilinta could also be one to watch, with full data from its Themis cardiovascular outcomes trial due to be detailed at the meeting; the company has already said that the study was a hit. On the medical device side, an academic trial of Cellaegis Devices’ technology for remote ischaemic conditioning in heart attack patients could expand the little-known company’s reach.

The ESC meeting will take place in Paris, France, from August 31 to September 4.

ESC 2019 highlights
Project Company Trial Setting Abstract # Location/time (CET)
Sunday 1 Sept
Brilinta Astrazeneca Themis, NCT01991795 Cardiovascular outcomes in type 2 diabetes 2097 Main auditorium, 14:30
Brilinta Astrazeneca Themis-PCI, NCT01991795 As above, with history of prior percutaneous intervention 2098 Main auditorium, 14:45
Entresto Novartis Paragon HF, NCT01920711 Heart failure with preserved ejection fraction 2101 Main auditorium, 15:00
Brilinta Astrazeneca Isarreact 5, NCT01944800 (investigator sponsored) Vs Effient in acute coronary syndrome  2306 Main auditorium, 16:40
AutoRIC Cellaegis Condi2/Eric-PPCI, NCT02342522 (investigator initiated) STEMI patients undergoing PCI 2303 Main auditorium, 16:40
Architect Stat troponin I assay Abbott Historic, NCT03005158 (investigator initiated) Ruling out myocardial infarction 2309 Main auditorium, 16:40
Monday 2 Sept
Inclisiran The Medicines Company Orion-11, NCT03400800  Atherosclerotic CV disease or risk equivalents and elevated LDL-C  2977 London, Village 2, 9:22
Xarelto J&J/Bayer Afire, NCT02642419 (investigator initiated) Xarelto monotherapy vs Xarelto-antiplatelet combo in pts with AF and CAD 3175 Main auditorium, 11:18
Renal denervation Medtronic Renal denervation symposium   3950-3955 Tbilisi, Village 6, 13:00
Tuesday 3 Sept
Elecsys troponin T assay  Roche Diagnostics Rapid-TnT, ACTRN12615001379505 (investigator initiated) Suspected acute coronary syndrome 6041 Main auditorium, 16:40
Source: ESC programme.

Until recently, the most eagerly awaited readout concerned Novartis’s Paragon study of Entresto in heart failure with preserved ejection fraction (HFpEF). The drug is already a blockbuster in HF with reduced ejection fraction, and approval HFpEF could double its market size.

Paragon failed to meet its primary endpoint, but Novartis is taking the tried-and-tested approach of relying on the “totality of evidence”, perhaps encouraged by the fact that there are no approved therapies for HFpEF (Novartis’s Paragon falls short of perfection, July 29, 2019). 

The company said today that Paragon found “clinically important benefits in select patients with HFpEF”, suggesting it has found a subgroup to home in on. There is also the possibility that Entresto had an impact on hospitalisation rates without reducing cardiovascular death. Either way, the full data from Paragon will be important for weighing the project’s chances of a green light here. 

Star turn?

Meanwhile, The Medicines Company could steal Novartis’s thunder if it can get a result with inclisiran in the Orion-11 study, the first of three pivotal trials of the project set to report this year (Medicines Company goes on the hunt for heartening Orion data, July 10, 2019). The Company is expected to release a top-line readout ahead of ESC.

Orion-11, which is being carried out outside the US, evaluates the twice-yearly inclisiran on top of lipid-lowering therapies like statins in patients both with and at risk of atherosclerotic cardiovascular disease.

On the primary cholesterol-lowering endpoints, inclisiran needs to perform at least as well as Repatha and Praluent, which showed placebo-adjusted LDL lowering of around 55% at one year in patients on background statin therapy.

But safety is just as important. Inclisiran, a small interfering RNA project, uses Alnylam’s Galnac delivery platform, which has been linked with toxicity worries.

If the project succeeds, the group’s next problem will be making inclisiran a commercial success, which is not a given after disappointing sales of the marketed PCSK9 inhibitors.

Upcoming phase III Orion trial readouts 
Trial name Details N ID Data due
Orion-11 OUS, atherosclerotic CV disease or risk equivalents and elevated LDL-C  1,617 NCT03400800 ESC 2019
Orion-9 Global, heterozygous familial hypercholesterolaemia 482 NCT03397121 H2 2019
Orion-10 US, atherosclerotic CV disease and elevated LDL-C  1,561 NCT03399370 H2 2019
Orion-5 OUS, homozygous familial hypercholesterolaemia 45 NCT03851705 Jun 2021
Orion-8 Global phase III long-term extension 3,700 NCT03814187 Aug 2023
Orion-4 UK, CV outcomes in pts with CV disease 15,000 NCT03705234 Dec 2024
Source: EvaluatePharma, clinicaltrials.gov.

Astrazeneca’s Brilinta is another drug that has not lived up to expectations, and the company’s attempts to expand into new uses have fallen short, though it finally has a win in the Themis trial.

The study evaluated whether Brilinta plus aspirin reduced major cardiovascular events versus aspirin alone in 19,000 patients with coronary artery disease and type 2 diabetes, who had not previously had a heart attack or stroke. 

The expense of adding Brilinta onto low-dose aspirin, which is already considered for these patients, means that ESC attendees will be keen to see more details on the magnitude of benefit seen with Brilinta and whether this is clinically meaningful. Another question is how much the Themis population could be worth in sales given the drug’s patent expiry in 2024; a spokesperson for Astra declined to speculate on this. 

Investigator-sponsored studies of both Brilinta and Johnson & Johnson’s anticoagulant, Xarelto, will also feature at this year’s ESC meeting.

Oxygen of publicity

Also investigator-sponsored is the Condi2/Eric-PPCI trial. This is assessing a technique called remote ischaemic conditioning (RIC), which aims to reduce the severity of ischaemia in heart attack patients.

The procedure involves repeatedly temporarily cutting off blood supply to a limb. The theory is that this activates the body’s natural protection against reperfusion injury and tissue damage caused by low oxygen levels. The trial’s protocol frankly admits that the mechanisms underlying RIC are unclear, but says that the cardioprotective effect has been attributed to a neuro-hormonal pathway.

Condi2/Eric-PPCI is testing RIC as provided by Cellaegis Devices’ AutoRIC device in 5,413 myocardial infarction patients who are undergoing angioplasty for a blocked coronary artery. The treatment group will have an AutoRIC cuff placed on the upper arm and inflated to 200mmHg for five minutes and then deflated for five minutes, with this cycle being performed four times. In the control group the cuff will be applied, but inflation and deflation will be simulated.

The study’s main endpoint is cardiac death and hospitalisation for heart failure at one year. Cellaegis, a private medtech, does not report sales of AutoRIC, but says that Condi2/Eric-PPCI is intended to boost adoption of the device in Europe – the system is not yet approved in the US. Evidence for RIC as a technique has so far been inconclusive; the ESC data could help settle the question for good.

Follow Madeleine Armstrong and Elizabeth Cairns on @ByMadeleineA and @LizVantage for live tweets from the ESC conference.

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