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.
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.
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.|
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.