ESC 2017 – Cancer death decrease might not save Cantos
Novartis's anti-inflammatory drug Ilaris has struggled to make its mark in cardiovascular disease, with just one dose – and not the highest one – meeting the primary endpoint of the Cantos study and the full data revealing an increased risk of fatal infection.
Despite this the Swiss group is determined to put a brave face on things, pushing on with a cardiovascular filing slated for the fourth quarter. Surprisingly, a large part of the discussion at the European Society of Cardiology meeting, where the data were presented today, focused on an intriguing – but exploratory – finding of a decrease in cancer deaths, which Novartis plans to investigate further.
Cantos tested three doses of the anti-IL-1 beta MAb – 50mg, 150mg and 300mg – with a primary endpoint of major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction and stroke.
Novartis had already reported that it had met this endpoint and the full details, which were also published simultaneously in the NEJM, had been awaited eagerly (Cantos could make Ilaris a blockbuster, June 22, 2017).
There can be only one
The company’s big moment fell somewhat flat, with only the 150mg dose meeting significance when adjusted for multiplicity. The respective reductions in MACE were 7%, 15% and 14% for the 50mg, 150mg and 300mg doses.
And the win with the 150mg dose was driven by a 24% reduction in myocardial infarction, with the other components of the composite endpoint not showing a significant improvement. There was a numerical cardiovascular mortality benefit, with a 10% reduction, and a neutral effect on stroke, said Novartis’s chief medical officer, Vas Narasimhan, during a media call.
The 300mg dose did not meet significance. The lead investigator of Cantos, Paul Ridker of the Brigham and Women's Hospital, put this lack of a dose-response down to a “very rigid statistical analysis”, and noted that the reductions seen in the 150mg and 300mg arms were almost identical.
Nevertheless, the results are a blow to Novartis, particularly when added to the increase in fatal infection seen with Ilaris in Cantos.
Dr Ridker seemed to think that this side effect would be manageable, saying that patients receiving Ilaris would merely need to be monitored for early signs of infection, in a similar way to patients on other anti-inflammatory biologics. Any infections could then be treated early using antibiotics.
Novartis was also encouraged by findings in high responders, based on levels of high sensitivity C-reactive protein (hsCRP), a marker of inflammation.
In this subgroup analysis, described variously as both pre-specified and exploratory, high responders, classified as those with an hsCRP value below the median at three months after the first injection of Ilaris, had a 27% reduction in cardiovascular events.
Responders could be easily identified by measuring hsCRP levels after initial treatment, similarly to how cholesterol levels are monitored in patients given statins, Dr Ridker said.
He believes that there are two distinct types of cardiovascular disease patient: those with residual cholesterol risk, who are currently treated with cholesterol-lowering drugs like statins and PCSK9 inhibitors, and those with residual inflammatory risk, who might benefit from the likes of Ilaris.
Ilaris’s anti-inflammatory effect could also make it useful in cancer, Novartis hopes. In another analysis that was also said to be both pre-planned and exploratory, Cantos found a 51% reduction in death from any cancer, and a 77% reduction in death from lung cancer.
Chronic inflammation can affect tumour initiation, invasiveness and metastatic progression, and is strongly linked with lung cancer in particular, Dr Ridker noted.
Mr Narasimhan said Novartis would discuss with the FDA whether the oncology data can be included in any new cardiovascular label; the company also plans to start a phase III trial in non-small cell lung cancer.
Getting approval in such different indications could raise questions about pricing: Ilaris is currently only marketed for rare diseases, and costs around $64,000 per year, a figure that would raise eyebrows in cardiology – but perhaps not the oncology – world.
But this would be a nice problem for Novartis for have. For now it has to focus on convincing the FDA that the Cantos data are enough for Ilaris to get approval in cardiovascular disease.