St. Jude Medical is unlikely to be able to secure U.S. approval for its Amplatzer device, a tiny mesh plug used to close holes in the heart, after it failed in two late-stage trials. The firm still intends to file for FDA approval, but will now have to run the gauntlet of an advisory committee at the very least.
The Amplatzer plug is CE marked and has been on sale since 1998 in Europe, where last year revenue totalled $40m, according to EvaluateMedtech. Last month, Wells Fargo analysts had suggested that, if approved for stroke prevention, the potential worldwide market for the device could have reached 10 times as much. This payday, which St. Jude could really use, now appears to be out of reach.
In July, St. Jude’s CEO, Dan Starks, said that trial was expected to succeed. During the company’s second-quarter 2012 earnings call, he said: “We're no longer blinded to the data … when the full trial results are reported, we're optimistic that these will be favourable." Back then, he said that a US filing would be made in the fourth quarter.
Can’t get no Respect
The first of the trials, dubbed Respect, enrolled 980 patients in the U.S. and Canada who had previously suffered a stroke with an unknown cause, with the primary endpoint of preventing further strokes. Patent foramen ovale (PFO), a hole between the two atria of the heart, is thought to be linked to cryptogenic stroke, as PFOs are present in a significantly higher percentage of cryptogenic stroke patients than in the general population or in non-cryptogenic stroke patients, though no definitive link has been proven.
The Amplatzer, made of Nitinol mesh and polyester, is inserted via the femoral artery using a catheter and stitched into the wall of the heart across the defect.
Nine patients treated with the Amplatzer (1.6%) had a stroke compared with 16 (3%) treated with drug therapy. This gave a 47% risk reduction with the plug, but this did not meet statistical significance, with a p value of 0.157.
There is a crumb of comfort for St. Jude in that the endpoint was met if the data are analysed in different ways. The non-significant 47% risk reduction was seen in the tougher intent-to-treat analysis; in patients treated per protocol, the 63% reduction in stroke was statistically significant. So was the 83% reduction seen in the as-treated analysis.
UBS analysts said that these analyses had some validity as they had been pre-specified, and pointed out that three strokes in the PFO arm had occurred in patients who did not in fact receive the device.
PC gone mad
The second trial, a European phase IV study called PC-Trial, saw Amplatzer reduce the risk of the primary endpoint, a composite of death from any cause, non-fatal stroke, transient ischaemic attack (TIA) and peripheral embolism, by a non-significant 37%. There was an 80% reduction in the risk of stroke, also non-significant; UBS said the trial was underpowered with respect to this endpoint.
“We assume St Jude can ultimately get PFO approved, but an Ad-Com will almost certainly be required,” the analysts wrote, adding that US approval would increase 2014 revenues by $25-50m, adding 1-2% to EPS.
But approval is by no means assured. The missed endpoints, which caused St Jude’s stock to fall 4%, are perhaps unsurprising given the poor record of PFO closure devices. The 2011 failure of NMT Medical’s STARflex device, which eventually forced the company to fold – despite its efforts to forestall this by suing a whistleblowing doctor for libel – is a case in point.
WL Gore is also seeking to exploit the PFO space. The Flagstaff, Arizona, company is conducting a study called Gore Reduce, evaluating its Gore Helex septal occluder and the newer Gore septal occluder in patients with PFO and a history of cryptogenic stroke or TIA.
The Gore septal occluder was CE marked in June 2011 for atrial septal defect, a different type of hole in the heart, and PFO. The company has reaffirmed that it will seek US approval for PFO indication in the US for both products.
As for St Jude, the next step will probably be to pool the data from Respect and PC-Trial to see whether particular groups of patients benefit from PFO closure. But having foundered in two trials, the plug will have to show great benefit in a subset to stand a chance of convincing the FDA.