If the kindest failures are those that occur swiftly and leave no room for doubt, then the one just suffered by Wilex, whose kidney cancer antibody Rencarex has flunked a phase III study begun over eight years ago, must be especially hard to bear.
Still, the company is putting a brave face on it, and says the study failed largely because patients were not progressing as fast as had been thought. “This is great news for patients, if not for the company,” Wilex’s chief executive, Dr Olaf Wilhelm, told EP Vantage in an interview this morning, adding: “Do patients really need an adjuvant therapy?” The question pertains not only to Rencarex but to all similar approaches.
The 864-patient phase III study, Ariser, was testing Rencarex in the adjuvant setting – to delay relapse in renal cancer patients who had already had the affected kidney removed. Specifically, it was looking at non-metastatic patients, the first of whom had been recruited in 2004.
Waiting for Godot
But it was never supposed to have taken eight years; previous trials in the adjuvant setting had suggested median relapse-free survival of around three years, and initially Ariser had progressed in line with this, said Dr Wilhelm.
After 100 events, reached in 2007, the trial passed an interim analysis for futility. However, relapses then slowed sharply, to the extent that an analysis a year ago suggested that it would be pointless to wait for all expected 512 progressions, and that the data were mature enough for the trial to be unblinded immediately.
Unfortunately, while there was some hope that, for instance, the delay in progressions had been due to the activity of Rencarex, this has not transpired. Yesterday’s announcement that Ariser did not meet its primary endpoint of median disease-free survival caused Wilex shares to plunge by 62% to value the company at €32m, although early this morning saw a 6% dead-cat bounce.
So why had the trial simply not been stopped for futility a year ago? “The data-monitoring committee only had blinded data – they did not unblind the trial,” said Dr Wilhelm. As to the hurdle that had successfully been cleared in 2007, he said that futility analyses only assess the probability of failure, not the probability of success.
At the time of the database lock only 389 patients had progressed, 192 of which were in the Rencarex group, and across the whole trial patients on average remained relapse-free for an astonishing six years or more. Tackling the obvious suggestion that the wrong types of patients had been recruited into Ariser, Dr Wilhelm insisted that this was not the case.
“They were all extremely high-risk,” he stated, adding that retrospective analyses had confirmed this. “The result was completely unexpected.”
Edison Investment Research’s John Savin suggested that a clue might have been that Ariser had recruited T1-2 patients – whose cancer had been confined to the kidney – as well as those with the more advanced T3-4 tumours that invade surrounding tissue. “The rate of diagnosis of T1 tumours under 4cm in diameter has risen rapidly over the past decade,” he told EP Vantage.
However, data in fact revealed that at least 652 of the 864 Ariser patients had had T3-4 grade tumours, with an even stratification between the active and placebo groups, so the shifting diagnosis landscape alone could not have accounted for the negative result. "They have an unusual result," said Mr Savin. "Most patients were at high risk of progression – they just did not do so. The length [of the study] deceived us all into thinking that Rencarex must have a big effect."
The overall result showed no discernible relapse-free survival difference between active and placebo groups. Launches of drugs for metastatic renal cancer since the start of Ariser could have confounded the overall survival result – a co-primary endpoint in the trial – and this will in any event not be followed up.
The Ariser finding that patients seemed to stay relapse-free for an unexpectedly long time raises questions over other projects designed for use in the same setting as Rencarex, said Dr Wilhelm. These include Bayer/Onyx’s Nexavar, Pfizer’s Sutent and GlaxoSmithKline’s Votrient, all of which are in large phase III studies in adjuvant treatment of non-metastatic renal cancer.
Wilex itself is not only about Rencarex, and Dr Wilhelm highlighted other R&D projects as well as its service and diagnostics businesses; cash levels were recently boosted by the receipt of an additional $17.5m under an earlier Rencarex deal with Nestlé.
The Ariser data might also hit another important Wilex project, Redectane, which comprises a radiolabelled version of the antibody used in Rencarex and was developed for presurgical detection of clear-cell renal cell carcinoma. Analysts had assumed that diagnosis with Redectane would point the way towards treatment with Rencarex, and the failure of the latter might call into question the logic behind the former.
But Dr Wilhelm insisted that Redectane was “not a companion diagnostic at all ... A Redectane image should help determine whether or not you do surgery and what type of surgery.”
He also deflected the issue of the company’s chief financial officer, Peter Llewellyn-Davies, leaving in August. “Certainly, no management had any inkling of [the Ariser] result,” he said. "His contract was not extended." Mr Llewellyn-Davies, now the finance chief of Wilex’s Munich cross-town rival Medigene, did not return calls from EP Vantage.
Dr Wilhelm said the Ariser results had been briefly talked over with Wilex’s Rencarex partners, Esteve in southern Europe and Nestlé in the US, and more discussions have yet to come. No news as to the future of these deals has yet emerged, but it seems logical that if Rencarex is formally scrapped then the alliances will go with it.
In any case, investors can now assume that to all intents and purposes the project is dead. It may have taken eight years to find out, but at least now they know for sure.
To contact the writer of this story email Jacob Plieth in London at firstname.lastname@example.org.