Editor

The 49-percent wallop taken by GTx Inc. on word of a complete-response letter from the FDA on the 80-mg version of toremifene for bone fractures in prostate cancer signaled an unpleasant surprise for investors and took the company by surprise, but at least a few saw potential trouble coming two years ago.

Memphis, Tenn.-based GTx said new trials will be necessary to provide the data wanted by regulators who insist on better proof that the drug can reduce fractures for men getting androgen deprivation therapy. The company is asking for a meeting with the FDA, and will decide later about toremifene's fate.

At the 80-mg dose, toremifene - an oral selective estrogen modulator - would be marketed as Acapodene. GTx already sells a 60-mg version as Fareston for metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

Cowen & Co. analyst Eric Schmidt said the drug is doomed in prostate cancer, since the path to approval would take at least four years (others estimated more like five) and predicted GTx ultimately will abandon the push.

Mitchell S. Steiner, GTx's CEO, said during a conference call that the letter from the FDA was "pretty short," and identified only two deficiencies, insisting on further work in safety and efficacy, as well as toremifene's possible effect on the cancer itself.

The company already has much data to take to the FDA meeting, he added, and cited "a lot of wiggle" room, though he declined to speculate on the outcome of the meeting. An ongoing Phase III program with the compound in prostate intraepithelial neoplasia (PIN, or precancerous lesions) is looking at cancer incidence, Steiner said.

"That's a pretty powerful endpoint to determine whether there's a detrimental effect, because on top of that we can look at Gleason scores and all that other stuff, in addition to the almost 2,500 [patients] who have already been subject to toremifene," he said.

In the letter, the FDA presented no new concerns about venous thromboembolic events or QTc effects that could lead to arrhythmia, and when asked by Lazard analyst Joel Sendek if those worries might be subsumed under the demand for more safety and efficacy, Steiner said he didn't think so.

"If that was the case, I would imagine they'd want a QTc study in ADT patients or some other way to characterize the QTc effects in this patient population," Steiner said, and the agency did not specifically request that.

In PC bone fractures, there had been reason for hope, not only in the fact that toremifene has been approved once at a lower dose, but also that the FDA had slated no advisory panel meeting - although the latter could have meant anything.

There had also, though, been storm clouds gathering for some time. Analysts at Leerink Swann were fidgeting over VTE and QTc as long ago as 2007, and a research report issued just days before the FDA letter was disclosed again brought the concerns to the fore, especially VTE.

In the trial, 13 vertebral fractures were blocked, but at the cost of 10 new VTEs, including some as disturbing as deep venous thrombosis and pulmonary embolism.

"Although fractures clearly can have severe health consequences, VTEs are also serious," wrote Leerink Swann analyst Howard Liang - and the numbers of each were almost the same.

All in all, Liang put more hope in GTx's effort, partnered with Merck & Co. Inc., for selective androgen receptor modulators against muscle loss, while "uncertainties in the Acapodene program give us pause." GTx entered the deal with Whitehouse Station, N.J.-based Merck in 2007, and got $40 million up front plus $15 million in research payments, and an potential value as high as $500 million. (See BioWorld Today, Nov. 7, 2007.)