GTx was taken by surprise with FDA's decision to issue a "complete response" letter for the firm's selective estrogen receptor modulator toremifene 80 mg - a drug whose clinical development program was designed with the agency's help under a Special Protocol Assessment.

"They moved the goal posts on us," said CEO Mitchell Steiner in a Nov. 2 call announcing the letter. "It almost appears like they disregarded the SPA."

FDA has taken to the podium at various conferences to clarify that an SPA is not a guarantee of regulatory acceptance (Also see "FDA Says "Agreement" Does Not Have To Be Holy Grail Of SPA Discussions" - Pink Sheet, 6 July, 2009.), but the agency's requests in the action letter reflect a level of deficiency in the application that the program is intended to avoid.

FDA is asking GTx for an entirely new Phase III trial to show safety and efficacy, as well as data from a clinical trial demonstrating that toremifene does not have a detrimental effect on either time-to-disease progression or overall survival.

"This is a complete surprise for us," Steiner said. "We would have never filed the NDA with the FDA if we knew the requirement all along was a second trial. We would have done the second trial. Why waste our time?"

Toremifene's proposed indication is to reduce fractures in men with prostate cancer receiving androgen deprivation therapy. GTx reported that no safety issues were raised in the letter.

Lots of Wiggle Room

The NDA is supported by a two-year, double-blind, placebo-controlled, randomized Phase III clinical trial of 1,382 prostate cancer patients on ADT, in which 80 mg of toremifene was shown to reduce risk of vertebral fractures by over 50 percent. The study also met all secondary endpoints, including increased bone mineral density, reduced hot flashes and improving lipid profiles.

Not only was GTx's NDA designed with the agency under a SPA, but the company said it also followed the 1994 osteoporosis guidance. The additional requirement for a second fracture study was not discussed at any time during the clinical development or the new drug review process, Steiner said.

He said he is holding out hope that the requirement of an additional clinical trial could be something the company does in the post-market setting. "There is lots of wiggle room here for us to meet with the agency and understand the next steps."

While the requirement for a second Phase III trial was a surprise, Steiner said that the second request was an "even a greater surprise," and argued that FDA "threw this in the last minute because of the new information they received from another company that was being reviewed by the same division," where the agency was concerned about detrimental effects on the underlying cancer in the patient population.

With Amgen's Prolia (denosumab), currently under review for a similar indication, FDA determined that more information was needed to assess the impact of the supportive care bone therapy on patients underlying cancer.

"Toremifene does not interfere with the mechanism of androgen deprivation therapy, nor does it appear to have an effect of the underlying prostate cancer itself," he said. "Consequently, we believe we already have sufficient evidence to satisfy the agency's request to demonstrate these points."

GTx's trials showed no signals that toremifene was worsening a patient's underlying cancer. "We did everything in that two year study to allow us to capture that information," Steiner said. "If there was a signal, it should have come out." He thinks that the company will be able to convince FDA that the existing data set does sufficiently evaluate the cancer question.

The Competition Heats Up

If a silver lining exists in this situation at all, it's that toremifene's competition - Amgen's Prolia - recently received two "complete response letters" from FDA, also asking for additional trials (Also see "Getting Past FDA's HALT: Can Amgen Escape New Trial Requirement For Prolia With Data From SRE Studies?" - Pink Sheet, 26 October, 2009.).

Toremifene was thought to have a clearer path to approval than denosumab, as it is already approved at a 60 mg dose ( Fareston ) for treatment of advanced breast cancer.

While denosumab and toremifene will compete if approved, the two have different mechanisms of action that will at least in part determine their use (Also see "Amgen’s Denosumab, GTx’s Toremifene Keep Pace At ASCO On Prevention Of Bone Fractures In Prostate Cancer Patients" - Pink Sheet, 1 June, 2009.). As a selective estrogen receptor modulator (SERM), toremifene comes from an established class of agents, while denosumab is a monoclonal antibody with a novel mechanism for preventing bone resorption.

Toremifene On The Chopping Block?

When asked whether the company would weigh the option of possibly killing the clinical development of toremifene if additional costly trials were required, Steiner said that the drug is important because it would treat an unmet medical need, but a five year, $30 million to $35 million clinical trial would mean the firm would need to consider other options.

"This is not our only pony," he said. "We stand behind our clinical work and we hope that we can see this forward, but if it turns out we have to invest even more money into this program to see it go forward, then we do have to take a hard look at all the other things we're doing."

Steiner said GTx's request for a meeting had been accepted as a Type A meeting, and FDA told the company they would meet within the regulated 30-day window. He added that there is no reason that Ipsen's marketing of the drug in Europe shouldn't move along as planned.

Additional information will be available during GTx's Nov. 9 earnings call, he said.

-Lauren Smith (lauren.smith@elsevier.com)

FDA's "Complete Response" On GTx's Toremifene Moves The Goal Posts, CEO Says

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