Cachexia drug failure falls heavily on GTx

Some credit is due to the executives of GTx for their never-say-die attitude. In the face of what is the complete failure of the cancer cachexia project enobosarm to meet its primary phase III endpoint they touted mixed signals of weight gain and improved survival as signs that regulators could yet accept a filing for the anabolic agent.

While this was no doubt an effort to keep shares from falling more than the 66% they did yesterday – to a record low of $1.43 – fast-track status could afford the Tennessee-based group several opportunities to advocate its point to agency staff in spite of its failure to show a consistent benefit for lung cancer patients on platinum-based chemotherapy. The results show that Merck & Co was right to have ended its partnership with GTX three years ago, as well as the difficulty in reversing the wasting syndrome that can complicate treatment and hasten death.

Sow's ear, meet silk purse

As designed after post-phase II meetings with the FDA, the Power 1 and 2 studies can be deemed nothing but failures. They failed to meet the co-primary endpoints of increased lean body mass and improved stair climb 12 weeks after beginning co-administration of enobosarm, formerly known as Ostarine, with chemotherapy (Event – GTx bulks up as cachexia trial readout nears, July 19, 2013).

On individual endpoints, Power 1 – a trial in patients on platinum-based chemotherapy with a taxane – managed to achieve statistical significance on the single lean body mass endpoint at a p value of 0.036, but as the trials were designed with weight gain and physical function as co-primaries, it was deemed a failure nonetheless.

To be sure, this was a difficult population: non-small lung cancer patients with locally advanced or metastatic disease, who have five-year survival of less than 20% at best. Advanced patients are where the need is greatest, however, as the weakness brought on by cachexia can make them less able to tolerate chemotherapy, and wasting is often cited as the cause of death (Therapeutic focus – Cachexia pipeline gaining weight, May 12, 2011).

In a call with analysts, chief executive Mitchell Steiner also pointed to more positive signs shown on a separate “continuous variable” analysis that did not have a single predefined date of measurement, an investigation that will take into account patients who drop out before the predefined 12-week endpoint or continue to improve afterwards. Mr Steiner said European regulators had asked for such a study.

Using such an analysis, both studies hit statistical significance on the body weight endpoint, and Power 1 also achieved it on the stair-climb power measurement. Whether this will wash with the European Medicines Agency given the almost complete failure on the hard 12-week endpoint is an open question, but it is hard to see it as persuasive.

The last slender reed on which Mr Steiner laid the hope of approvability was signs of improved survival in patients who did gain weight after taking enobosarm – a trend that in all likelihood would also be seen in the placebo arm. Overall survival is a safety endpoint in the trial, and GTx is well short of the 450 deaths necessary to conduct that analysis, so regulators might want to wait on these data before making any conclusions.

Tick tick tick

With failure of the two trials, GTx has very few options. Its pipeline is almost completely bare, with toremifene underperforming in two separate prostate cancer settings and safety worries surrounding its other prostate cancer project, Capesaris (GTx goes back to ensure the future of Capesaris, February 22, 2012). A win on enobosarm and a hoped-for licensing deal would have taken a great deal of pressure off.

Having burnt more than $24m in the first six months of the year to take its cash pile to $31.6m at June 30, GTx is in a weak position to support new trials for enobosarm in cachexia or continued work for the Capesaris clinical programme. Analysts from Leerink Swann set a new price target of $1, which would value the company at about twice cash levels, which seems generous. Enobosarm remains in clinical trials in breast cancer, in addition to phase II trials for Capesaris, but ascribing value to either compound seems a little kind.

The best scenario for GTx in the remainder of the year would be for investors to react positively to news of meetings with regulators, a potential uplift that might allow it to make a small public offering. But do not count on it, or a filing for enobosarm, any time soon.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @JonEPVantage on Twitter