GTx goes back to ensure the future of Capesaris

GTx is hoping that going backwards maybe the way forward for its prostate cancer drug Capesaris. Shares in the company lost a third of their value yesterday following the FDA’s decision to place the product on clinical hold, while investigations are made into the high rate of blood clots seen in phase II dosing trials.

Rather than spelling the end of the drug’s development GTx is determined to soldier on and is proposing to continue studying it in lower doses in a second line setting. But while this strategy might save Capesaris from being scrapped, it will position the product in what is becoming an increasingly crowded market with much higher bars to prove efficacy and gain approval.

Speaking yesterday on a conference call Mitchell Steiner, chief executive of GTx, said he believed there was a clear path forward for Capesaris in metastatic castration resistant prostate cancer (mCRPC). “I do not believe this is a ‘go back to the drawing board’. I do believe this is a possible path forward - for second line we can lower the dose,” he said. The market, however, took a more pessimistic view, sending the group's shares down 36% to $3.69; the stock was trading lower again at $3.55 in early trade today.

The clotting factor

What tripped up Capesaris, an androgen deprivation therapy (ADT), were the high rates of clots seen in patients given induction doses of the drug at both the 1000mg and 1500mg level, and also in a maintenance trial pitching the drug against market leader Lupron. While clots are a recognised side effect of oestrogen therapies, the incidence seen the Capesaris trial and the severity, enough to hospitalise patients, were responsible for the hold.

As part of the treatment sufficient amounts of the drug are initially given to induce chemical castration of prostate cancer sufferers to reduce production of testosterone, which is responsible for speeding up disease progression. Then patients are maintained on the drug to keep hormone levels at near zero.

The clinical hold has stopped the group’s phase II loading dose finding trial, its phase II maintenance dosing trial with Lupron and a second line trial in mCRPC. Interestingly, although the drug was being studied at 2000mg in the second line setting there were no reports of clots, or VTEs.

New hope

Prior to the clinical hold there had been high hopes for Capesaris. The drug, an oestrogen receptor alpha agonist, had appeared to avoid the problems associated with many androgen deprivation therapies, such as hot flashes and changes in body appearance. This had been down to it binding to only one oestrogen receptor, making it more targeted than other ADTs, inclidng Abbott Laboratories’ Lupron.

More importantly it had not shown any changes in insulin resistance or increases in hepatic enzymes and had demonstrated a reduction in bone turnover markers, indicating that unlike other therapies men taking the drug might not be at risk of developing osteoporosis.

Forecasts for sales had reached $108m by 2016, with the assumption of a 2013 launch, these figures are almost certain to be completely removed until the future of the drug becomes clearer.

Side effects

It is this relatively benign side effect profile and the fact that the drug appeared not to throw up any VTEs in the second line setting that is keeping GTx stoking the fires of hope with Capesaris.

Speaking yesterday Mr Steiner said possible solutions to get the drug to perform in mCRPC could include inducing castration by another method ie the use of Lupron and then using Capaseris at a much lower 500mg dose.

If this will work is questionable, the drug has not been tested in prostate cancer patients in a maintenance setting at this dose and it is still unclear if long term use of the drug, even at lower levels, could lead to VTEs.

These questions aside, even if Capesaris does eventually prove to be an effective treatment in a second line setting, not only will it face competition from newer drugs, approval will be harder won. The FDA is increasingly looking for an overall survival benefit in cancers where there are a lot of options, a much higher bar than progression free survival that the group could have pursued in a front line setting.

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