Cyclacel’s long-suffering shareholders will shortly see the outcome of its seemingly endless, so-called Seamless trial of sapacitabine in elderly patients with newly diagnosed acute myeloid leukaemia, after the study finally reached the number of events needed for its primary analysis.
Investors have very low expectations for the study, and with good reason. Seamless failed its interim futility analysis in December 2014, and has continued only because the data review board took the unusual step of requiring Cyclacel to keep monitoring patients until the pre-specified 424 deaths for the final analysis had occurred. These events have now taken place, and the data will show whether a late-onset survival difference has emerged.
Seamless is testing whether alternating cycles of sapacitabine and decitabine confer survival advantage over continuous cycles of decitabine. Currently decitabine has to be given by continuous IV infusion over one hour, each day, for the first five days of each 28-day cycle. Cyclacel also believes that substituting an oral drug, sapacitabine, for alternate cycles of decitabine might offer some convenience or cost advantages.
The study is powered to show a ≥27.5% reduction in risk of death, on the assumption that there is a two-month survival improvement (eight versus six months), a hurdle that now seems very high.
The group says Seamless can show superiority, equivalence or inferiority. It is not clear whether it is also powered statistically to show non-inferiority, or if “equivalence” is the situation where the study renders a hazard ratio close to 1.0.
The trial started in 2011, and enrolled 486 patients with newly diagnosed AML who were either not candidates for or had refused induction chemotherapy. Patients were originally randomised to one of three arms: sapacitabine, sapacitabine and decitabine in alternating cycles, and decitabine alone. In 2012 the sapacitabine alone arm was dropped on futility grounds.
Cyclacel argues that the December 2014 interim analysis had primarily been driven by deaths that occurred within the first six months of treatment – which accounted for 70% of the 247 deaths examined – and that survival curves beyond this point were poorly estimated.
It is therefore theoretically possible, though highly unlikely, that with longer follow-up a treatment effect beyond six months will be observed.
A poor run
With a market cap of under $20m Cyclacel comprehensively fails the infamous Feuerstein-Ratain rule for predicting success, but this has not stopped a few investors speculating on a positive outcome. Historically, however, the stock’s run has not been good.
Indeed, Cyclacel must hold some sort of biotech record, with a share price fall of 99.73%, adjusted for reverse splits, since its 2004 IPO. To arrest this slide it will need some sort of positive showing in Seamless.