Forget the binary outcome; Regado faces a bigger problem

Regado Biosciences was already on shaky ground. It was running a huge phase III study that it lacked the funds to complete and was asking investors to take a massive gamble on the biary outcome of this trial’s interim efficacy analysis, due by the end of the year.

Yesterday’s unscheduled halt to recruitment, caused by serious allergic adverse events, thus came as a bolt out of the blue. That said, the resulting 50% share price fall could present a cheap entry point since the study has not been declared a bust, though this investment strategy requires nerves of steel.

The study in question, code-named Regulate, intends to recruit 13,200 patients undergoing percutaneous coronary intervention (PCI), and compares the efficacy of Regado’s lead project, the anticoagulant REG1, head-to-head against The Medicine Company’s bivalirudin (Regado remains a huge binary bet despite share price bump, September 17, 2013).

The primary endpoint is superiority over bivalirudin, according to a composite of death, non-fatal myocardial infarction, non-fatal stroke and urgent target lesion revascularization through day three after PCI. Three interim analyses are scheduled, the third of which, after half the patients have been enrolled, was until now seen as crunch time since it would look at efficacy.

However, the data safety monitoring board review just initiated was unscheduled, and came about because of what Regado said were serious adverse events related to allergic reactions. The result of this review will be revealed within eight weeks, and in the meantime enrolment of new patients into Regulate has been halted.

This halt occurred with 3,234 patients recruited – only 66 patients short of the 25% enrolment target to trigger the second planned interim review, to recommend continuing or discontinuing Regulate on the basis of safety. Allergic events were clearly expected, as they feature as one of the safety endpoints that interim analyses were to look at.

Blind faith

Curiously, while Regulate is an open-label trial the result is blinded, and the blinding will remain in place during the monitoring board review. As such nothing will be known about how the allergic events relate to REG1 until a central review assesses which patients in which of the two arms had suffered them.

This type of study design is known as PROBE, standing for prospective randomised open, blinded endpoint. In PROBE trials the results are evaluated by a blinded endpoint committee, maintaining a level of robustness while affording greater similarity to standard clinical practice and a lower study cost.

The cost consideration is particularly applicable in Regado’s case; with an enrolment target of 13,200 patients Regulate is a huge undertaking for a small biotech like Regado, and even with the PROBE design is likely to set the group back some $150m.

The group’s $47m IPO last year came up well short of expectations; Regado was asking investors not only to place a bet on the binary outcome of an interim analysis but also to be prepared to provide additional funding later to complete Regulate, so it is hardly surprising that demand for the float was tepid.

Beginning a clinical trial without having the funds in place to complete it is ethically questionable, but the safety setback brings up the possibility of Regado not even getting as far as having to ask investors for the extra cash.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobEPVantage on Twitter

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