The sector will not know for a couple of months whether potency of the new cholesterol-lowering agents Praluent and Repatha will translate into improved survival for heart disease patients. Sanofi (NYSE:SNY) and Regeneron’s (NASDAQ:REGN) announcement today that Praluent’s Odyssey Outcomes trial will not be stopped early because of persuasive evidence of efficacy shifts the spotlight to a final analysis of Repatha’s Fourier trial, now approaching in early 2017.
Specialists are looking for a 20% reduction in the risk of cardiovascular deaths and hospitalization to widen their use of these new agents, a benefit both of these trials could demonstrate. However, meeting that 20% bar was necessary for Odyssey Outcomes to be stopped early, so the fact that it continues ought to heighten the suspense over the approaching readout of Fourier.
Even before their launches last year, Praluent and Repatha, which reduce low-density lipoprotein cholesterol through the PCSK9 pathway, were controversial because of their cost and the well-documented underuse of statins (Payer demands threaten rosy PCSK9 forecasts, September 11, 2014). They have underperformed bullish pre-launch forecasts because of tight insurer controls that have included value-based contracting.
Thus the outcomes trials are essential to persuading payers that the two products are worth their $14,000-a-year list prices. With the Praluent trial’s continuation to final analysis, the next sign of whether the PCSK9 class will meet high expectations – or, conversely, need to have its prices slashed even more to satisfy payer demands – will come with Fourier’s results.
The 20% bar
The Fourier trial randomized 27,564 cardiovascular disease patients with elevated LDL cholesterol at high risk of a recurrent event to receive either Repatha or placebo on top of their regular effective statin dose. The primary endpoint is time to cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina.
It will proceed to final analysis when 1,630 events have occurred, which the investigators estimate will provide 90% power to detect a relative reduction of 15% or more in the risk of cardiovascular events.
In the Odyssey Outcomes interim analysis that has just been announced, for termination on positive efficacy Praluent would have needed to have achieved a 20% relative risk reduction after 75% of the necessary 1,613 events.
Thus, one conclusion from the decision is that the trial has not shown the necessary 0.802 hazard ratio at a highly statistically significant p value, although ISI Evercore analyst John Scotti wrote today that other conclusions might be that the stopping criteria were met but the data-monitoring committee wanted the trial to continue to see conclusive evidence on secondary endpoints.
In an analysis of the two outcomes trials published last year, Leerink analysts estimated that the 20% threshold could have been met if the average drop in LDL-C was greater than 35mg/dl, from a baseline 90mg/dl, a scenario that they described as “realistic". Regeneron shares fell 3% in early trading today after the news.
The final countdown
The Fourier trial of Repatha had no interim analysis, so the first look at the data will come with the final readout. This was originally expected by the end of 2016, although it has been set back to early 2017.
Giving comfort to the Repatha bulls this week has been the release of data from the Glagov trial, which analyzed plaque regression through the use of intravascular ultrasound. This detected a 5.8 cubic millimetre reduction in atheroma volume for patients taking Repatha plus statins, a statistically significant difference from patients taking only statins, which saw a shrinkage of 0.9 cubic millimetres.
Of the patients in the Repatha arm, 12.2% suffered a cardiovascular event, compared with 15.3% in the statins-only arm, although in a trial of fewer than 1,000 patients the statistical power to detect a difference in outcomes is more limited.
However, this plus findings from earlier, smaller phase III trials like Osler 1 and 2, which found around a 50% reduction in the risk of cardiovascular events, has given the Leerink analysts the belief that it will succeed.
Achieving the 20% reduction in risk of death or cardiovascular hospitalization is the open question. This was a level above which specialists surveyed by Leerink believed to represent a clinically relevant improvement, on a par with the reduction seen in trials of Lipitor.
A foreboding note is that Leerink did not believe that Praluent would be able to get to the 20% threshold in its final analysis if Odyssey Outcomes was not stopped early. If true, this means Amgen (NASDAQ:AMGN) has it all to play for with Fourier.