AHA 2021 – Phasebio takes a step towards reversal agent filing
But questions remain around bentracimab’s data package.
Astrazeneca’s Brilinta might not have become as big a drug as the company had once hoped, but Phasebio believes that stopping the blood thinner’s effects could still provide a lucrative business. With interim phase 3 data now in hand, the company plans to file for accelerated approval of its reversal agent bentracimab next year.
Results from the pivotal uncontrolled Reverse-It study, reported yesterday at the American Heart Association meeting, suggest that bentracimab is doing what it is supposed to, reversing Brilinta’s effects and stopping bleeding. However, questions raised during the presentation clearly spooked investors, with Phasebio’s stock closing down 18%.
Many of these issues had already been known before the Reverse-It data, so the magnitude of the selloff is puzzling. Chief among the questions is whether bentracimab can get the go-ahead in both of Phasebio’s intended indications, patients requiring surgery and those with a major bleed.
This is because Reverse-It has, so far, mainly recruited the former, even though the FDA had asked for an even split between the two populations.
Another issue raised by the AHA discussant, Professor Gilles Montalescot of the Pitié-Salpêtrière Hospital in Paris, centred around Reverse-It's design. The study was uncontrolled for ethical reasons, but he questioned whether it would have truly been unethical to include a placebo cohort, given that no reversal agent for Brilinta is currently approved. However, presumably this design has been agreed with the FDA.
More worrying were Professor Montalescot’s comments about thrombotic events. There were eight such events in Reverse-It, but all were deemed unrelated to bentracimab. But he noted that four of these occurred immediately after bentracimab was given, with no alternative explanation, and questioned whether this might represent a toxicity signal.
Still, these are sick patients at risk of thrombotic events, which is why they are receiving Brilinta in the first place. Stifel analysts suggested that the thrombotic events could in fact be a result of the reversal of the blood thinner’s effects.
Aside from these questions, bentracimab looked safe, with no serious drug-related adverse events or infusion-related reactions.
And Reverse-It met its two co-primary endpoints: firstly it reversed Brilinta’s anti-platelet effects, as measured by the VerifyNow PRUTest platelet function assay, among the 129 patients eligible for this analysis. The reduction in platelet inhibition was seen within minutes of infusion, and was maintained for 24 hours.
The second co-primary was achievement of haemostasis; to meet this, bleeding had to be defined as mild or moderate based on the Gusto clinical bleeding scale. Of 122 patients available for this analysis 98% achieved this target. Phasebio had hoped to exceed a 50% response here.
However, the bleeding results were less convincing in patients presenting with major bleeds versus those needing surgery: all the surgery patients achieved haemostasis, while only seven of nine in the major bleed group did so; however, the small number of patients involved in the latter cohort make the data here hard to interpret.
The question now is whether these data will convince the FDA of bentracimab’s benefits in those with bleeds. Stifel noted that surgical patients were a “slightly healthier and more controlled population overall”.
However, Dr Deepak Bhatt of the Brigham and Women’s Hospital, presenting the data at AHA, contended that surgery was nevertheless a good model of bleeding.
Phasebio is now focused on enrolling patients into the bleeding cohort, but the lack of balance will likely come up during bentracimab’s review.