After a tortuous development process Pacira managed to secure US approval for Exparel in postsurgical anaesthesia in 2011, but an important extension – use of the drug as a nerve block – was hit by a complete response letter three years later. Based on yesterday’s study data the group’s pain with the broader use could continue.
Only one of the two pivotal trials needed for a resubmission has worked, with Pacira pointing the finger of blame at a high-recruiting hospital that apparently breached a protocol. The markets seemed unconvinced yesterday, sending the group’s stock down 12% after a strong run-up into the trials’ readout this year.
The stock decline came despite the group’s chief executive, Dave Stack, insisting on an analyst call that “We believe we now have the necessary data to satisfy the FDA questions and resubmit our supplemental NDA. We have every expectation that this is approvable.”
One for two
Based on yesterday’s announcement, the new data package comprises two phase III studies using Exparel as a nerve block – a successful trial in upper extremities, and a failed one in lower extremities.
These had been initiated after the US FDA’s complete response to Pacira’s initial nerve block extension filing in 2014. While this was based on a successful trial in femoral nerve blockade, the agency demanded further evidence – specifically in upper extremities and with longer patient follow-up.
On the former requirement Pacira seems to be on safe ground, with Exparel 133mg safely beating placebo on the primary endpoint, cumulative pain scores over 48 hours, and key secondary measures. But the problem arises with the second trial, in lower extremities, which presumably is needed to fulfil the longer follow-up requirement.
Pacira said Exparel failed to hit the primary endpoint – cumulative pain score at 72 hours – because at one hospital the protocol study was breached, resulting in an unspecified number of the 232 subjects not having bupivacaine additionally administered into the knee’s posterior capsule before surgery, apparently because a couple of surgeons did not understand the protocol.
Pacira insists that if these non-protocol patients are excluded this second study yields a positive results – though only for the higher 233mg Exparel dose. Mr Stack remained untroubled, saying the 133mg dose's failure in this setting was “no surprise”, given that it would have allowed half the duration of pain relief of the larger dose.
|Upper extremity||Shoulder surgery, 156 pts, 48hr pain score endpoint met||NCT02713230|
|Lower extremity||Total knee arthroplasty, 232 pts, 72hr pain score endpoint missed||NCT02713178|
Pacira says it will submit a supplemental NDA for the nerve block indication in the near future, expecting a six-month review. This represents an important new indication for Exparel, extending its use into specific settings like anterior cruciate ligament repair, and surgeries of the rotator cuff, hand, foot and ankle.
Leerink analysts had been expecting the nerve block indication to account for around $200m of Exparel sales in 2021, a point at which the drug’s combined revenues could hit $636m, according to sellside consensus compiled by EvaluatePharma.
Pacira cites Exparel’s potential to replace peripheral nerve block catheters and infusion pumps, and says the prospect of the drug shifting US procedures from hospitals to ambulatory surgery centres could prove attractive to payers.
Will the US FDA be equally forgiving of the study failure, however? Bullish investors must now bank on the regulator’s new, industry-friendly stance.