UPDATED: A snakebit biotech receives second CRL for reformulated pain med, potentially putting the kibosh on its chances
Fortress Biotech’s small cap company Avenue Therapeutics has run into another roadblock at the FDA, and this time it may prove to be a TKO.
Avenue received its second CRL for an IV formulation of the drug tramadol to treat post-operative pain, the biotech announced Monday morning, following an initial rejection last October. The thumbs down was due to the FDA finding the “delayed and unpredictable onset” of pain reduction from tramadol didn’t suggest a benefit as a monotherapy, and there’s not enough information to know whether it works in combination with other therapies, Avenue said.
The biotech disagrees with the FDA’s interpretation of the data and will continue pursuing approval, it added. Per the release, regulators found no manufacturing issues in Avenue’s application.
October’s CRL sent Avenue shares plummeting roughly 60%, and the biotech fared similarly on Monday. Investors turned their noses up at the news, with Avenue $ATXI down about 46% to about $2.28 per share as the market opened. The biotech’s stock reached as high as $12 last August.
Avenue didn’t offer any further information beyond its brief press release. It’s not yet clear when Avenue will resubmit its application, if the biotech will pursue an approval as a combination therapy or if further studies will be required to do so. Endpoints News has reached out for comment.
David Juurlink, a professor at the University of Toronto and outspoken critic of tramadol, said news of Avenue’s CRL was not surprising. By its very nature, the drug is unpredictable because it’s essentially an anti-depressant that is converted to an opioid by the liver — but only some patients with the genetic capacity to do so, he said, something that’s been known for years.
There also isn’t a consistent combination for tramadol that would work due to its “inherent irrationality,” he added. And even though Avenue could set up easy screening tests for patients with the proper genetic makeup to metabolize the drug into an opioid, this isn’t something that happens in the real world.
“If you want to give somebody an opioid, we have morphine,” Juurlink told Endpoints. “If you want to give someone anti-depressants we have tons of those. So why would you go through these pharmacokinetic acrobatics? You wouldn’t.”
The biotech has been developing IV tramadol as an alternative to opioid treatments, tweaking a European IV formulation of the drug. Tramadol has only been OKed as an oral treatment in the US, seeing use over the last quarter century. Generic tramadol pills cost roughly $1.50.
Their first pivotal study proved a success back in 2018, hitting statistical significance in improving the sum of pain intensity difference over 48 hours compared to placebo. A second study from 2019 also hit its primary for the same endpoint over 24 hours, and Avenue submitted its initial pitch at the end of that year.
But in rejecting the submission the next October, the FDA found that IV tramadol was not safe for its intended population, Avenue said at the time. Despite passing the efficacy tests, regulators noted the drug would be susceptible to the phenomenon of opioid “stacking.” In cases where patients need an extra analgesic after their first tramadol dose, opioid treatments would be the likely rescue choice, Avenue said of the FDA’s reasoning.
This was the only safety concern related to Avenue’s pitch at the time, and the biotech re-submitted its NDA in February. Avenue had included revised language for the proposed product label and report on terminal sterilization validation, but it still wasn’t enough for approval on the second go-around.
This article has been updated with comments from David Juurlink.