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.

The FDA on Tuesday released a warning letter sent earlier this month to the Mason, OH-based site of Procter & Gamble Manufactura, raising questions about the list of ingredients on the label and in the electronic filing.

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