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.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

FDA warns Proc­ter & Gam­ble over NyQuil la­bel's in­gre­di­ent list­ings

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.

The warning says that for P&G’s over-the-counter Vicks Nyquil Severe Hot Remedy Cold and Flu Plus Congestion, there’s a “mismatched” list of active ingredients between the labeling and the electronic listing file. The listing file for the active ingredients did not match the active ingredients in the electronic file.

No­vo Nordisk re­mains un­der UK scruti­ny as MHRA con­ducts its own re­view in 'in­cred­i­bly rare' case

The UK’s Medicines and Healthcare products Regulatory Agency is now reviewing Novo Nordisk’s marketing violation that resulted in its loss of UK trade group membership last week. Novo Nordisk was suspended on Thursday from the Association of the British Pharmaceutical Industry (ABPI) for two years after an investigation by its regulatory arm found the pharma broke its conduct rules.

MHRA said on Tuesday that its review of the Prescription Medicines Code of Practice Authority (PMCPA) investigation is standard practice. An MHRA spokesperson emphasized in an email to Endpoints News that the situation with Novo Nordisk is “incredibly rare” while also noting ABPI took “swift and proportionate action.”

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FDA in­di­cates will­ing­ness to ap­prove Bio­gen ALS drug de­spite failed PhI­II study

Ahead of Wednesday’s advisory committee hearing to discuss Biogen’s ALS drug tofersen, the FDA appeared open to approving the drug, newly released briefing documents show.

Citing the need for flexibility in a devastating disease like ALS, regulators signaled a willingness to consider greenlighting tofersen based on its effect on a certain protein associated with ALS despite a failed pivotal trial. The documents come after regulatory flexibility was part of the same rationale the agency expressed when approving an ALS drug last September from Amylyx Pharmaceuticals, indicating the FDA’s openness to approving new treatments for the disease.

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Andy Plump, Takeda R&D chief (Jeff Rumans for Endpoints News)

What kind of PhI­Ib da­ta is worth $4B cash? Take­da’s Andy Plump has some thoughts on that

A few months back, when Takeda caused jaws to drop with its eye-watering $4 billion cash upfront for a mid-stage TYK2 drug from Nimbus, it had already taken a deep dive on the solid Phase IIb data Nimbus had assembled from its dose-ranging study in psoriasis.

Now, it’s rolling that data out, eager to demonstrate what inspired the global biopharma to go long in a neighboring, but new, disease arena for the pipeline. And the most avid students of the numbers will likely be at Bristol Myers Squibb, who will have a multi-year head start on pioneering the TYK2 space with Sotyktu (deucravacitinib) as Takeda makes its lunge for best-in-class status.

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FTC says patent bat­tle over Parkin­son's drug could have 'sig­nif­i­cant im­pli­ca­tion­s' for pa­tients

The Federal Trade Commission has gotten involved in a patent feud over Supernus’ Parkinson’s drug Apokyn, a case the agency said may have ‘‘significant implications” for patients who rely on the drug.

Sage Chemical won the first generic approval for its Apokyn formulation (also known as apomorphine hydrochloride injection) back in 2022. The non-ergoline dopamine agonist is approved to treat Parkinson’s symptoms during “off episodes,” such as difficulty moving, tremors and intense cramping. However, regulators specified that the approval pertained to the generic drug cartridges only, not the injector pen required for administration.

Growth hor­mone from No­vo Nordisk is in short­age over man­u­fac­tur­ing de­lays

Novo Nordisk’s growth hormone Norditropin is in shortage because of manufacturing delays, according to an FDA site that tracks drug shortages as well as the American Society of Health-System Pharmacists’ shortages list.

The FDA has shortages of the drug listed for its 5, 10, 15 and 30 mg doses, while the pharmacists’ group, also known as ASHP, reported shortages of the same doses, except for the 15 mg version.

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PhRMA calls for more di­verse in­fra­struc­ture up­grades to US emer­gency tri­als frame­work

The White House’s Office of Science and Technology Policy (OSTP) last year sought to find ways to better coordinate large-scale clinical trials in the US — as the UK lead by example during the pandemic — especially for these emergency clinical trials.

The lobbying group PhRMA Tuesday called for more clinical trial diversity in underserved areas, including by making participation less of a burden, and expanding eligibility criteria when appropriate.

President Joe Biden (AP Photo/Susan Walsh)

Biden signs law re­quir­ing more de­clas­si­fi­ca­tions on Covid-19's ori­gins

President Joe Biden yesterday signed into law a bill requiring the Office of the Director of National Intelligence to declassify information on the origins of Covid-19 within 90 days.

The new law directs the federal government to “declassify any and all information relating to potential links between the Wuhan Institute of Virology and the origin of the Coronavirus Disease 2019”, including information regarding researchers at the lab who fell ill in the fall of 2019 like names, symptoms, and job roles.