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.

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer drugs; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 150,800+ biopharma pros reading Endpoints daily — and it's free.

EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

FDA's out­side ex­perts vote in fa­vor of Fer­ring's fe­cal trans­plant for C. dif­fi­cile, set­ting the stage for Seres

FDA’s outside advisors voted in favor of Ferring Pharmaceuticals’ RBX2660, an experimental poop-based drug implant that the company says would be the first microbiota-based live biotherapeutic to receive an FDA green light.

That was a point repeatedly discussed during the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, meeting Thursday when evaluating Ferring’s fecal microbiota transplant, or FMT, for reducing the recurrence of Clostridioides difficile infection in adults who have received antibiotics. Multiple members brought up the need for a regulated product amid a landscape of unregulated FMTs already happening in clinical care.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 150,800+ biopharma pros reading Endpoints daily — and it's free.

Richard Pazdur, FDA's OCE director (Flatiron Health via YouTube)

FDA's OCE makes the case for ac­cel­er­at­ed ap­proval rid­er in user fee reau­tho­riza­tion

Four experts from the FDA’s Oncology Center of Excellence took to the New England Journal of Medicine yesterday to make the case for not only improving the agency’s ability to expeditiously pull dangling accelerated approvals when, on the rare occasion, confirmatory trials fail, but also better building “quality and efficiency into the AA on-ramp.”

The timely perspective arrives as Congress has exactly one week left to draft, release and sign off on the reauthorized user fee deals before layoff notices will be sent to drug reviewers. That package, which is likely to hitch a ride with the continuing resolution, may or may not include several policy riders (opposed by Republicans), including one that would allow the FDA to require confirmatory trials to be underway before an AA is granted, and would improve the process by which FDA can withdraw AAs.

An­oth­er Cipla site lands a Form 483 over clean­ing is­sues and QC con­trols

A Cipla drug manufacturing site in India has once again landed in the crosshairs of FDA inspectors.

The facility in question is Cipla’s drug manufacturing facility in the village of Verna, in the state of Goa in India’s southwest. In a sign that foreign inspections might ramp up again, the FDA’s visit from Aug. 16 to Aug. 22 uncovered six observations.

The 11-page report noted that environmental monitoring at the site did not properly ensure that microbial contaminants were not making any impact in the aseptic filling areas. It also found that procedures meant to stop microbial contamination were not adequately conducted in aseptic areas of the facility.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 150,800+ biopharma pros reading Endpoints daily — and it's free.

FDA ad­comm takes down Se­cu­ra Bio's leukemia drug af­ter fi­nal tri­al re­sults show po­ten­tial OS detri­ment

The FDA’s Oncologic Drugs Advisory Committee on Friday voted 8-4 against the benefit-risk profile of Secura Bio’s PI3K inhibitor Copiktra (duvelisib), which won approval in September 2018 as a third-line treatment for relapsed or refractory CLL or SLL, but updated pivotal trial results raised safety questions.

In addition to the serious and fatal toxicities of duvelisib, FDA speakers at the ODAC meeting pointed to an evolved treatment landscape for CLL and SLL, with targeted BTK or BCL2 inhibitors (front-line or second-line), and data pointing to a “potential detriment” in overall survival for duvelisib. But some ODAC members noted that the detriment was likely small and that there is some efficacy even as the data are difficult to interpret.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 150,800+ biopharma pros reading Endpoints daily — and it's free.

Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.