Pair of Lancet stud­ies give fi­nal word on a promis­ing Sh­iono­gi an­tibi­ot­ic that turned out to be 'as good' as the oth­er 'sub­op­ti­mal' op­tions

Last Oc­to­ber, the FDA OK’d a se­mi-con­tro­ver­sial new an­tibi­ot­ic from Sh­iono­gi.

In one of two large stud­ies for the drug, known chem­i­cal­ly as ce­fide­ro­col and com­mer­cial­ly as Fetro­ja, more pa­tients died in the treat­ment arm than the con­trol arm. But it had al­ready cleared an­oth­er ran­dom­ized con­trolled tri­al and the agency de­ter­mined the ben­e­fits at a time of grow­ing drug re­sis­tance out­weighed the risk.

Now, a year and an ex­pand­ed ap­proval lat­er, Sh­iono­gi has pub­lished the full re­sults from both of those stud­ies in a sin­gle is­sue of The Lancet In­fec­tious Dis­ease. And while the pa­pers don’t pro­vide any rad­i­cal­ly new in­for­ma­tion, they give a fi­nal, tem­pered note on the ben­e­fits of a drug that was de­vel­oped for its new and promis­ing ap­proach to re­sis­tant bac­te­ria, but whose late-stage tri­als left as many ques­tions and an­swers.

Prani­ta Tam­ma

“The best in­ter­pre­ta­tion of ce­fide­ro­col that can be gleaned from these stud­ies is that it is as good as com­para­tor agents that are frankly sub­op­ti­mal,” Uni­ver­si­ty of Mary­land School of Med­i­cine pro­fes­sor Emi­ly Heil and Johns Hop­kins pe­di­atrics pro­fes­sor Prani­ta Tam­ma wrote in a con­cur­rent re­view.

The re­sults “have ad­mit­ted­ly tem­pered some of our ini­tial en­thu­si­asm for ce­fide­ro­col, and more da­ta are need­ed to con­fi­dent­ly de­fine its role in the treat­ment of drug-re­sis­tant in­fec­tions,” they added.

Heil and Tam­ma ti­tled the re­view “Ce­fide­ro­col: the Tro­jan horse has ar­rived but will Troy fall?” Fetro­ja earned the Gre­cian moniker be­cause it en­tered bac­te­ria through the iron trans­port path­way they re­ly on to sur­vive, of­fer­ing a gate­way through the cell wall that helps gram-neg­a­tive bac­te­ria avoid an­tibi­otics and cir­cum­vent­ing sev­er­al of the key meth­ods they use to evolve drug re­sis­tance. Un­like oth­er ex­per­i­men­tal an­tibi­otics, it al­so was ac­tive against a va­ri­ety of bac­te­ria as op­posed to any sin­gle one.

Sure enough, in one of the Phase III stud­ies, called APEKS-NP,  Fetro­ja proved just as good at treat­ing pa­tients with hos­pi­tal-ac­quired pneu­mo­nia as pa­tients who re­ceived the an­tibi­ot­ic meropen­em. The dif­fer­ence in deaths — from any cause — at 14 days was 0.8%, far more than close enough to meet the pri­ma­ry end­point of non-in­fe­ri­or­i­ty. Heil and Tam­ma not­ed that 70% of pa­tients were in se­vere con­di­tion, and they com­mend­ed Sh­iono­gi for us­ing meropen­em, which they deemed a bet­ter com­para­tor than what oth­er com­pa­nies had used.

In the sec­ond study, though, known as CRED­I­BLE-CR, pa­tients with drug-re­sis­tant bac­te­ria were ran­dom­ly as­signed to re­ceive Fetro­ja or the best avail­able ther­a­py. Of these pa­tients, 45% had hos­pi­tal-ac­quired pneu­mo­nia and 31% had blood-stream in­fec­tion.

The re­sults met the pri­ma­ry end­point, a physi­cian-as­sessed met­ric known as “clin­i­cal cure,” for both types of in­fec­tion.

Emi­ly Heil

Yet, on mor­tal­i­ty, the da­ta were far worse for pneu­mo­nia and blood-stream in­fec­tion than for uri­nary tract in­fec­tions. A quar­ter of pneu­mo­nia pa­tients died by day 14 on the treat­ment, com­pared with 11% on the con­trol arm. For blood­stream in­fec­tions, those fig­ures were 22% vs 11%.  For com­pli­cat­ed UTIs, though, the fig­ures were re­versed: 12% mor­tal­i­ty in the treat­ment arm, 42% in the con­trol arm.

Those high mor­tal­i­ty rates were pri­mar­i­ly dri­ven by one strain of bac­te­ria, called Acine­to­bac­ter bau­man­nii. Sh­iono­gi at­trib­uted the mor­tal­i­ty rates in those pa­tients to pre-ex­ist­ing risk fac­tors, echo­ing in­ves­ti­ga­tors who not­ed lit­tle dif­fer­ence in that bac­te­ria in the APEKS study. The re­view­ers ar­gued, though, that APEKS didn’t have enough A bau­man­nii pa­tients to draw a con­clu­sion.

The mor­tal­i­ty could mean Fetro­ja might just be a bad op­tion for that bac­te­ria, the re­view­ers wrote, but it could al­so mean that Fetro­ja just isn’t much bet­ter than the al­ter­na­tives.

“It adds cre­dence to the idea that ce­fide­ro­col is as good as, but no bet­ter than, oth­er drugs for most car­bapen­em-re­sis­tant or­gan­isms,” they said.

Go­ing for­ward, Heil and Tam­ma rec­om­mend­ed Fetro­ja for com­pli­cat­ed UTIs and as a “sal­vage op­tion” for pa­tients with most oth­er gram-neg­a­tive, drug-re­sis­tant in­fec­tions. They added it was still un­clear how ef­fec­tive­ly bac­te­ria will learn to re­sist the new drug.

“Ce­fide­ro­col will be a valu­able sol­dier in bat­tles against gram-neg­a­tive re­sis­tance,” they wrote, “but it prob­a­bly will not win the war.”

Michel Vounatsos, Biogen CEO (via YouTube)

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Biogen has flagged a pair of setbacks in the pipeline, spotlighting the final failure for a one-time top MS prospect while scrapping a gene therapy for SMA after the IND was put on hold due to toxicity.

Both failures will raise the stakes even higher on aducanumab, the Alzheimer’s drug that Biogen is betting the ranch on, determined to pursue an FDA OK despite significant skepticism they can make it with mixed results and a reliance on post hoc data mining. And the failures are being reported as Biogen was forced to cut its profit forecast for 2020 as a generic rival started to erode their big franchise drug.

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Stephen Hahn, FDA commissioner (AP Images)

As FDA sets the stage for the first Covid-19 vac­cine EUAs, some big play­ers are ask­ing for a tweak of the guide­lines

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All of this has already been spelled out to the developers. But the devil is in the details, and it’s clear from the first round of posted responses that some of the top players — including J&J and Pfizer — would like some adjustments and added feedback. And on Thursday, the experts can offer their own thoughts on shaping the first OKs.

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A new chap­ter in the de­cen­tral­ized clin­i­cal tri­al ap­proach

Despite the promised decentralized trial revolution, we haven’t yet moved the needle in a significant way, although we are seeing far bolder commitments to this as we continue to experience the pandemic restrictions for some time to come. The vision of grandeur is one thing, but operationalizing and execution are another and recognising that change, particularly mid-flight on studies, is worthy of thorough evaluation and consideration in order to achieve success. Here we will discuss one of the critical building blocks of a Decentralized and Remote Trial strategy: TeleConsent; more than paper under glass, it is a paradigm change and key digital enabler.

Pfizer CEO Albert Bourla (Drew Angerer/Getty Images)

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CRISPR Ther­a­peu­tics gets a snap­shot of off-the-shelf CAR-T suc­cess in B-cell ma­lig­nan­cies — marred by the death of a pa­tient

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Using their gene editing tech, researchers for CRISPR engineered cells from healthy donors into an attack vehicle aimed at cancer, something that has been achieved with great success using patients’ own cells — the autologous approach. But autologous CAR-T is hampered by the more complex vein-to-vein requirement that delays treatment, and now CRISPR Therapeutics along with other players like Allogene are determined to replace the pioneers with CAR-T 2.0.

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Un­fazed by PhII miss, Roche ush­ers Prothena's Parkin­son's drug in­to late-stage tri­al — a $60M move

Prothena’s prasinezumab may not have met the primary endpoint in Phase II, but its partners at Roche are seeing enough to move it into a late-stage trial for Parkinson’s disease.

The Phase IIb will build on the Phase II PASADENA study, adding a subgroup of early Parkinson’s patients on stable levodopa therapy to the population.

It’s a significant milestone for a $600 million deal that dates back to 2013, as dosing of the first patient — expected next year — will trigger a $60 million milestone payment to Prothena.

RBC's Bri­an Abra­hams holds a mock ad­comm on Bio­gen's iffy ad­u­canum­ab da­ta — and most of these ex­perts don't see a path to an ap­proval

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With its big franchise under assault, Biogen is betting the ranch that its mixed late-stage Alzheimer’s data can squeak past the experts and regulators and get onto the market. And the topic — after a decade of Alzheimer’s R&D disasters in what still represents the El Dorado of drug markets — remains in the center ring of discussions around late-stage pipeline prospects.

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CEO Grace Colón (InCarda)

Look­ing to re­pur­pose an old drug to treat ir­reg­u­lar heart­beats, In­Car­da rais­es $30M in first Se­ries C close

A little less than two years after completing its $42 million Series B round, InCarda has returned to the venture well.

The San Francisco-based biotech announced the first portion of its Series C on Wednesday, pulling in $30 million in new funding. Most of the money will give enough runway for InCarda’s InRhythm program, an inhaled therapeutic aiming to treat sudden episodes of irregular heartbeats, through its Phase II trials and prepare it for Phase III.

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Abbott Laboratories, one of the companies at the forefront of Covid-19 testing, is seeing big windfalls as a result of the pandemic.

The company reported its third-quarter results Wednesday morning, noting that overall profit went up 26.9% over the same period in 2019 as well as 28.2% in the first nine months of 2020 compared to that timeframe last year. Abbott’s Covid-19 tests drove the profits after seeing strong demand and helped the company beat quarterly estimates.

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