Mark Pruzanski, Intercept CEO (GlobeNewswire via YouTube)

FDA re­jects In­ter­cept’s pitch for NASH as CEO fires back at the agency’s ‘evolv­ing’ guide­lines

In a ma­jor set­back for an al­ready ail­ing field, the FDA has re­ject­ed obeti­cholic acid, the In­ter­cept Phar­ma­ceu­ti­cals com­pound that would have been the first drug specif­i­cal­ly ap­proved to treat NASH.

The In­ter­cept drug had, in Feb­ru­ary of 2019, yield­ed the first pos­i­tive Phase III re­sults for the obe­si­ty-re­lat­ed liv­er con­di­tion and its sub­se­quent NDA sub­mis­sion was close­ly watched around the in­dus­try as the first test for how reg­u­la­tors would treat the nascent but fast-grow­ing field.

Yet con­fi­dence that an ap­proval would come had been wan­ing for months. The drug was sched­uled for an ad­vi­so­ry com­mit­tee hear­ing on April 22, but in March In­ter­cept an­nounced the meet­ing was de­layed to June 9th due to Covid-19. Then in May, In­ter­cept said that hear­ing was post­poned again to “ac­com­mo­date the re­view of ad­di­tion­al da­ta re­quest­ed by the FDA.” In­ter­cept didn’t spec­i­fy what da­ta the FDA want­ed, but shares flagged and an­a­lysts were di­vid­ed over how omi­nous the de­lay was. SVB Leerink’s Thomas Smith wrote it “in­jects ad­di­tion­al un­cer­tain­ty” on “po­ten­tial ap­proval/la­bel/tim­ing.”

Now, In­ter­cept says, the FDA re­ject­ed the drug be­cause they were un­cer­tain if the sur­ro­gate end­point from their Phase III tri­al — re­duc­tion in liv­er fi­bro­sis — would ac­tu­al­ly trans­late in­to ben­e­fit for pa­tients. The FDA in­vit­ed them to re-sub­mit with longer term da­ta from the Phase III tri­al, but In­ter­cept spoke harsh­ly against the de­ci­sion.

In a state­ment that could lay the ground­work for an ap­peal, CEO Mark Pruzan­s­ki crit­i­cized the agency for can­cel­ing the ad­vi­so­ry com­mit­tee hear­ing, said their re­view as “in­com­plete,” and ar­gued the agency re­peat­ed­ly moved the goal­posts for ap­proval in a way that could pre­vent the de­vel­op­ment of new ther­a­pies.

At no point dur­ing the re­view did the FDA com­mu­ni­cate that OCA was not ap­prov­able on an ac­cel­er­at­ed ba­sis, and we strong­ly be­lieve that the to­tal­i­ty of da­ta sub­mit­ted to date both meet the re­quire­ments of the Agency’s own guid­ance and clear­ly sup­port the pos­i­tive ben­e­fit-risk pro­file of OCA. We are dis­ap­point­ed to see the de­ter­mi­na­tion the Agency has reached based on an ap­par­ent­ly in­com­plete re­view, and with­out hav­ing pro­vid­ed med­ical ex­perts and pa­tients the op­por­tu­ni­ty to be heard at the an­tic­i­pat­ed Ad­com on the mer­its of OCA, which is a des­ig­nat­ed Break­through Ther­a­py. The FDA has pro­gres­sive­ly in­creased the com­plex­i­ty of the his­to­log­ic end­points, cre­at­ing a very high bar that on­ly OCA has so far met in a piv­otal Phase 3 study. On be­half of the he­pa­tol­ogy com­mu­ni­ty, we are very con­cerned that the Agency’s ap­par­ent­ly still evolv­ing ex­pec­ta­tions will make it ex­ceed­ing­ly chal­leng­ing to bring in­no­v­a­tive ther­a­pies to NASH pa­tients with high un­met med­ical need.

Shares of the com­pa­ny nose­dived on the news from $77 to to $48, shav­ing off over a $1 bil­lion in mar­ket cap. Pro­ject­ing In­ter­cept to trend to­ward $50, Jef­feries’ Michael Yee called the news “a sur­prise down­side sce­nario that was not ex­pect­ed and un­for­tu­nate­ly leaves in­vestors in a pro­longed pe­ri­od of chal­leng­ing un­cer­tain­ty now.”

On a con­fer­ence call Mon­day morn­ing, Pruzan­s­ki told an­a­lysts that the last he heard from the agency was that they would get back to In­ter­cept about resched­ul­ing an ad­vi­so­ry hear­ing. Then on the PDU­FA date of June 26, they re­ceived a let­ter that an im­prove­ment in fi­bro­sis — which, In­ter­cept said, the FDA had in­di­cat­ed would be enough for ap­proval — wasn’t enough to prove the drug was worth its risk.

“What’s new here is the ques­tion­ing — with­out re­al­ly sub­stan­ti­a­tion, as far as we could tell — on the ben­e­fit side,” Pruzan­s­ki said. “It’s hard to know what’s go­ing on.”

Al­though mixed in their re­ac­tions to the news, an­a­lysts ex­pressed ex­pressed broad sur­prise the FDA and In­ter­cept would be on such marked­ly dif­fer­ent pages, giv­en that the drug had achieved a break­through des­ig­na­tion that is sup­posed to open close chan­nels be­tween the par­ties. The frac­ture, they said, could be spe­cif­ic to In­ter­cept, but could al­so point to where the bar will be for fu­ture NASH sub­mis­sions.

“It is un­clear at this point how sig­nif­i­cant­ly the CRL af­fects OCA’s reg­u­la­to­ry path for­ward in NASH,” Smith wrote in a note fol­low­ing the news, “nor are the broad­er im­pli­ca­tions on the reg­u­la­to­ry path­way for oth­er drugs be­ing de­vel­oped in NASH clear at this time.”

The re­jec­tion is the lat­est in a se­ries of strug­gles for the NASH field. NASH, or non­al­co­holic steato­hep­ati­tis, refers to fat buildup in the liv­er that caus­es in­flam­ma­tion and scar­ring. It was lit­tle known in the biotech world be­fore the 2014 JP Mor­gan con­fer­ence, when In­ter­cept re­leased a batch of Phase II da­ta that sent their stock soar­ing. With mil­lions of Amer­i­cans po­ten­tial­ly suf­fer­ing from the con­di­tion, the dis­ease has since at­tract­ed sig­nif­i­cant buzz, but in the past year, it’s seen a string of tri­al fail­ures, most no­tably from Gilead.

Al­though nu­mer­ous drug­mak­ers have ear­ly-stage can­di­dates in the pipeline, the In­ter­cept CRL could push the first ap­proval back sig­nif­i­cant­ly. The oth­er ma­jor late-stage ef­fort, from the French biotech Gen­Fit, failed in May.

Al­though it’s im­pos­si­ble to know the pre­cise guid­ance the FDA gave In­ter­cept and oth­er com­pa­nies, sig­nif­i­cant ques­tions did ex­ist for the ef­fi­ca­cy of their drug and oth­er NASH com­pounds. Com­pa­nies have large­ly fo­cused on test­ing to see if their med­i­cines can halt fi­bro­sis or fat ac­cu­mu­la­tion, but they have not yet proven that those will then lead to im­proved sur­vival or pre­vent cir­rho­sis.

In a note, Stifel’s Derek Archi­la ar­gued the CRL was a re­sult of a sin­gle ad­verse event: raised LDL cho­les­terol, which in turn raised car­dio­vas­cu­lar risk. That, he said, could’ve tipped the risk-ben­e­fit pro­file cal­cu­lus for the agency.

An­a­lysts will be watch­ing close­ly to see what da­ta the FDA asks for and its im­pli­ca­tions for all NASH de­vel­op­ers, but there will be im­me­di­ate im­pli­ca­tions for In­ter­cept. The com­pa­ny hired a sales team in prepa­ra­tion for an ap­proval and, Yee not­ed, is cur­rent­ly burn­ing through $300 mil­lion per year, with on­ly $554 mil­lion and $690 mil­lion in debt.

“As we pre­pare to meet with FDA, we will si­mul­ta­ne­ous­ly be­gin plan­ning to make sure we’re in a good po­si­tion fi­nan­cial­ly,” Pruzan­s­ki said on the call.

Scoop: Boehringer qui­et­ly shut­ters a PhII for one of its top drugs — now un­der re­view

Boehringer Ingelheim has quietly shut down a small Phase II study for one of its lead drugs.

The private pharma player confirmed to Endpoints News that it had shuttered a study testing spesolimab as a therapy for Crohn’s patients suffering from bowel obstructions.

A spokesperson for the company tells Endpoints:

Taking into consideration the current therapeutic landscape and ongoing clinical development programs, Boehringer Ingelheim decided to discontinue our program in Crohn’s disease. It is important to note that this decision is not based on any safety findings in the clinical trials.

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Vas Narasimhan (Photographer: Jason Alden/Bloomberg via Getty Images)

No­var­tis de­tails plans to axe 8,000 staffers as Narasimhan be­gins sec­ond phase of a glob­al re­org

We now know the number of jobs coming under the axe at Novartis, and it isn’t small.

The pharma giant is confirming a report from Swiss newspaper Tages-Anzeiger that it is chopping 8,000 jobs out of its 108,000 global staffers. A large segment will hit right at company headquarters in Basel, as CEO Vas Narasimhan axes some 1,400 of a little more than 11,000  jobs in Switzerland.

The first phase of the work is almost done, the company says in a statement to Endpoints News. Now it’s on to phase two. In the statement, Novartis says:

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Lina Gugucheva, NewAmsterdam Pharma CBO

Phar­ma group bets up to $1B-plus on the PhI­II res­ur­rec­tion of a once dead-and-buried LDL drug

Close to 5 years after then-Amgen R&D chief Sean Harper tamped the last spade of dirt on the last broadly focused CETP cholesterol drug — burying their $300 million upfront and the few remaining hopes for the class with it — the therapy has been fully resurrected. And today, the NewAmsterdam Pharma crew that did the Lazarus treatment on obicetrapib is taking another big step on the comeback trail with a €1 billion-plus regional licensing deal, complete with close to $150 million in upfront cash.

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How pre­pared is bio­phar­ma for the cy­ber dooms­day?

One of the largest cyberattacks in history happened on a Friday, Eric Perakslis distinctly remembers.

Perakslis, who was head of Takeda’s R&D Data Sciences Institute and visiting faculty at Harvard Medical School at the time, had spent that morning completing a review on cybersecurity for the British Medical Journal. Moments after he turned it in, he heard back from the editor: “Have you heard what’s going on right now?”

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Aurobindo Pharma co-founders P. V. Ram Prasad Reddy (L) and K. Nityananda Reddy

Au­robindo Phar­ma re­ceives warn­ing let­ter from In­di­a's SEC fol­low­ing more FDA ques­tion marks

Indian-based generics manufacturer Aurobindo Pharma has been in the crosshairs of the FDA for several years now, but the company is also attracting attention from regulators within the subcontinent.

According to the Indian business news site Business Standard, a warning letter was sent to the company from the Securities Exchange Board of India, or SEBI.

The letter is related to disclosures made by the company on an ongoing FDA audit of the company’s Unit-1 API facility in Hyderabad, India as well as observations made by the US regulator between 2019 and 2022.

Ankit Mahadevia, Spero CEO

Spero’s UTI can­di­date gets the CRL ham­mer as the com­pa­ny falls in­to pen­ny stock sta­tus

Spero Therapeutics has been struggling in the past few years, dealing with FDA holds and staff reductions amidst a rough biotech market, and the latest news from the Massachusetts-based company confirms what it anticipated in May: a CRL.

The company was slapped with the no-go for its NDA, the biotech disclosed Monday. The company was seeking approval for tebipenem HBr oral tablets, intended for the treatment of adult patients with complicated urinary tract infection, or cUTI, including pyelonephritis. The FDA had set a PDUFA date of June 27.

Scoop: Roche scraps one of two schiz­o­phre­nia PhII tri­als af­ter fail­ing the pri­ma­ry end­point

Roche has terminated one of two Phase II trials testing its drug ralmitaront in patients with schizophrenia, the Big Pharma confirmed to Endpoints News.

The study was terminated last month, according to a June 22 update to the registry on clinicaltrials.gov. Begun in September 2020, the trial was looking at ralmitaront in patients with acute schizophrenia. The trial enrolled 286 patients out of an originally planned 308.

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(AP Photo/Gemunu Amarasinghe)

Some phar­ma com­pa­nies promise to cov­er abor­tion-re­lat­ed trav­el costs — while oth­ers won't go that far yet

As the US Department of Health and Human Services promises to support the millions of women who would now need to cross state lines to receive a legal abortion, a handful of pharma companies have said they will pick up employees’ travel expenses.

GSK, Sanofi, Johnson & Johnson, BeiGene, Alnylam and Gilead have all committed to covering abortion-related travel expenses just four days after the Supreme Court overturned Roe v. Wade and revoked women’s constitutional right to an abortion.

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Herriot Tabuteau, Axsome CEO (Owen Hoffmann/Patrick McMullan via Getty Images)

Ax­some's long de­layed de­pres­sion drug is back up for la­bel dis­cus­sions at the FDA, trig­ger­ing a big spike in the share price

Axsome’s on-and-off quest to obtain an FDA approval for their depression drug AXS-05 is back on again.

After the markets closed on Monday, the biotech issued a short, simple alert in an SEC filing saying the team had “received from the U.S. Food and Drug Administration (the “FDA”) proposed labeling for the Company’s AXS-05 product candidate with respect to its New Drug Application (the “NDA”) for AXS-05 for the treatment of major depressive disorder. The Company is reviewing the proposed labeling and will reply to the FDA to secure final labeling agreement.”