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.

The DCT-OS: A Tech­nol­o­gy-first Op­er­at­ing Sys­tem - En­abling Clin­i­cal Tri­als

As technology-enabled clinical research becomes the new normal, an integrated decentralized clinical trial operating system can ensure quality, deliver consistency and improve the patient experience.

The increasing availability of COVID-19 vaccines has many of us looking forward to a time when everyday things return to a state of normal. Schools and teachers are returning to classrooms, offices and small businesses are reopening, and there’s a palpable sense of optimism that the often-awkward adjustments we’ve all made personally and professionally in the last year are behind us, never to return. In the world of clinical research, however, some pandemic-necessitated adjustments are proving to be more than emergency stopgap measures to ensure trial continuity — and numerous decentralized clinical trial (DCT) tools and methodologies employed within the last year are likely here to stay as part of biopharma’s new normal.

Onno van de Stolpe, Galapagos CEO (Thierry Roge/Belga Mag/AFP via Getty Images)

Gala­pa­gos chops in­to their pipeline, drop­ping core fields and re­or­ga­niz­ing R&D as the BD team hunts for some­thing 'trans­for­ma­tive'

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An­oth­er failed tri­al for Or­p­hazyme's 'pipeline-in-a-pro­duc­t' leaves shad­ow on drug's fu­ture

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Angela Merkel (AP Photo/Michael Sohn)

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Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, previously told Endpoints News that the review of the BLA should take between three and four months, but it may be even faster than that.

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Stéphane Bancel, Getty

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Ad­comm splits slight­ly in fa­vor of FDA ap­prov­ing Chemo­Cen­tryx’s rare dis­ease drug

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The vote on whether the FDA should approve the drug was preceded by a split vote of 9 to 9 on whether the efficacy data support approval, and 10 to 8 that the safety profile of avacopan is adequate enough to support approval.