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.

Tar­get­ing a Po­ten­tial Vul­ner­a­bil­i­ty of Cer­tain Can­cers with DNA Dam­age Re­sponse

Every individual’s DNA is unique, and because of this, every patient responds differently to disease and treatment. It is astonishing how four tiny building blocks of our DNA – A, T, C, G – dictate our health, disease, and how we age.

The tricky thing about DNA is that it is constantly exposed to damage by sources such as ultraviolet light, certain chemicals, toxins, and even natural biochemical processes inside our cells.¹ If ignored, DNA damage will accumulate in replicating cells, giving rise to mutations that can lead to premature aging, cancer, and other diseases.

Doug Ingram (file photo)

Why not? Sarep­ta’s third Duchenne MD drug sails to ac­cel­er­at­ed ap­proval

Sarepta may be running into some trouble with its next-gen gene therapy approach to Duchenne muscular dystrophy. But when it comes to antisense oligonucleotides, the well-trodden regulatory path is still leading straight to an accelerated approval for casimersen, now christened Amondys 45.

We just have to wait until 2024 to find out if it works.

Amondys 45’s approval was unceremonious, compared to its two older siblings. There was no controversy within the FDA over approving a drug based on a biomarker rather than clinical benefit, setting up a powerful precedent that still haunts acting FDA commissioner Janet Woodcock as biotech insiders weighed her potential permanent appointment; no drama like the FDA issuing a stunning rejection only to reverse its decision and hand out an OK four months later, which got more complicated after the scathing complete response letter was published; no anxious tea leaf reading or heated arguments from drug developers and patient advocates who were tired of having corticosteroids as their loved ones’ only (sometimes expensive) option.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 102,100+ biopharma pros reading Endpoints daily — and it's free.

Fol­low biotechs go­ing pub­lic with the End­points News IPO Track­er

The Endpoints News team is continuing to track IPO filings for 2021, and we’ve designed a new tracker page for the effort.

Check it out here: Biopharma IPOs 2021 from Endpoints News

You’ll be able to find all the biotechs that have filed and priced so far this year, sortable by quarter and listed by newest first. As of the time of publishing on Feb. 25, there have already been 16 biotechs debuting on Nasdaq so far this year, with an additional four having filed their S-1 paperwork.

Ken Frazier, Merck CEO (Bess Adler/Bloomberg via Getty Images)

UP­DAT­ED: Mer­ck takes a swing at the IL-2 puz­zle­box with a $1.85B play for buzzy Pan­dion and its au­toim­mune hope­fuls

When Roger Perlmutter bid farewell to Merck late last year, the drugmaker perhaps best known now for sales giant Keytruda signaled its intent to take a swing at early-stage novelty with the appointment of discovery head Dean Li. Now, Merck is signing a decent-sized check to bring an IL-2 moonshot into the fold.

Merck will shell out roughly $1.85 billion for Pandion Pharmaceuticals, a biotech hoping to gin up regulatory T cells (Tregs) to treat a range of autoimmune disorders, the drugmaker said Thursday.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 102,100+ biopharma pros reading Endpoints daily — and it's free.

With dust set­tled on ac­tivist at­tack, Lau­rence Coop­er leaves Zio­pharm to a new board

Laurence Cooper has done his part.

In the five years since he left a tenured position at Houston’s MD Anderson Cancer Center to become CEO of Boston-based Ziopharm, he’s steered the small-cap immunotherapy player through patient deaths in trials, clinical holds, short attacks and, most recently, an activist attack on the board.

So when the company has “fantastic news” like an IND clearance for a TCR T cell therapy program, he’s ready to pass on the baton.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 102,100+ biopharma pros reading Endpoints daily — and it's free.

Steve Cutler, Icon CEO (Icon)

In the biggest CRO takeover in years, Icon doles out $12B for PRA Health Sci­ences to fo­cus on de­cen­tral­ized clin­i­cal work

Contract research M&A had a healthy run in recent years before recently petering out. But with the market ripe for a big buyout and the Covid-19 pandemic emphasizing the importance of decentralized trials, Wednesday saw a tectonic shift in the CRO world.

Icon, the Dublin-based CRO, will acquire PRA Health Sciences for $12 billion in a move that will shake up the highest rungs of a fragmented market. The merger would combine the 5th- and 6th-largest CROs by 2020 revenue, according to Icon, and the merger will set the newco up to be the second-largest global CRO behind only IQVIA.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 102,100+ biopharma pros reading Endpoints daily — and it's free.

Tal Zaks, Moderna CMO (AP Photo/Rodrique Ngowi, via still image from video)

CMO Tal Zaks bids Mod­er­na a sur­prise adieu as biotech projects $18.4B in rev­enue, plots post-Covid ex­pan­sion

How do you exit a company after six years in style? Developing one of the most lucrative and life-saving products in pharma history is probably not the worst way to go.

Tal Zaks, Moderna’s CMO since 2015, will leave the mRNA biotech in September, the biotech disclosed in their annual report this morning. The company has already retained the recruitment firm Russell Reynolds to find a replacement.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 102,100+ biopharma pros reading Endpoints daily — and it's free.

Glax­o­SmithK­line re­thinks strat­e­gy for Covid-19 an­ti­body — not the Vir ones — af­ter tri­al flop. Is there hope in high-risk pa­tients?

In the search for a better Covid-19 therapeutic, GlaxoSmithKline and Vir have partnered up on two antibodies they hope have a chance. GSK is also testing its own in-house antibody, and early results may have shut the door on its widespread use.

A combination of GSK’s monoclonal antibody otilimab plus standard of care couldn’t best standard of care alone in preventing death and respiratory failure in hospitalized Covid-19 patients after 28 days, according to data from the Phase IIa OSCAR study unveiled Thursday.

Mod­er­na's Stéphane Ban­cel plans to dou­ble down on vac­cine pro­duc­tion, new vari­ants as mR­NA rules in pan­dem­ic fight

Stéphane Bancel thought he’d be sleeping more by now.

The 48-year-old Moderna CEO figured that by 2021 he’d have his vaccine through the clinic, authorized, and in mass production — that the hard part would be over. Instead, he’s still working Saturdays and Sundays, talking with his lab and manufacturing teams and fielding calls with two to three world leaders a day to answer their concerns about supply and emerging new variants.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 102,100+ biopharma pros reading Endpoints daily — and it's free.