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.

Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

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Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

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FDA bars the door — for now — against Mer­ck’s star can­cer drug af­ter Roche beat them to the punch

Merck has been handed a rare setback at the FDA.

After filing for the accelerated approval of a combination of their star PD-1 drug Keytruda with Eisai’s Lenvima as a first-line treatment for unresectable hepatocellular carcinoma, the FDA nixed the move, handing out a CRL because Roche beat them to the punch on the same indication by a matter of weeks.

According to Merck:

Ahead of the Prescription Drug User Fee Act action dates of Merck’s and Eisai’s applications, another combination therapy was approved based on a randomized, controlled trial that demonstrated overall survival. Consequently, the CRL stated that Merck’s and Eisai’s applications do not provide evidence that Keytruda in combination with Lenvima represents a meaningful advantage over available therapies for the treatment of unresectable or metastatic HCC with no prior systemic therapy for advanced disease. Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval, both companies plan to work with the FDA to take appropriate next steps, which include conducting a well-controlled clinical trial that demonstrates substantial evidence of effectiveness and the clinical benefit of the combination.

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Covid-19 roundup: EU backs Os­i­vax's pur­suit of a uni­ver­sal vac­cine to fight Covid-19

The race to find a vaccine for the novel coronavirus continues to heat up, as the European Commission’s pilot R&D arm taps French biotech Osivax to head up its unique approach to the research.

Aiming to develop a universal jab for the flu and Covid-19, Osivax secured around $20 million in “blended financing” from the European Innovation Council. About $3 million comes from a Covid-19 “accelerator grant” and will go toward completing Osivax’s signature flu vaccine, dubbed OVX836 and currently in Phase IIa. The rest will be included as part of Osivax’s Series B funding, which aims to launch the Phase IIb portion of the study.

Adrian Gottschalk, Foghorn CEO

Mer­ck dan­gles up to $425 mil­lion to team with Flag­ship’s Foghorn Ther­a­peu­tics on drug­ging the shape of DNA

Two years after it first emerged from stealth mode, Flagship’s Foghorn Therapeutics has nabbed its first Big Pharma partner as Merck signs on to the biotech’s vision of drugging the very shape of DNA.

The deal, worth up to $425 million but with the upfront cash undisclosed, comes as Foghorn nears a pivot to a clinical stage biotech. The Cambridge-based company has added nearly 60 staffers from the 25 it had when it first emerged out of Flagship and, CEO Adrian Gottschalk said, they have finally refined the screening technology at the heart of the company, with plans to file their first IND towards the end of the year.

GSK sets the stage for a toe-to-toe mar­ket show­down with Gilead­'s HIV cham­pi­on Tru­va­da

ViiV Healthcare and majority owner GlaxoSmithKline have cleared another important hurdle on a long-running quest to challenge Gilead’s dominance in preventative HIV treatments.

The final analysis of a new study shows the GSK subsidiary’s long-lasting injection, cabotegravir, proved 66% more effective in HIV prevention than Gilead’s breakthrough Truvada pill. And they now intend to carve away some of the blockbuster revenue that Gilead has enjoyed for years.

Trump and Navar­ro press again for hy­drox­y­chloro­quine. Can the FDA stay in­de­pen­dent?

Tuesday morning, economist and Trump advisor Peter Navarro walked onto the White House driveway and promptly brought a political cloud back onto the FDA.

Speaking to a White House pool reporter, Navarro said that four Detroit doctors were, based on a single disputed study, filing for the FDA to again issue an emergency authorization for hydroxychloroquine, the anti-malarial pill that President Trump hyped for months as a Covid-19 treatment over the objections of his own scientists. Then, while avoiding directly calling for the FDA to OK the drug, blasted the agency. He said its decision to pull an earlier authorization “was based on bad science” and “had a tremendously negative effect” on doctors and patients.

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John Reed, Sanofi R&D chief (Endpoints News)

John Reed brings NK cells in­to Sanofi's CD38 ri­val­ry with J&J — and of­fers thumbs up for Kiadis' new fo­cus

Sanofi doesn’t just want to be a challenger to J&J’s dominant Darzalex multiple myeloma franchise. It’s looking to pioneer a new approach by pairing its own — newly approved — anti-CD38 drug with an NK cell therapy it’s just picked up.

The French pharma giant has teed up $19.7 million (€17.5 million) upfront and close to a billion dollars (€857.5 million) in milestones for a license to Kiadis Pharma’s preclinical K-NK004 program, which consists of NK cells that have been genetically engineered not to express CD38.

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Cel­lec­tis slammed af­ter pa­tient dies and FDA slaps a hold on their tri­al for an off-the-shelf CAR-T for mul­ti­ple myelo­ma

Cellectis was slammed after the market close on Monday as the biotech reported that the FDA demanded it hit the brakes on their MELANI-01 trial for their off-the-shelf cell therapy UCARTCS1A after one of the patients in the study died of treatment-related cardiac arrest.

The multiple myeloma patient had previously been treated unsuccessfully with various therapies, noted the biotech, and had been given dose level two (DL2) of their allogeneic CAR-T.

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