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.

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Dipal Doshi, Entrada Therapeutics CEO

Ver­tex just found the next big ‘trans­for­ma­tive’ thing for the pipeline — at a biotech just down the street

Back in the summer of 2019, when I was covering Vertex’s executive chairman Jeff Leiden’s plans for the pipeline, I picked up on a distinct focus on myotonic dystrophy Type I, or DM1 — one of what Leiden called “two diseases (with DMD) we’re interested in and we continue to look for those assets.”

Today, Leiden’s successor at the helm of Vertex, CEO Reshma Kewalramani, is plunking down $250 million in cash to go the extra mile on DM1. The lion’s share of that is for the upfront, with a small reserve for equity in a deal that lines Vertex up with a neighbor in Seaport that has been rather quietly going at both of Vertex’s early disease targets with preclinical assets.

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Ahead of ad­comm, FDA rais­es un­cer­tain­ties on ben­e­fit-risk pro­file of Cy­to­ki­net­ic­s' po­ten­tial heart drug

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet next Tuesday to discuss whether Cytokinetics’ potential heart drug can safely reduce the risk of cardiovascular death and heart failure in patients with symptomatic chronic heart failure with reduced ejection fraction.

The drug, known as omecamtiv mecarbil and in development for more than 15 years, has seen mixed results, with a first Phase III readout from November 2020 hitting the primary endpoint of reducing the odds of hospitalization or other urgent care for heart failure by 8%. But it also missed a key secondary endpoint analysts had pegged as key to breaking into the market.

David Light, Valisure CEO

Val­isure in the hot seat: New Form 483 over a 2021 in­spec­tion as CEO fires back

The notorious drug testing company Valisure, which has made a name for itself by forcing FDA’s hand with some of its safety-related uncoverings, received a letter this week after the FDA uncovered violations at its Connecticut-based testing lab in 2021.

The letter, which was sent on Dec. 5, stated that the FDA is “concerned” that Valisure was not aware of  drug supply chain security requirements.

Rami Elghandour, Arcellx CEO

Up­dat­ed: Gilead, Ar­cel­lx team up on an­ti-BC­MA CAR-T as biotech touts a 100% re­sponse rate at #ASH22

Gilead and Kite are plunking down big cash to get into the anti-BCMA CAR-T game.

The pair will shell out $225 million in cash upfront and $100 million in equity to Arcellx, Kite announced Friday morning, to develop the biotech’s lead CAR-T program together. Kite will handle commercialization and co-development with Arcellx, and profits in the US will be split 50-50.

Concurrent with the deal, Arcellx revealed its latest cut of data for the program known as CART-ddBCMA, ahead of a full presentation at this weekend’s ASH conference — a 100% response rate among patients getting the therapy. Investors jumped at the dual announcements, sending Arcellx shares $ACLX up more than 25% in Friday’s morning session.

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Christian Itin, Autolus CEO (UKBIO19)

Au­to­lus tips its hand, bags $220M as CAR-T show­down with Gilead looms

The first batch of pivotal data on Autolus Therapeutics’ CAR-T is in, and execs are ready to plot a path to market.

With an overall remission rate of 70% at the interim analysis featuring 50 patients, the results set the stage for a BLA filing by the end of 2023, said CEO Christian Itin.

Perhaps more importantly — given that Autolus’ drug, obe-cel, is going after an indication that Gilead’s Tecartus is already approved for — the biotech highlighted “encouraging safety data” in the trial, with a low percentage of patients experiencing severe immune responses.

WIB22: Am­ber Salz­man had few op­tions when her son was di­ag­nosed with a rare ge­net­ic dis­ease. So she cre­at­ed a bet­ter one

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Amber Salzman’s life changed on a cold, damp day in Paris over tiny plastic cups of lukewarm tea.

She was meeting with Patrick Aubourg, a French neurologist studying adrenoleukodystrophy, or ALD, a rare genetic condition that causes rapid neurological decline in young boys. It’s a sinister disease that often leads to disability or death within just a few years. Salzman’s nephew was diagnosed at just 6 or 7 years old, and died at the age of 12.

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FDA re­view­ers head back to White Oak in 2023, with lead­er­ship look­ing to ap­pease a new Con­gress

Republicans have taken a stand against the pandemic era habit of lax work-from-home schedules. Now that they’ve wrestled control of the House majority, the FDA’s leadership is playing ball, sending many of the agency’s more than 18,000 employees back to their desks early next year.

Whether this exodus back to White Oak in Silver Spring, MD (many staff will still be allowed to work from home for multiple days per week) will mean more defections to industry and elsewhere remains to be seen.

Bags of shred­ded docs: In­di­an drug­mak­er Lupin hand­ed a Form 483 by FDA in­spec­tors

The generics manufacturer Lupin has been given another Form 483 from the FDA this year.

US regulators inspected Lupin’s pharmaceutical manufacturing site in the town of Mandideep, India from Nov. 14 through Nov. 23, with the 14-page report marking 16 observations.

The inspection report stated that the site did not have the appropriate controls over its computer systems to ensure that changes in “master production” or records are only done by authorized personnel, along with written procedures not being established to conduct annual reviews of records associated with drug batches.