FDA pan­el of­fers a wa­ver­ing thumbs up for Eli Lil­ly's 2 mg baric­i­tinib, thumbs down on 4 mg

A large pan­el of out­side rheuma­toid arthri­tis ex­perts gath­ered at the FDA to dis­cuss Eli Lil­ly’s $LLY con­tro­ver­sial re-ap­pli­ca­tion for an ap­proval of baric­i­tinib, vot­ing in lop­sided fa­vor of the ef­fi­ca­cy and safe­ty of the 2 mg dose of the rheuma­toid arthri­tis drug, but turned their thumbs down on the 4 mg dose.

Ten vot­ed in fa­vor of the risk/ben­e­fit bal­ance of the 2 mg dose, 5 against. The num­bers were re­versed for the 4 mg, falling 10 against and 5 in fa­vor.

Jose Sch­er

These ex­pert votes hinged on a con­sid­er­able amount of con­fu­sion and un­cer­tain­ty, though, which sev­er­al mem­bers were quick to ac­knowl­edge.

Said one mem­ber who vot­ed yes on the ad­e­qua­cy of the safe­ty da­ta of the 2 mg dose: “This whole thing is a house of cards and I could have gone ei­ther way.”

An­oth­er: ”My best guess is yes.”

Er­i­ca Brit­tain: “I vot­ed yes, I could have def­i­nite­ly vot­ed no.”

“We still don’t have enough da­ta,” said one mem­ber who vot­ed in fa­vor of the ad­e­qua­cy of the 2 mg dose.

“I would urge the spon­sor to get as much da­ta as pos­si­ble on the safe­ty side,” com­ment­ed com­mit­tee chair Jose Sch­er, who vot­ed against both the 2 mg and 4 mg dos­es based on in­ad­e­quate safe­ty da­ta.

That all could emerge as a ma­jor headache for Eli Lil­ly and its part­ners at In­cyte $IN­CY, as the com­pa­ny wants to start treat­ment-re­sis­tant pa­tients at 4 mg and then ta­per down to 2 mg if they sta­bi­lize their dis­ease.

Lil­ly’s shares ini­tial­ly dropped 3% in ear­ly trad­ing Tues­day, then man­aged to climb back up in­to the green, bare­ly. In­cyte shares, though, are still down 5% in mid-morn­ing trad­ing.

The pan­el dis­cus­sion in­clud­ed a me­an­der­ing se­ries of com­ments, with some voic­es sup­port­ing an ap­proval to of­fer a new op­tion for pa­tients and a few flag­ging some se­ri­ous safe­ty is­sues and oth­ers un­cer­tain just what was demon­strat­ed by the da­ta on dis­play.

On one point, the ad­vi­so­ry com­mit­tee found clear con­sen­sus around ef­fi­ca­cy. By a vote of 14 to 1 they con­clud­ed that there was clear ev­i­dence of the “sub­stan­tial ev­i­dence” that backed the drug’s ef­fi­ca­cy, with a unan­i­mous vote in fa­vor of ef­fi­ca­cy as a sec­ond-line ther­a­py af­ter pa­tients had failed on their front­line drug.

Much of the dis­cus­sion, though, cen­tered on the safe­ty of the drug, where reg­u­la­tors raised some of their most se­ri­ous ob­jec­tions to the drug, with a star­tling sig­nal on throm­boem­bolism.

One com­mit­tee mem­ber not­ed a dis­cus­sion con­cern­ing whether rheuma­tol­o­gists are used to look­ing for and mon­i­tor­ing for ad­verse events. But, he added, “rheuma­tol­o­gists do not typ­i­cal­ly look for throm­boem­bol­ic events, that’s not on the list of things that are tra­di­tion­al­ly watched for.”

There was a con­sid­er­able dis­cus­sion whether the com­mit­tee had the da­ta need­ed to make a con­clu­sion on the drug’s safe­ty, par­tic­u­lar­ly when it came to the 2 mg dose. 

“None of these stud­ies are pow­ered to look for rare events,” said Sch­er, high­light­ing stud­ies that weren’t pow­ered to de­ter­mine the risk of throm­boem­bolisms, or blood clots, and not­ing that there was con­sid­er­able con­fu­sion about the da­ta and the con­clu­sions that could be drawn from them — par­tic­u­lar­ly re­lat­ing to the 2 mg dose, where the da­ta were lack­ing.

Baric­i­tinib is a re­mark­able test case for the FDA. Re­ject­ed in 2017 in a stun­ning set­back for a drug that had been billed as a block­buster in the mak­ing, the agency re­versed course and al­lowed Lil­ly to re­file for an ap­proval as a sec­ond-line ther­a­py with­out the added da­ta that had been in­sist­ed on. The agency’s re­view makes clear that while Eli Lil­ly in­ves­ti­ga­tors pro­vid­ed more in­for­ma­tion, none of it ad­dressed their core con­cerns, es­pe­cial­ly re­gard­ing a high­er rate of throm­bo­sis that ap­peared for the first time in the field.

FDA re­view­ers dis­agreed on the da­ta of­fered for the 2 mg and 4 mg dos­es, with some will­ing to wave it through and oth­ers not­ing that the study da­ta for the 2 mg nev­er pro­vid­ed suf­fi­cient in­for­ma­tion for a de­ci­sion on safe­ty and ef­fi­ca­cy. There was al­so no con­sis­tent da­ta to back up the 4 mg dose over the 2 mg dose, ac­cord­ing to reg­u­la­tors. 

Even if it gets an ap­proval now, Lil­ly is go­ing to have an up­hill fight against Pfiz­er’s Xel­janz (to­fac­i­tinib), the first JAK in­hibitor to make it to the mar­ket — with­out the harsh FDA crit­i­cism or is­sues with throm­bo­sis that promise to cap­size Lil­ly’s launch.

Why of­fer an ap­proval now if there are oth­er drugs on the mar­ket that could do as well or bet­ter? And if it is ap­proved, will this drug be re­served for last-chance op­por­tu­ni­ties?

“We know we didn’t make your lives any eas­i­er,” said Sch­er as he turned at the end to the FDA’s rep­re­sen­ta­tives.

Martin Shkreli [via Getty]

Pris­on­er #87850-053 does not get to add drug de­vel­op­er to his list of cred­its

Just days after Retrophin shed its last ties to founder Martin Shkreli, the biotech is reporting that the lead drug he co-invented flopped in a pivotal trial. Fosmetpantotenate flunked both the primary and key secondary endpoints in a placebo-controlled trial for a rare disease called pantothenate kinase-associated neurodegeneration, or PKAN.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology
ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development
CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Hal Barron. GSK

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive piv­otal for cru­cial an­ti-BC­MA ther­a­py, point­ing to a push for quick OKs in a crowd­ed field

Hal Barron has his second positive round of Phase III data in hand for his anti-BCMA antibody drug conjugate belantamab mafodotin (GSK2857916). And GSK’s research chief says the data paves the way for their drive in search of an FDA approval for treating multiple myeloma.

It’s hard to overestimate the importance of this drug for GSK, a cornerstone of Barron’s campaign to make a dramatic impact on the oncology market and provide some long-lost excitement for the pharma giant’s pipeline. They’re putting this BCMA program at the front of that charge — looking to lead a host of rivals all aimed at the same target.

We don’t know what the data are yet, but DREAMM-2 falls on the heels of a promising set of data delivered 5 months ago for DREAMM-1. There investigators noted that complete responses among treatment-resistant patients rose to 15% in the extra year’s worth of data to look over, with a median progression-free survival rate of 12 months, up from 7.9 months reported earlier. The median duration of response was 14.3 months.

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UP­DAT­ED: An em­bold­ened As­traZeneca splurges $95M on a pri­or­i­ty re­view vouch­er. Where do they need the FDA to hus­tle up?

AstraZeneca is in a hurry.

We learned this morning that the pharma giant — not known as a big spender, until recently — forked over $95 million to get its hands on a priority review voucher from Sobi, otherwise known as Swedish Orphan Biovitrum.

That marks another step down on price for a PRV, which allows the holder to slash 4 months off of any FDA review time.

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Bob Smith, Pfizer

Pfiz­er is mak­ing a $500M state­ment to­day: Here’s how you be­come a lead play­er in the boom­ing gene ther­a­py sec­tor

Three years ago, Pfizer anted up $150 million in cash to buy Bamboo Therapeutics in Chapel Hill, NC as it cautiously stuck a toe in the small gene therapy pool of research and development.

Company execs followed up a year later with a $100 million expansion of the manufacturing operations they picked up in that deal for the UNC spinout, which came with $495 million in milestones.

And now they’re really going for it.

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Video: Putting the AI in R&D — with Badhri Srini­vasan, Tony Wood, Rosana Kapeller, Hugo Ceule­mans, Saurabh Sa­ha and Shoibal Dat­ta

During BIO this year, I had a chance to moderate a panel among some of the top tech experts in biopharma on their real-world use of artificial intelligence in R&D. There’s been a lot said about the potential of AI, but I wanted to explore more about what some of the larger players are actually doing with this technology today, and how they see it advancing in the future. It was a fascinating exchange, which you can see here. The transcript has been edited for brevity and clarity. — John Carroll

As­traZeneca’s Imfinzi/treme com­bo strikes out — again — in lung can­cer. Is it time for last rites?

AstraZeneca bet big on the future of their PD-L1 Imfinzi combined with the experimental CTLA-4 drug tremelimumab. But once again it’s gone down to defeat in a major Phase III study — while adding damage to the theory involving targeting cancer with a high tumor mutational burden.

Early Wednesday the pharma giant announced that their NEPTUNE study had failed, with the combination unable to beat standard chemo at overall survival in high TMB cases of advanced non-small cell lung cancer. We won’t get hard data until later in the year, but the drumbeat of failures will call into question what — if any — future this combination can have left.

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Why would Am­gen want to buy Alex­ion? An­a­lysts call hot­ly ru­mored takeover un­like­ly, but seize the mo­ment

A rumor that Amgen is closing in on buyout deal for Alexion has sparked a guessing game on just what kind of M&A strategy Amgen is pursuing and how much Alexion is worth.

Mizuho analyst Salim Syed first lent credence to the report out of the Spanish news outlet Intereconomía, which said Amgen is bidding as much as $200 per share. While the source may be questionable, “the concept of this happening doesn’t sound too crazy to me,” he wrote.