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.

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Jim Scholefield via PR Newswire

Mer­ck los­es its chief dig­i­tal of­fi­cer, spot­light­ing tal­ent hunt for the hottest ti­tle in Big Phar­ma

Over the last few years we’ve seen the chief digital officer title become one of the hottest commodities in Big Pharma as global organizations hunt the best talent to sharpen the cutting edge of their tech platforms.

But Merck just discovered how hard it may be to keep them focused on pharma.

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Kathy High (file photo)

Gene ther­a­py pi­o­neer Kathy High has left Spark af­ter com­plet­ing $4.3B union with Roche

Kathy High dedicated the past seven years of her life shepherding experimental gene therapies she’s developed at Children’s Hospital of Philadelphia toward the market as president and head of R&D at Spark Therapeutics. Now that the biotech startup is fully absorbed into Roche — with an FDA approval, a $4.3 billion buyout and a promising hemophilia program to boast — she’s ready to move on.

Roche confirmed her departure with Endpoints News and noted “she will take some well-deserved time off and then will begin a new chapter in a sabbatical at a university.”

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Say good­bye to Toca­gen, strug­gling brain can­cer biotech to re­verse merge with Forte Bio­sciences

Five months after a huge Phase III failure triggered mass layoffs at the company, Tocagen will sign itself out of existence.

The biotech, once focused on brain cancer, announced it has signed a reverse merger agreement with Forte Biosciences, a biotech tackling atopic dermatitis and other inflammatory skin diseases. Tocagen’s stock shot up 85% on the news, although that only translated to a 41-cent bump for a company that saw the last of its value go poof in September. The new company will trade under the ticker $FBRX.

Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

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JJ Bienaimé (BioMarin via YouTube)

Speedy re­view and no ad­comm for Bio­Mar­in's pi­o­neer­ing he­mo­phil­ia gene ther­a­py

BioMarin’s keenly anticipated hemophilia A gene therapy — which CEO JJ Bienaimé envisions pricing at an eye-watering $2 million to $3 million a shot — has secured red carpet treatment at the FDA.

The therapy, fondly called valrox, has won priority review — and there the agency has indicated there are no plans for an advisory committee meeting. The US regulator’s final decision is expected by August 21. If approved, it will be the pioneering gene therapy for hemophilia.

“While the company…indicated that FDA does not currently plan on convening an advisory committee meeting to discuss the merits of the application, we caution that the possibility of such still remains as the agency digs into its review, which could be interpreted negatively by the Street,” BMO Capital Market’s George Farmer wrote.

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Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

Special report

Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

“I’m ok, I don’t have Ebola,” Pascal told them. “I see that death toll rising and I can’t not do something about it.”

Last August, Regeneron learned they had succeeded: In a large trial across West Africa, their drug, REGN-EB3, was vastly more effective than the standard treatments. It was surprise news for the company, coming just 10 months into a trial they thought would take several years and a major victory in the global fight against a deadly virus that killed over 2,000 in 2019 and can carry a mortality rate of up to 90%.

For Kyratsous and Pascal, though, it brought only fleeting reprieve. Just four months after the NIH informed them REGN-EB3 worked, Kyratsous was back in his office reading the New York Times for updates on a new outbreak on another continent, and wondering alongside Pascal and senior management whether it was time to pull the trigger again.

In late January, as the death toll swelled and the first confirmed cases outside China broke double digits, they made a decision. Soon they were back on the phone with the multiple government agencies and their coronavirus partners at the University of Maryland’s Level 3 bio lab. The question was simple: Can Kyratsous and his team use a process honed over two previous outbreaks, and create a treatment before the newest epidemic ends? Or worse, if, as world health experts fear, it doesn’t vanish but becomes a recurrent virus like the flu?

“Christos likes things immediately,” Matt Frieman, Regeneron’s coronavirus collaborator at the University of Maryland, told Endpoints. “That’s what makes us good collaborators: We push each other to develop things faster and faster.”

Kristen Pascal (Regeneron)

Click on the image to see the full-sized version

The first time Regeneron tried to respond to a global outbreak, it was something of a systems test, Kyratsous explains from his office at Regeneron’s Tarrytown headquarters. Kyratsous, newly promoted, has crammed it with photos of his family, sketches of viral vectors and a shark he drew for his 3-year-old son. He speaks rapidly – an idiosyncrasy his press person says has only been aggravated this afternoon by the contents of his “Regeneron Infectious Diseases”-minted espresso glass – and he gesticulates with similar fluidity, tumbling through antibodies, MERS, the novel coronavirus, Ebola-infected monkeys.

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Phar­ma­co­ge­net­ics: FDA re­leas­es ta­ble of gene-drug in­ter­ac­tions

The FDA on Thursday published a table identifying more than 50 gene-drug interactions that the agency says are supported by scientific evidence and announced it is considering new approaches to evaluating pharmacogenetic associations.

“Consistent with our mission to protect and promote public health, we believe it is important to take steps now to help ensure that claims being made for pharmacogenetic tests offered today are grounded in sound science to avoid inappropriate management of patients’ medications,” said Center for Devices and Radiological Health Director Jeff Shuren and Center for Drug Evaluation and Research Director Janet Woodcock.

Don't let Ab­b­Vie fool FTC with an easy di­vesti­ture, plead crit­ics in lat­est at­tack on $63B Al­ler­gan buy­out

If the FTC must let AbbVie and Allergan go ahead with their merger, at least make them divest their latest blockbuster on the market, a chorus of unions, consumer groups and public interest organizations plead in a new attempt to rein in the megamerger.

There’s a second part to their argument: If the antitrust watchdog does greenlight the divestiture AbbVie wants, then at least ensure the pharma giant cannot corner its future rivals with its exclusionary tactics.

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