Bris­tol-My­ers makes Op­di­vo pitch for front­line lung can­cer with open la­bel PhI­II study

De­spite a head start, when Bris­tol-My­ers Squibb and its pi­o­neer­ing check­point in­hibitor Op­di­vo suf­fered a key lung can­cer set­back in 2016, they found them­selves rel­e­gat­ed to the back­seat as Mer­ck’s Keytru­da seized the wheel on the road to im­munother­a­py star­dom. Bris­tol-My­ers has since suf­fered blow af­ter blow in its quest to take a big slice of the lu­cra­tive mar­ket, pep­pered with some small suc­cess­es. On Tues­day, the New Jer­sey drug­mak­er tout­ed pos­i­tive da­ta from a Phase III open-la­bel study in a bid to carve it­self a piece of the front­line lung can­cer mar­ket.

The study, dubbed Check­Mate -9LA, test­ed Bris­tol-My­ers’ Op­di­vo in com­bi­na­tion with its CT­LA-4 Yer­voy in ad­di­tion to chemother­a­py (two cy­cles) ver­sus chemother­a­py alone (up to four cy­cles fol­lowed by op­tion­al peme­trexed main­te­nance ther­a­py if el­i­gi­ble) as a first-line treat­ment in pa­tients with ad­vanced non-small cell lung can­cer (NSCLC) re­gard­less of PD-L1 ex­pres­sion.

The PD-L1 drug met the main tri­al goal of su­pe­ri­or over­all sur­vival at a pre­spec­i­fied in­ter­im analy­sis, the com­pa­ny said, adding that de­tailed da­ta will be pre­sent­ed at a fu­ture med­ical con­fer­ence. The com­pa­ny’s shares $BMY rose more than 5% to $55.94 in Tues­day pre­mar­ket trad­ing.

Sec­ondary end­points in­clud­ed pro­gres­sion-free sur­vival, over­all re­sponse rate, and ef­fi­ca­cy mea­sures ac­cord­ing to bio­mark­ers.

In Jan­u­ary, the com­pa­ny re­scind­ed its ap­pli­ca­tion to mar­ket the Op­di­vo/Yer­voy com­bo in front­line NSCLC cas­es with high tu­mor mu­ta­tion­al bur­den (TMB), af­ter dis­cus­sions with the agency sug­gest­ed they need­ed more da­ta to re­in­force the con­nec­tion be­tween TMB and PD-L1.

The ap­pli­ca­tion was based on the Check­Mate-227 study, in which re­searchers said they had ob­served a “high­ly” sig­nif­i­cant pro­gres­sion-free sur­vival rate in pa­tients with high TMB, re­gard­less of PD-L1 ex­pres­sion. The high TMB group ac­counts for 45% of all front­line pa­tients, the com­pa­ny es­ti­mat­ed at the time. Bris­tol-My­ers had re­designed the study to fo­cus on TMB af­ter stum­bling on a piv­otal tri­al that in­volved a broad­er pa­tient pop­u­la­tion.

Over­all sur­vival da­ta, pre­sent­ed months lat­er, showed that the haz­ard ra­tio in pa­tients get­ting the Op­di­vo/Yer­voy com­bo was com­pa­ra­ble whether they were high or low TMB pa­tients. How­ev­er, the me­di­an over­all sur­vival in pa­tients with high TMB was 23.03 months on the Op­di­vo/Yer­voy arm, ver­sus 16.72 months in the chemother­a­py group. In the low TMB group, the me­di­an OS was 16.20 months and was 12.42 months on the com­bi­na­tion and chemother­a­py arms, re­spec­tive­ly.

The re­sults of Check­Mate-227 sug­gest­ed that Yer­voy has ac­tiv­i­ty in lung can­cer when com­bined with Op­di­vo — but the da­ta sug­gest that pa­tients have to wait for some pe­ri­od of time for the ben­e­fit to man­i­fest, Wolfe Re­search’s Tim An­der­son wrote in a note.

“Chemother­a­py, when giv­en to lung can­cer pa­tients, of­ten shows a fast ini­tial re­sponse, but one that lacks dura­bil­i­ty.  But by com­bin­ing chemother­a­py+Op­di­vo+Yer­voy, BMY may have (fi­nal­ly) found a cock­tail of drugs that de­liv­ers both near- and longer-term ben­e­fit, lead­ing to an ear­ly re­sponse and im­proved long-term sur­vival.”

How­ev­er, An­der­son was cau­tious about the cock­tail’s safe­ty pro­file in Check­Mate -9LA.

“Op­di­vo+Yer­voy by it­self shows tox­i­c­i­ty and adding chemother­a­py in­to the mix will on­ly in­crease this,” he said.  “The com­mer­cial val­ue of CM-9LA will, there­fore, de­pend on the bal­ance be­tween the clin­i­cal ben­e­fit and the tox­i­c­i­ty.  It will on­ly be once full re­sults are pre­sent­ed that this risk:ben­e­fit as­sess­ment will be pos­si­ble.  Ad­di­tion­al­ly, adding a third drug in­to the mix al­so rais­es the cost of ther­a­py some­what.”

Mean­while, the com­pa­ny’s hunt for adop­tion in small cell lung can­cer (SCLC) mar­ket has al­so been punc­tu­at­ed with fail­ure.

Last year saw an Op­di­vo/Yer­voy com­bo miss the pri­ma­ry end­point for over­all sur­vival in the Check­Mate-451 study, where the Bris­tol-My­ers drugs were be­ing eval­u­at­ed as a main­te­nance ther­a­py for SCLC, fol­low­ing an ini­tial round of chemother­a­py. The re­sults came just over a month af­ter the drug­mak­er un­veiled an Op­di­vo flop in the Check­Mate-331 study, which test­ed the im­munother­a­py against the sec­ond-line small cell lung can­cer stan­dard-of-care.

Still, over the years, Op­di­vo has seen some lung can­cer suc­cess — in­clud­ing the ap­proval of the drug in squa­mous NSCLC pa­tients whose can­cer has pro­gressed de­spite plat­inum-based chemother­a­py as well as pa­tients with metasta­t­ic SCLC pa­tients, whose can­cer has pro­gressed af­ter plat­inum-based chemother­a­py and at least one oth­er line of ther­a­py.

The re­sults of Check­Mate -9LA could have an im­pact on As­traZeneca, which is run­ning the PO­SEI­DON tri­al, An­der­son added.

The tri­al is struc­tural­ly sim­i­lar to CM-9LA but with one key dif­fer­ence — in­stead of on­ly giv­ing a short course of chemother­a­py in ad­di­tion to its own check­point in­hibitor Imfinzi  and CT­LA-4 treme­li­mum­ab, it gives chemother­a­py con­tin­u­ous­ly, he said.

“This may or may not be a good thing – it can be pre­dict­ed that more chemother­a­py like­ly yields more tox­i­c­i­ty, but will it yield more ben­e­fit?  Fur­ther­more, AZN’s an­ti-CT­LA4 ther­a­py (treme­li­mum­ab) has yet to show it works in any tu­mor type (by con­trast, BMY’s Yer­voy is al­ready ap­proved in dif­fer­ent set­tings) po­ten­tial­ly re­flec­tive of the fact that it has slight­ly dif­fer­ent prop­er­ties ver­sus Yer­voy.”

Op­di­vo, which is al­so ap­proved for use in a host of oth­er can­cers, gen­er­at­ed about $3.6 bil­lion in the first half of this year. By 2025, Op­di­vo is set to be the fourth best-sell­ing drug in the world with an­nu­al sales fore­cast­ed to hit $12 bil­lion. King Keytru­da, how­ev­er, is ex­pect­ed to take top spot and rake in more than $22 bil­lion, ac­cord­ing to Glob­al­Da­ta cal­cu­la­tions.

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.

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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Tim Mayleben (file photo)

Es­pe­ri­on's goldilocks cho­les­terol fight­er wins FDA ap­proval — will its 'tra­di­tion­al' pric­ing ap­proach spur adop­tion?

It’s more effective than decades-old statins but not as good as the injectable PCSK9 — the goldilocks treatment for cholesterol-lowering, bempedoic acid, has secured FDA approval.

Its maker, Esperion Therapeutics, is betting that their pricing strategy — a planned list price of between $10 to $11 a day — will help it skirt the pushback the PCSK9 cholesterol fighters, Repatha and Praluent, got from payers for their high sticker prices.

The sky-high expectations for the pair of PCSK9 drugs that were first approved in 2015 quickly simmered — and despite a 60% price cut, coupled with data showing the therapies also significantly cut cardiovascular risk, sales have not really perked up.

Esperion is convinced that by virtue of being a cheaper oral therapy, bempedoic acid will hit that sweet spot in terms of adoption.

“We’re kind of like the old comfortable shoe,” Esperion’s chief commercial officer Mark Glickman remarked in an interview with Endpoints News ahead of the decision date. “It’s an oral product, once-daily and nontitratable — these are things that just resonate so true with patients and physicians and I think we’ve kind of forgotten about that.”

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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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James Collins, Broad Institute via Youtube

UP­DAT­ED: A space odyssey for new an­tibi­otics: MIT's ma­chine learn­ing ap­proach

Drug development is complex, expensive and comes with lousy odds of success — but in most cases, if you make it across the finish line brandishing a product with an edge (and play your cards right) it can be a lucrative endeavor.

As it stands, the antibiotic market is cursed — it harbors the stink of multiple bankruptcies, a dearth of innovation, and is consequently barely whetting the voracious appetites of big pharma or venture capitalists. Enter artificial intelligence — the biopharma industry’s cure-all for the pesky process of making a therapeutic, including data mining, drug discovery, optimal drug delivery, and addressable patient population.

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Gilead los­es two more patent chal­lenges on HIV pill, set­ting up court­room fight in Delaware

Gilead sustained two more losses in their efforts to rid themselves of an activist-backed patent lawsuit from the US government over a best-selling HIV pill.

Urged on by activists seeking to divert a portion of Gilead’s revenue to clinics and prevention programs, the Department of Health and Human Services made a claim to some of the patents for the best-selling HIV prevention drug, Truvada, also known as PrEP. Gilead responded by arguing in court that HHS’s patents were invalid.

Today, the US Patent and Trademark Office ruled that Gilead was likely to lose the last two of those challenges as well. The USPTO ruled against Gilead on the first two patents earlier this month.

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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.

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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)

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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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Bank­rupt an­tibi­otics mak­er Ar­a­digm turns to old part­ner/in­vestor for fi­nal $3M fire sale

Grifols once paid Aradigm $26 million for a stake in its inhaled antibiotics. But with Aradigm now in bankruptcy, the Spanish drugmaker is dishing out a final $3.2 million to buy it all.

The fire sale — which comes one year after Aradigm filed for Chapter 11 following a regulatory trifecta for disaster — will see Grifols obtain assets and IP to Apulmiq (formerly Pulmaquin and Linhaliq in Europe), Lipoquin and free ciprofloxacin. In addition to waiving its claims in the bankruptcy case, Grifols also agreed to milestone payments up to $3 million more upon any regulatory approvals.

DB­V's peanut pre­ven­tion patch ap­proach­es key stage of ap­proval process

Almost a year and a half after DBV Technologies pulled its peanut allergy immunotherapy patch from FDA review, the biotech will get their day in court. The FDA has scheduled an advisory committee hearing for May 15.

In the two-horse race to develop the first immunotherapy for peanut allergy, DBV had the early lead, filing an NDA for their patch in 2018. But on December 20 of that year, the company withdrew their application after, they said, meeting with regulators and determining they had not submitted “sufficient detail regarding data on manufacturing procedures and quality controls.” Aimmune filed their BLA 3 days later and won approval as the first immunotherapy for peanuts this month.