FDA re­view rais­es some se­ri­ous ques­tions for Puma, but shares rock­et up on pos­i­tive notes

Puma Biotech­nol­o­gy will face some tough ques­tions from reg­u­la­tors dur­ing Wednes­day’s long-await­ed pan­el re­view for its ex­per­i­men­tal can­cer drug ner­a­tinib.

Not on­ly did the FDA re­view, out this morn­ing, raise point­ed ques­tions about the many changes that were made to Puma’s study for ear­ly-stage ERBB2-pos­i­tive breast can­cer, it al­so high­light­ed — as ex­pect­ed — the high rate of se­ri­ous di­ar­rhea ex­pe­ri­enced by pa­tients in the study.

One crit­i­cal is­sue: At one point, just four months be­fore Puma filed for an ap­proval, reg­u­la­tors al­so ad­vised Puma ex­ecs against fil­ing for an OK.

Pre-NDA meet­ing with Puma – FDA ad­vised they did not en­cour­age an NDA sub­mis­sion based on the ef­fi­ca­cy and safe­ty re­sults of Study 3004. This was due to sev­er­al study con­duct is­sues which would make in­ter­pre­ta­tion of the re­sults prob­lem­at­ic. The Ap­pli­cant was ad­vised that if an NDA was sub­mit­ted, an On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee dis­cus­sion would be re­quired.

At the same time, reg­u­la­tors did not con­demn the drug, not­ing that even with the ar­ray of changes to the study, there is da­ta sup­port­ing ef­fi­ca­cy. And the bulls ran with the win com­bined with an over­all neu­tral tone to the prob­lems Puma may face. Its shares $PBYI rock­et­ed up 80%, then quick­ly slid back down to a 50% gain on a sec­ond take of the re­view.

In its sum­ma­ry, the FDA not­ed that:

De­spite the un­planned amend­ments and po­ten­tial un­cer­tain­ty in­tro­duced with re­spect to the mag­ni­tude of ner­a­tinib ef­fect, based on the sen­si­tiv­i­ty analy­ses con­duct­ed, the re­sults ap­pear to be gen­er­al­ly sim­i­lar to the pri­ma­ry analy­sis re­sults, sup­port­ing an ef­fect of ner­a­tinib.

The FDA set up a rel­a­tive­ly short pan­el re­view for Wednes­day, which had trig­gered spec­u­la­tion from a host of short sell­ers who have dogged this biotech at every step that Puma was in line for a thump­ing. But as of now, that’s all it is.

Reg­u­la­tors not­ed, though, that they have con­cerns with the re­sults from the study.

There re­mains some un­cer­tain­ty re­gard­ing the true mag­ni­tude of the treat­ment ef­fect since the pri­ma­ry analy­sis (trun­cat­ed at 2-years fol­low-up) ob­served a haz­ard ra­tio of 0.66 (95% CI: 0.49, 0.90) which changed to 0.68 (95% CI: 0.51, 0.91) with the ex­plorato­ry up­dat­ed 2-year analy­sis and the ex­plorato­ry 5-year analy­sis ob­served a haz­ard ra­tio of 0.73 (95% CI: 0.57, 0.92).

Puma has been pil­lo­ried rou­tine­ly for the way it han­dled the se­vere in­stances of di­ar­rhea in its stud­ies. As the re­view notes, even with the ad­di­tion of an an­tidiar­rheal drug in Puma’s stud­ies there was still a high rate of dropouts.

While there were few­er dose re­duc­tions and dose holds in the Lop­eramide Co­hort of Study 6201 com­pared to pa­tients in Study 3004, there re­mained a sub­stan­tial rate of dis­con­tin­u­a­tion due to di­ar­rhea de­spite an­tidiar­rheal pro­phy­lax­is with Lop­eramide (16.8% in Study 3004 and 20.4% in Study 6201). In ad­di­tion, a high­er in­ci­dence of con­sti­pa­tion and nau­sea was re­port­ed in the Lop­eramide co­hort.

The FDA re­view should raise some ob­vi­ous ques­tions on Wednes­day. But the ju­ry still re­mains out on Puma’s fate. Matthew Eck­ler at RBC looked over the docs and saw much to be hap­py with.

In our ini­tial read, we didn’t come across any­thing that we view as over­ly sur­pris­ing. As ex­pect­ed, the FDA doc­u­ments read as harsh in some sec­tions (many FDA brief­ing books can), but ul­ti­mate­ly we see the points raised as hav­ing al­ready been wide­ly known in­clud­ing: 1) the clin­i­cal sig­nif­i­cance of iDFS ben­e­fit seen in Ex­teNET; 2) changes made to the de­sign of Ex­teNET; 3) Ner­a­tinib-as­so­ci­at­ed G3 di­ar­rhea; and 4) ben­e­fit of ner­a­tinib in the HR+ sub­group. We al­so note that we don’t see any men­tion of Aphin­i­ty in the FDA brief­ing book. The bot­tom line is that the FDA doc­u­ments read very bal­anced to us, and are frankly more pos­i­tive than we an­tic­i­pat­ed, set­ting the stage ODAC to make an un­am­bigu­ous rec­om­men­da­tion.

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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UP­DAT­ED: 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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Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

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Daniel O'Day, Gilead CEO (Kevin Dietsch/UPI/Bloomberg via Getty Images)

A new study points to $6.5B in pub­lic sup­port build­ing the sci­en­tif­ic foun­da­tion of Gilead­'s remde­sivir. Should that be re­flect­ed in the price?

By drug R&D standards, Gilead’s move to repurpose remdesivir for Covid-19 and grab an emergency use authorization was a remarkably easy, low-cost layup that required modest efficacy and a clean safety profile from just a small group of patients.

The drug OK also arrived after Gilead had paid much of the freight on getting it positioned to move fast.

In a study by Fred Ledley, director of the Center for Integration of Science and Industry at Bentley University in Waltham, MA, researchers concluded that the NIH had invested only $46.5 million in the research devoted to the drug ahead of the pandemic, a small sum compared to the more than $1 billion Gilead expected to spend getting it out this year, all on top of what it had already cost in R&D expenses.

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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: Mod­er­na sticks to Ju­ly for its Phase III as ru­mors swirl; Fol­low­ing US lead, EU buys up Covid-19 treat­ments

The Phase III might be delayed from its original early July goal, but Moderna says it will still kick off the pivotal study for what could ultimately be the first Covid-19 vaccine before the end of the month.

A day after Reuters reported that squabbling between the Cambridge biotech and government regulators had held up the trial by about two weeks, Moderna released a statement saying that they had completed enrollment of their 650-person Phase II trial and were on track to begin Phase III by the end of the month. The protocol for that study, which is meant to prove whether or not the vaccine can prevent people from becoming sick, has been finalized, they said.

Stephen Hahn, AP

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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Noubar Afeyan, Flagship CEO and Tessera chairman (Victor Boyko/Getty Images)

Flag­ship ex­ecs take a les­son from na­ture to mas­ter ‘gene writ­ing,’ launch­ing a star-stud­ded biotech with big am­bi­tions to cure dis­ease

Flagship Pioneering has opened up its deep pockets to fund a biotech upstart out to revolutionize the whole gene therapy/gene editing field — before gene editing has even made it to the market. And they’ve surrounded themselves with some marquee scientists and execs who have crowded around to help shepherd the technology ahead.

The lead player here is Flagship general partner Geoff von Maltzahn, an MIT-trained synthetic biologist who set out in 2018 to do CRISPR — a widely used gene editing tool — and other rival technologies one or two better. Von Maltzahn has been working with Sana co-founder Jake Rubens, another synthetic biology player out of MIT who he describes as his “superstar,” who’s taken the CSO role.

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Covid-19 roundup: Squab­bles with gov­ern­ment de­lay Mod­er­na’s PhI­II — re­ports; No­vavax se­cures largest Warp Speed deal yet: $1.6B

A much-anticipated Phase III trial for Moderna’s Covid-19 vaccine is being held up as the company delayed submitting trial protocols and sparred with government scientists on how to run the study and even what the benchmark for success should be, Reuters reported.

Moderna, the first US company to put their vaccine into human testing, was supposed to enter a 30,000-person study this month in partnership with the NIH to determine whether it can prevent infection. STAT reported last week that the trial was facing delays over the protocol, but that a July start was still possible. Neither the NIH nor Moderna ever disclosed a specific date the trial should start, but Reuters reported that the agency had hoped to begin on July 10.

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