The FDA’s cau­tion­ary Hall of Shame: 22 ‘break­through’ drugs that sud­den­ly crashed in PhI­II

We still don’t know who will run the FDA un­der Don­ald J. Trump, the 45th Amer­i­can pres­i­dent. Com­mis­sion­er Robert Califf steps down at noon to­day. But Trump’s high-pro­file sit-downs with some un­ortho­dox can­di­dates for the job have put the spot­light on some new clin­i­cal short­cuts that could be used to speed drug de­vel­op­ment.

Some on the lib­er­tar­i­an side have said they want to sim­ply toss out the gold stan­dard on ef­fi­ca­cy and safe­ty al­to­geth­er, ex­co­ri­at­ing the old rules of mar­ket en­gage­ment.

That tox­ic ar­gu­ment rais­es some im­por­tant ques­tions about each stage of drug de­vel­op­ment. And there’s a new re­port out from the FDA that cov­ers just what you can miss if you cut Phase III out al­to­geth­er.

The au­thors raised some im­por­tant and time­ly ques­tions with their re­view of 22 case stud­ies — you could al­so call them cau­tion­ary tales — of drugs that fell no­to­ri­ous­ly short of the reg­u­la­to­ry mark. And they in­clude a batch of po­ten­tial­ly dan­ger­ous ther­a­pies that made it through Phase II look­ing like sol­id ad­di­tions to the na­tion’s phar­ma­copeia.

The Hall of Shame in­cludes:

  • Dara­pladib, the Glax­o­SmithK­line cho­les­terol drug that in­ves­ti­ga­tors were ab­solute­ly con­vinced was help­ing car­dio pa­tients. GSK went on to re­cruit 28,000 pa­tients for two Phase III tri­als that proved they were flat wrong.
  • Eli Lil­ly’s no­to­ri­ous sema­gace­s­tat for Alzheimer’s. Yes, the drug did have an im­pact on amy­loid be­ta, the sus­pect­ed tox­ic clus­ters of­ten found in pa­tients’ brains. It al­so dou­bled the risk of skin can­cer and a host of oth­er lethal side ef­fects while ac­tu­al­ly wors­en­ing out­comes for pa­tients. Lil­ly, though, dou­bled down on Alzheimer’s with solanezum­ab, which al­so failed mul­ti­ple clin­i­cal stud­ies.
  • Fig­i­tu­mum­ab from Pfiz­er, which al­so cleared the Phase II hur­dle as an add-on treat­ment for non-small cell lung can­cer, on­ly to demon­strate worse ad­verse events in Phase III. Pfiz­er went on to re­tract three of their stud­ies, cit­ing dis­crep­an­cies in the da­ta.
  • Sanofi tout­ed both bet­ter sur­vival rates and promis­ing tu­mor re­spons­es for ini­parib at one point. But this PARP in­hibitor, to the ex­treme em­bar­rass­ment of Sanofi, wasn’t even a PARP in­hibitor. In Phase III, the out­comes looked very sim­i­lar to stan­dard chemo.

Sure, new tech­nolo­gies of­fer added in­sights at an ear­li­er stage of de­vel­op­ment, notes the FDA re­port. But Phase II­Is were cru­cial in these cas­es, and like­ly will be in oth­ers.

And some­thing for the lib­er­tar­i­ans in Sil­i­con Val­ley to re­mem­ber:

As a re­sult of the Phase III stud­ies dis­cussed in this pa­per, pa­tients out­side of clin­i­cal tri­als were not sub­ject­ed to drugs that would not ben­e­fit them or to the risk of un­nec­es­sary se­ri­ous tox­i­c­i­ties, and did not suf­fer un­nec­es­sary fi­nan­cial ex­pen­di­tures. Where ef­fec­tive al­ter­na­tive ther­a­pies ex­ist­ed, they were not di­vert­ed from proven treat­ments…

Close to 38% of all drugs in the Phase III/NDA phase of de­vel­op­ment nev­er make it to an ap­proval. In Phase II/III, the chances of suc­cess are 35%, ac­cord­ing to a Tufts study of the de­vel­op­ment process. That leaves some big mar­gins for er­ror.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

Two wild weeks for Grail end in $8B Il­lu­mi­na buy­out

Grail’s whirlwind two weeks have ended in the wealthy arms of its former founder and benefactors.

Illumina has shelled out $8 billion to reacquire the closely-watched liquid biopsy startup they spun out just 5 years ago and sold off much of its shares just 3 years ago. The deal comes nearly two weeks after the well-heeled startup filed for a potentially massive IPO — one that was disrupted just a week later when Bloomberg reported that Illumina was in talks to buy their former spinout for up to $8 billion.

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Roche vaults to the front of the NL­RP3 clin­i­cal race, pay­ing $448M up­front to bag In­fla­zome

Roche is going all in on NLRP3.

The pharma giant is putting down $448 million (€380 million) upfront to snatch Novartis-backed Inflazome, which makes it a clinical player in the space overnight.

Dublin and Cambridge, UK-based Inflazome is the second NLRP3-focused biotech Roche has acquired in less than two years, and although no numbers were disclosed in the Jecure buyout, this is almost certainly a much larger deal.

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As­traZeneca pub­lish­es Covid-19 vac­cine PhI­II pro­to­cols in lock­step with Mod­er­na and Pfiz­er. How are they dif­fer­ent?

Following in the steps of Moderna and Pfizer, the other two American drugmakers currently in Phase III trials for their Covid-19 vaccines, AstraZeneca posted its own study protocols over the weekend. The move is the latest in a series of rare peeks behind the curtain, as such blueprints are typically shared once such trials are completed.

“Given the unprecedented global impact of the Coronavirus pandemic and the need for public information, AstraZeneca has published the detailed protocol and design of our AZD1222 clinical trial. As with most clinical development, protocols are not typically shared publicly due to the importance of maintaining confidentiality and integrity of trials. AstraZeneca continues to work with industry peers to ensure a consistent approach to sharing timely clinical trial information,” the company said in a statement.

Sebastian Nijman (file photo)

Roche looks to ge­net­ic mod­i­fiers for new drug tar­gets, team­ing up with Dutch biotech in $375M deal

Roche is gambling on a new way of discovering drug targets and, ultimately, promising to infuse more than $375 million into a small biotech if all goes well.

A spinout of the Netherlands Cancer Institute and Oxford University, Scenic Biotech set out to pioneer a field that’s gaining some traction among top VCs in the US: to harness the natural protecting powers of genetic modifiers — specific genes that suppress a disease phenotype.

Donald Trump and White House chief of staff Mark Meadows, before boarding Marine One (Getty Images)

Pric­ing deal col­laps­es over Big Phar­ma's re­fusal to is­sue $100 'cash card­s' be­fore the elec­tion — re­port

Late in August, as negotiations on a pricing deal with President Trump reached a boiling point, PhRMA president Stephen Ubl sent an email update to the 34 biopharma chiefs that sit on his board. He wrote that if the industry did not agree to pay for a $100 “cash card” sent to seniors before November, White House chief of staff Mark Meadows was going to tell the news media Big Pharma was refusing to “share the savings” with the elderly — and that all of the blame for failed drug pricing negotiations would lie squarely on the industry.

#ES­MO20: As­traZeneca aims to spur PRO­found shift in prostate can­cer treat­ment with Lyn­parza OS da­ta

AstraZeneca has unveiled the final, mature overall survival data that cemented Lynparza’s first approval in prostate cancer approval — touting its lead against rivals with the only PARP inhibitor to have demonstrated such benefit.

But getting the Merck-partnered drug to the right patients remains a challenge, something the companies are hoping to change with the new data cut.

The OS numbers on the subgroup with BRCA1/2 or ATM-mutated metastatic castration-resistant prostate cancer are similar to the first look on offer when the FDA expanded the label in May: Lynparza reduced the risk of death by 31% versus Xtandi and Zytiga. Patients on Lynparza lived a median of 19.1 months, compared to 14.7 months for the anti-androgen therapies (p = 0.0175).

Eli Lilly CSO Dan Skovronsky (file photo)

UP­DAT­ED: #ES­MO20: Eli Lil­ly shows off the da­ta for its Verzenio suc­cess. Was it worth $18 bil­lion?

The press release alone, devoid of any number except for the size of the trial, added nearly $20 billion to Eli Lilly’s market cap back in June. Now investors and oncologists will get to see if the data live up to the hype.

On Sunday at ESMO, Eli Lilly announced the full results for its Phase III MonarchE trial of Verzenio, showing that across over 5,000 women who had had HR+, HER2- breast cancer, the drug reduced the odds of recurrence by 25%. That meant 7.8% of the patients on the drug arm saw their cancers return within 2 years, compared with 11.3% on the placebo arm.

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Greg Friberg (File photo)

#ES­MO20: Am­gen team nails down sol­id ear­ly ev­i­dence of AMG 510’s po­ten­tial for NSCLC, un­lock­ing the door to a wave of KRAS pro­grams

The first time I sat down with Amgen’s Greg Friberg to talk about the pharma giant’s KRAS G12C program for sotorasib (AMG 510) at ASCO a little more than a year ago, there was high excitement about the first glimpse of efficacy from their Phase I study, with 5 of 10 evaluable non-small cell lung cancer patients demonstrating a response to the drug.

After decades of failure targeting KRAS, sotorasib offered the first positive look at a new approach that promised to open a door to a whole new approach by targeting a particular mutation to a big target that had remained “undruggable” for decades.

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