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.

Why it Works: Man­u­fac­tur­ing a Vac­cine in a Mul­ti-Prod­uct Fa­cil­i­ty.

COVID-19 launched the pharmaceutical industry to the frontline in the battle against the fast-spreading global pandemic. The goal: distribute a safe, effective vaccine as quickly as possible. Major players in the vaccine market needed to partner with contract development and manufacturing organizations (CDMOs) to achieve the goal of mass vaccine quantities under expedited timelines. With CDMOs stepping up to play a critical role in the vaccine manufacturing process, multi-product CDMO facilities took the spotlight. Partnerships quickly formed as the race to save lives and fight a pandemic was on.

Merck CEO Rob Davis

Mer­ck emerges as lead bid­der in po­ten­tial Ac­celeron buy­out with deal pos­si­ble this week — re­port

With rumors swirling about a potential buyout of biotech Acceleron and its lead PAH drug sotatercept, market watchers have been keeping close tabs on industry movers and shakers due up for an expensive bolt-on. According to a new report, it appears Merck may be the one.

Merck is in “advanced talks” on a deal to acquire Cambridge, MA-based Acceleron in what previous reports pegged as a potential $11 billion buyout, the Wall Street Journal reported Monday. A deal could come as early as this week, according to the Journal.

Habib Dable, Acceleron CEO

Days of heat­ed ru­mors cul­mi­nate in a re­port that Ac­celeron is in ad­vanced buy­out talks

Days of frothy rumors about possible M&A discussions at Acceleron were capped late Friday with a Bloomberg report asserting that the biotech company is in advanced talks for an $11 billion buyout deal.

Bloomberg was unable to identify any bidders in the deal, but speculation has been running rampant that the surging value of Acceleron stock had to be the result of leaks around the auction of the company. As of early Monday morning, we’re still awaiting the final word.

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Alexander Lefterov/Endpoints News

The coro­n­avirus vac­cine that the world for­got could still help save it

Back at the beginning of the pandemic — back when we still called the virus “novel” and a single case in Washington state could make headlines — there emerged the story of the coronavirus vaccine that the world forgot.

It was an allegory for our pandemic ill-preparedness. At a time when the world had been caught so flat-footed, there were a pair of scientists who had seen the crisis coming, lab-coated Cassandras with an antidote if only the world had listened sooner.

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Ash Shehata, KPMG

As sup­ply chain wor­ries ease up, Big Phar­ma CEOs have a new top con­cern: re­cruit­ing and keep­ing em­ploy­ees

As the industry goes through a boom, Big Pharma’s CEOs seem to have realized one thing above the rest: It’s time to reward the people doing the leg work.

KPMG, a Big Four accounting network, has compiled a business confidence report for pharma CEOs for the past few years, and while 2020’s report had top executives soul-searching for answers and predictions amidst a chaotic time, it appears that some normalcy, coupled with the skyrocketing growth of the industry, has restored confidence levels at the top.

Safe­ty fears force Pfiz­er to change piv­otal DMD gene ther­a­py tri­al pro­to­col

As one of the biggest players in an increasingly packed gene therapy space, Pfizer has taken an early lead over specialists like Sarepta in taking a Duchenne muscular dystrophy (DMD) candidate into late-stage testing. But new safety fears have led Pfizer to scale back that trial, cutting out patients with certain genetic mutations.

Pfizer has amended its enrollment protocol for a Phase III test for gene therapy fordadistrogene movaparvovec in DMD after investigators flagged severe side effects tied to specific mutations, according to a letter the drugmaker sent to Parent Project Muscular Dystrophy, a patient advocacy group.

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Kevin Boyle, Ziopharm Oncology CEO

Zio­pharm lays off half its staff af­ter man­u­fac­tur­ing is­sues force de­lays

New Ziopharm CEO Kevin Boyle has only been at the biotech for less than a month, but he’s already engineering major changes.

Late Monday afternoon, Ziopharm announced a sweeping restructuring that involved eliminating more than half its workforce and 60 jobs in total. The layoffs were necessary to help the penny stock player refocus its attention on advancing its TCR program, which saw a setback earlier this year after “unforeseen delays” at a contract manufacturer, Ziopharm said.

Albert Bourla, Pfizer CEO (John Thys, Pool via AP Images)

Covid-19 roundup: Pfiz­er/BioN­Tech sub­mit vac­cine da­ta to FDA for younger chil­dren; Doc­tors kept pre­scrib­ing hy­drox­y­chloro­quine

Pfizer and BioNTech said Tuesday they submitted to FDA positive data from a Phase II/III trial of their Covid-19 vaccine in children aged 5 to less than 12 years old.

A formal EUA submission for the vaccine in these children is expected to follow “in the coming weeks,” the companies said in a statement.

The trial of 2,268 healthy participants aged 5 to less than 12 years old showed the vaccine was safe and elicited robust neutralizing antibody responses using a two-dose regimen of 10 μg doses, which is one-third the dose that’s administered to adults.

From left to right: Mark Springel, Kristina Wang, Lin Ao, Soufiane Aboulhouda

George Church, his stu­dents, and top VCs go na­tion­wide with a biotech train­ing camp

One night last fall, Floris Engelhardt sat down in her Boston apartment and logged onto a Zoom call, armed with a comic and a vague idea about starting a biotech.

Engelhardt was joining a student-run “match night.” A postdoc at MIT’s Bathe BioNanoLab, where researchers use DNA and RNA like Lego blocks for nanometer-sized structures, Engelhardt wanted to find real-world applications for her work. She sketched out — literally — a plan to use DNA origami, a decade-old technique for precisely folding DNA, to make therapies.

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