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.

A fa­vorite in Alex­ion’s C-suite is leav­ing, and some mighty sur­prised an­a­lysts aren’t the least bit hap­py about it

Analysts hate to lose a biotech CFO they’ve come to trust and admire — especially if they’re being blindsided by a surprise exit.

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David Grainger [file photo]

'Dis­con­nect the bas­tard­s' — one biotech's plan to break can­cer cell­s' uni­fied de­fens­es

Chemotherapy and radiotherapy are the current gladiators of cancer treatment, but they come with well-known limitations and side-effects. The emergence of immunotherapy — a ferocious new titan in oncologist’s toolbox — takes the brakes off the immune system to kill cancer cells with remarkable success in some cases, but the approach is not always effective. What makes certain forms of cancer so resilient? Scientists may have finally pieced together a tantalizing piece of the puzzle, and a new biotech is banking on a new approach to fill the gap.

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While No­var­tis ban­ish­es Zol­gens­ma scan­dal scars — Bio­gen goes on a Spin­raza 'of­fen­sive'

While Novartis painstakingly works to mop up the stench of the data manipulation scandal associated with its expensive gene therapy for spinal muscular atrophy (SMA) Zolgensma— rival Biogen is attempting to expand the use of its SMA therapy, Spinraza. 

The US drugmaker $BIIB secured US approval for Spinraza for use in the often fatal genetic disease in 2016. The approval covered a broad range of patients with infantile-onset (most likely to develop Type 1) SMA. 

Jason Kelly. Mike Blake/Reuters via Adobe

Eye­ing big ther­a­peu­tic push, Gink­go bags $290M to build a cell pro­gram­ming em­pire

Ginkgo Bioworks is on a roll. Days after publicizing a plan to nurture new startups via partnerships with accelerators Y Combinator and Petri, the Boston biotech says it has raised another $290 million for its cell programming platform to reach further and wider.

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UP­DAT­ED: Speak­er Nan­cy Pelosi to un­veil bill for fed­er­al­ly ne­go­ti­at­ed drug prices

After months of buzz from both sides of the aisle, Speaker Nancy Pelosi will today introduce her plan to allow the federal government to negotiate prices for 250 prescription drugs, setting up a showdown with a pharmaceutical industry working overtime to prevent it.

The need to limit drug prices is a rare point of agreement between President Trump and Democrats, although the president has yet to comment on the proposal and will likely face pressure to back a more conservative option or no bill at all. Republican Senator Chuck Grassley is reportedly lobbying his fellow party members on a more modest proposal he negotiated with Democratic Senator Ron Wyden in July.

Jeff Kindler's Cen­trex­ion re­news bid to make pub­lic de­but

Jeffrey Kindler’s plan to take his biotech — which is developing a slate of non-opioid painkillers — public, is back on.

The Boston based company, led by former Pfizer $PFE chief Kindler, originally contemplated a $70 million to $80 million IPO last year— but eventually postponed that strategy. On Wednesday, the company revived its bid to make a public debut in a filing with the SEC — although no pricing details were disclosed.

Zachary Hornby. Boundless

'A fourth rev­o­lu­tion in can­cer ther­a­pies': ARCH-backed Bound­less Bio flash­es big check, makes big­ger promis­es in de­but

It was the cellular equivalent of opening your car door and finding an active, roaring engine in the driver seat.

Scientists learned strands of DNA could occasionally appear outside of its traditional home in the nucleus in the 1970s, when they appeared as little, innocuous circles on microscopes; inexplicable but apparently innate. But not until UC San Diego’s Paul Mischel published his first study in Science in 2014 did researchers realize these circles were not only active but potentially overactive and driving some cancer tumors’ superhuman growth.

It’s fi­nal­ly over: Bio­gen, Ei­sai scrap big Alzheimer’s PhI­I­Is af­ter a pre­dictable BACE cat­a­stro­phe rais­es safe­ty fears

Months after analysts and investors called on Biogen and Eisai to scrap their BACE drug for Alzheimer’s and move on in the wake of a string of late-stage failures and rising safety fears, the partners have called it quits. And they said they were dropping the drug — elenbecestat — after the independent monitoring board raised concerns about…safety.

We don’t know exactly what researchers found in this latest catastrophe, but the companies noted in their release that investigators had determined that the drug was flunking the risk/benefit analysis.

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Mer­ck helps bankroll new part­ner Themis' game plan to fin­ish the chikun­gun­ya race and be­gin on­colyt­ic virus quest

As Themis gears up for a Phase III trial of its chikungunya vaccine, the Vienna-based biotech has closed out €40 million ($44 million) to foot the clinical and manufacturing bills.

Its heavyweight partners at Merck — which signed a pact around a mysterious “blockbuster indication” last month — jumped into the Series D, led by new investors Farallon Capital and Hadean Ventures. Adjuvant Capital also joined, as did current investors Global Health Investment Fund, aws Gruenderfonds, Omnes Capital, Ventech and Wellington Partners Life Sciences.