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.

M&A: a crit­i­cal dri­ver for sus­tain­able top-line growth in health­care

2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

15 LGBTQ lead­ers in bio­phar­ma; Paul Stof­fels’ Gala­pa­gos re­vamp; As­traZeneca catch­es up in AT­TR; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

A return to in-person conferences also marks a return to on-the-ground reporting. My colleagues Beth Synder Bulik and Nicole DeFeudis were on-site at Cannes Lions, bringing live coverage of pharma’s presence at the ad festival — accompanied by photos from Clara Bui, our virtual producer, that bring you right to the scene. You can find a recap (and links to all the stories) below.

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AstraZeneca's new Evusheld direct to consumer campaign aims to reach more immunocompromised patients.

As­traZeneca de­buts first con­sumer cam­paign for its Covid-19 pro­phy­lac­tic Evusheld — and a first for EUA drugs

AstraZeneca’s first consumer ad for Evusheld is also a first for drugs that have been granted emergency use authorizations during the pandemic.

The first DTC ad for a medicine under emergency approval, the Evusheld campaign launching this week aims to raise awareness among immunocompromised patients — and spur more use.

Evusheld nabbed emergency authorization in December, however, despite millions of immunocompromised people looking for a solution and now more widespread availability of the drug.

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Abortion-rights protesters regroup and protest following Supreme Court's decision to overturn Roe v. Wade. (AP Photo/Gemunu Amarasinghe)

Fol­low­ing SCO­TUS de­ci­sion to over­turn abor­tion pro­tec­tions, AG Gar­land says states can't ban the abor­tion pill

Following the Supreme Court’s historic decision on Friday to overturn Americans’ constitutional right to an abortion after almost 50 years, Attorney General Merrick Garland sought to somewhat reassure women that states will not be able to ban the prescription drug sometimes used for abortions.

Following the decision, the New England Journal of Medicine also published an editorial strongly condemning the reversal, saying it “serves American families poorly, putting their health, safety, finances, and futures at risk.”

De­spite a slow start to the year for deals, PwC pre­dicts a flur­ry of ac­tiv­i­ty com­ing up

Despite whispers of a busy year for M&A, deal activity in the pharma space is actually down 30% on a semi-annualized basis, according to PwC’s latest report on deal activity. But don’t rule out larger deals in the second half of the year, the consultants said.

PwC pharmaceutical and life sciences consulting solutions leader Glenn Hunzinger expects to see Big Pharma companies picking up earlier stage companies to try and fill pipeline gaps ahead of a slew of big patent cliffs. Though a bear market continues to maul the biotech sector, Hunzinger said recent deals indicate that pharma companies are still paying above current trading prices.

Joe Wiley, Amryt Pharma CEO

Am­ryt Phar­ma sub­mits a for­mal dis­pute res­o­lu­tion to the FDA over re­ject­ed skin dis­ease drug

The story of Amryt Pharma’s candidate for the genetic skin condition epidermolysis bullosa, or EB, will soon enter another chapter.

After the Irish drugmaker’s candidate, dubbed Oleogel-S10 and marketed as Filsuvez, was handed a CRL earlier this year, the company announced in a press release that it plans to submit a formal dispute resolution request for the company’s NDA for Oleogel-S10.

Sen. Thom Tillis (R-NC) (J. Scott Applewhite/AP Images)

Phar­ma-friend­ly sen­a­tor calls on FDA for a third time to show patent pro­tec­tions should­n't be blamed for high drug prices

North Carolina Republican Sen. Thom Tillis made a name for himself in the 2020 election cycle as the darling of the pharma industry, accepting hundreds of thousands in campaign contributions, even from the likes of Pfizer CEO Albert Bourla.

Those contributions have led Tillis to attempt to re-write patent laws in pharma’s favor, a move which failed to gain steam in 2019, and request for a third time since January that the FDA should help stop “the false narrative that patent protections are to blame for high drug prices.”

EMA signs off on 3 drugs re­cent­ly re­ject­ed by FDA, in­clud­ing Bio­Mar­in's new he­mo­phil­ia gene ther­a­py

The EMA’s human medicines committee on Friday recommended three new drugs for approval or conditional approval, even as their US counterparts have rejected these three for various reasons.

In a major move, CHMP offered a thumbs-up to a conditional marketing authorization for the first gene therapy to treat severe hemophilia A, although the agency cautioned that it’s so far unknown how long the effects of infusion will last.

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Joe Papa (Ryan Remiorz/The Canadian Press via AP, File)

Joe Pa­pa re­signs as chair of Bausch Health as bil­lion­aire John Paul­son takes over

Joe Papa, chair of Bausch Health, officially resigned on Thursday and the board appointed billionaire hedge fund manager John Paulson as the new chair, effective immediately.

The specialty pharma company sought to make clear that Papa’s abrupt departure “was not due to any dispute or disagreement with the Company, its management or the Board on any matter relating to the Company’s operations, policies or practices.”

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