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.

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Dipal Doshi, Entrada Therapeutics CEO

Ver­tex just found the next big ‘trans­for­ma­tive’ thing for the pipeline — at a biotech just down the street

Back in the summer of 2019, when I was covering Vertex’s executive chairman Jeff Leiden’s plans for the pipeline, I picked up on a distinct focus on myotonic dystrophy Type I, or DM1 — one of what Leiden called “two diseases (with DMD) we’re interested in and we continue to look for those assets.”

Today, Leiden’s successor at the helm of Vertex, CEO Reshma Kewalramani, is plunking down $250 million in cash to go the extra mile on DM1. The lion’s share of that is for the upfront, with a small reserve for equity in a deal that lines Vertex up with a neighbor in Seaport that has been rather quietly going at both of Vertex’s early disease targets with preclinical assets.

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Ab­b­Vie slapped with age dis­crim­i­na­tion law­suit, fol­low­ing oth­er phar­mas

Add AbbVie to the list of pharma companies currently facing age discrimination allegations.

Pennsylvania resident Thomas Hesch filed suit against AbbVie on Wednesday, accusing the company of passing him over for promotions in favor of younger candidates.

Despite 30 years of pharma experience, “Hesch has consistently seen younger, less qualified employees promoted over him,” the complaint states.

David Light, Valisure CEO

Val­isure in the hot seat: New Form 483 over a 2021 in­spec­tion as CEO fires back

The notorious drug testing company Valisure, which has made a name for itself by forcing FDA’s hand with some of its safety-related uncoverings, received a letter this week after the FDA uncovered violations at its Connecticut-based testing lab in 2021.

The letter, which was sent on Dec. 5, stated that the FDA is “concerned” that Valisure was not aware of  drug supply chain security requirements.

Mark Cuban (Jed Jacobsohn/AP Images)

Mov­ing to the em­ploy­er side of health­care, Mark Cuban's Cost Plus Drugs part­ners with a PBM

From “Shark Tank” to direct-to-consumer generic drugs, Mark Cuban has made another inroad in the ongoing battle over prescription drug prices. His cost-plus-15% generic drug company, frequently undercutting many competitors, now has its sights set on the employer healthcare market.

Cost Plus Drugs, which originally pledged to cut out PBMs, has now partnered with the PBM EmsanaRx, majority owned by the Purchaser Business Group on Health, to launch a supplemental drug discount program designed specifically for self-funded employers, the company announced Thursday.

WIB22: Am­ber Salz­man had few op­tions when her son was di­ag­nosed with a rare ge­net­ic dis­ease. So she cre­at­ed a bet­ter one

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Amber Salzman’s life changed on a cold, damp day in Paris over tiny plastic cups of lukewarm tea.

She was meeting with Patrick Aubourg, a French neurologist studying adrenoleukodystrophy, or ALD, a rare genetic condition that causes rapid neurological decline in young boys. It’s a sinister disease that often leads to disability or death within just a few years. Salzman’s nephew was diagnosed at just 6 or 7 years old, and died at the age of 12.

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Ahead of ad­comm, FDA rais­es un­cer­tain­ties on ben­e­fit-risk pro­file of Cy­to­ki­net­ic­s' po­ten­tial heart drug

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet next Tuesday to discuss whether Cytokinetics’ potential heart drug can safely reduce the risk of cardiovascular death and heart failure in patients with symptomatic chronic heart failure with reduced ejection fraction.

The drug, known as omecamtiv mecarbil and in development for more than 15 years, has seen mixed results, with a first Phase III readout from November 2020 hitting the primary endpoint of reducing the odds of hospitalization or other urgent care for heart failure by 8%. But it also missed a key secondary endpoint analysts had pegged as key to breaking into the market.

Bags of shred­ded docs: In­di­an drug­mak­er Lupin hand­ed a Form 483 by FDA in­spec­tors

The generics manufacturer Lupin has been given another Form 483 from the FDA this year.

US regulators inspected Lupin’s pharmaceutical manufacturing site in the town of Mandideep, India from Nov. 14 through Nov. 23, with the 14-page report marking 16 observations.

The inspection report stated that the site did not have the appropriate controls over its computer systems to ensure that changes in “master production” or records are only done by authorized personnel, along with written procedures not being established to conduct annual reviews of records associated with drug batches.

Rami Elghandour, Arcellx CEO

Up­dat­ed: Gilead, Ar­cel­lx team up on an­ti-BC­MA CAR-T as biotech touts a 100% re­sponse rate at #ASH22

Gilead and Kite are plunking down big cash to get into the anti-BCMA CAR-T game.

The pair will shell out $225 million in cash upfront and $100 million in equity to Arcellx, Kite announced Friday morning, to develop the biotech’s lead CAR-T program together. Kite will handle commercialization and co-development with Arcellx, and profits in the US will be split 50-50.

Concurrent with the deal, Arcellx revealed its latest cut of data for the program known as CART-ddBCMA, ahead of a full presentation at this weekend’s ASH conference — a 100% response rate among patients getting the therapy. Investors jumped at the dual announcements, sending Arcellx shares $ACLX up more than 25% in Friday’s morning session.

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