Top 10 pipeline blowups, set­backs and sna­fus in H1 2016

Some years you have to stretch a bit to find a line­up of 10 no­table set­backs in the pipeline. In the first half of this year, I could have done one in each quar­ter and had a few left over for the dis­hon­or­able men­tion col­umn.

What we have here is a col­lec­tion of grue­some self-in­flict­ed wounds, more ev­i­dence that the home run swing looks good on pa­per and ter­ri­ble in ex­e­cu­tion and a new cat­e­go­ry: the drug that post­ed pos­i­tive da­ta but looked bad com­pared to the com­pe­ti­tion.

You can mark that last one in red; it will be back in fu­ture lists. Get­ting pos­i­tive da­ta against a place­bo or an old­er stan­dard of care is less and less like­ly to cut it. More and more con­tenders will need to be com­pared in­stant­ly against ri­vals in the pipeline. And with ex­pec­ta­tions run­ning high in fields like can­cer, more an­a­lysts (though not all) are go­ing to be mak­ing some re­al de­mands.

No doubt you’ll be think­ing of oth­er set­backs that didn’t make the list. And there were some doozies. J&J walked away from its an­ti-NGF pain drug ful­ranum­ab with bare­ly a nod of the head. No­var­tis’ “break­through” mus­cle drug bima­grum­ab failed a key study. Aduro’s com­bo failed a key test. Es­pe­ri­on was evis­cer­at­ed af­ter it told in­vestors that the FDA was chang­ing course on its tri­al de­mands.

So it goes.

Drug de­vel­op­ment is a tough field. Just ask the fol­low­ing com­pa­nies.

 


1. Clo­vis On­col­o­gy  rocile­tinib

CEO Patrick Ma­haffy

Boul­der, CO
$CLVS

CEO: Patrick Ma­haffy

The prob­lem: Clo­vis On­col­o­gy billed its lead-up to the sub­mis­sion for rocile­tinib as an Olympic dive. For play­ing a di­rect role in turn­ing the dive in­to a world-class bel­ly flop, the biotech wins the top spot as H1’s biggest im­plo­sion.

Clo­vis watch­ers will re­mem­ber that the com­pa­ny once played ri­val to As­traZeneca’s Tagris­so (9291). But then the FDA called them out on some sus­pi­cious tu­mor re­spons­es and a slew of con­firmed hits had to be trad­ed for miss­es. Its stock col­lapsed, FDA in­sid­ers could bare­ly con­ceal their dis­taste and the com­pa­ny lost a con­sid­er­able amount of rep along with the bulk of its mar­ket cap.

Ro­ci was quick­ly buried and now no men­tion is made of it — even when the FDA’s PDU­FA date rolled around June 28 with­out so much as a 2-sen­tence SEC fil­ing to mark the for­mal re­jec­tion.

Cur­rent­ly un­der in­ves­ti­ga­tion by the feds, Clo­vis is now ramp­ing up a new ef­fort to back ru­ca­parib, which finds it­self in yet an­oth­er late-stage horse race with se­ri­ous com­pe­ti­tion. Fail­ure here is not an op­tion, but it’s a very re­al pos­si­bil­i­ty.


2. As­traZeneca — ZS-9/treme­li­mum­ab

CEO Pas­cal So­ri­ot

Lon­don
$AZN

CEO: Pas­cal So­ri­ot

The prob­lems: You don’t pay $2.7 bil­lion for a hy­per­kalemia drug that’s await­ing reg­u­la­to­ry ac­tion at the FDA, tell every­one you’re go­ing to make more than a bil­lion dol­lars a year off of it and then get hand­ed a re­jec­tion with­out hav­ing a few red faces to show for it.

As­traZeneca says it won’t have to run a new tri­al for ZS-9, but it does have some ex­plain­ing to do about man­u­fac­tur­ing that was se­ri­ous enough to war­rant a CRL. As­traZeneca is a Big Phar­ma in a hur­ry, though, and caught up in a bid­ding war it bar­reled in­to a set­back.

ZS-9 is now like­ly on hold un­til around the end of the year or ear­ly 2017 as Re­lyp­sa’s ri­val Veltas­sa con­tin­ues to make progress on the mar­ket. Yet to be de­cid­ed: Which of these drugs will have the most fa­vor­able safe­ty pro­file, though ZS-9 still has sev­er­al ad­vo­cates on its side.

As­traZeneca, mean­while, al­so had to ex­plain a so­lo set­back for the CT­LA-4 drug treme­li­mum last Feb­ru­ary. A top prospect at As­traZeneca, the drug failed a Phase IIb tri­al for mesothe­lioma af­ter in­ves­ti­ga­tors re­cruit­ed 571 pa­tients for the test.


3. Bio­Marin  dris­apersen

San Rafael, CA
$BM­RN

CEO: Jean-Jacques Bi­en­aimé

The prob­lem: Bio­Marin paid $680 mil­lion to get dris­apersen in its buy­out of Pros­en­sa. But that big gam­ble end­ed up be­ing more than a com­plete write-off.

First, the FDA re­ject­ed the drug, which had al­ready failed a Phase III in the hands of Glax­o­SmithK­line, which quick­ly washed its hands of the drug and walked away. Then the EMA said no as well, and Bio­Marin not on­ly jet­ti­soned the lead drug, the com­pa­ny deep-sixed three fol­low-up ther­a­pies it was work­ing with in Phase II.

The com­pa­ny’s in­ves­ti­ga­tors couldn’t get any­where with their ar­gu­ment that there was a treat­ment strat­e­gy that could help boys af­fect­ed by the lethal dis­ease. The out­side and in­side ex­perts at the FDA gave that dis­cus­sion short shrift. Now the R&D group is go­ing back to the draw­ing board as Sarep­ta pre­pares to see if it can sur­vive an at­tempt at an ac­cel­er­at­ed ap­proval.


4. Alk­er­mes — ALKS-5461

CEO Richard Pops

Dublin
$ALKS

CEO Richard Pops

The prob­lem: A few weeks be­fore the read­out on the first two stud­ies for ALKS-5461 hit in Jan­u­ary, CEO Richard Pops called it a pend­ing “seis­mic” event.

And how.

The first six months of this year was no time to dis­ap­point in­vestors grap­pling with a bear mar­ket for biotech stocks. Alk­er­mes learned that les­son the hard way when its de­pres­sion drug failed two stud­ies and the mar­ket quick­ly re­lieved it of $4 bil­lion in mar­ket cap.

The rea­son de­vel­op­ers have three or four Phase III stud­ies for a de­pres­sion drug is be­cause they are like­ly to fail. One af­ter an­oth­er has been done in by the place­bo ef­fect, but Alk­er­mes be­lieved that it had an edge with a nov­el new tri­al de­sign aimed at thwart­ing that out­come. So two down means the drug is dead, right?

Not quite. The com­pa­ny came up with some post hoc rea­sons to be­lieve they were still on to some­thing and some an­a­lysts be­lieve that a pos­i­tive read­out for the third study could yet sal­vage the sit­u­a­tion. But it’s a nar­row, dan­ger­ous path to be trav­el­ing at this stage.

Alk­er­mes’ stock has been mak­ing a come­back since the com­pa­ny was blast­ed, but it’s been a slow climb.


5. In­fin­i­ty Phar­ma­ceu­ti­cals — du­velis­ib

CEO Ade­lene Perkins

Cam­bridge, MA
$IN­FI

CEO Ade­lene Perkins

The prob­lem: Some­times even a sta­tis­ti­cal win can be a big los­er. Case in point: Du­velis­ib.

A few weeks ago their lead drug hit the pri­ma­ry end­point in the Phase II study for in­do­lent non-Hodgkin lym­phoma, and its part­ner Ab­b­Vie quick­ly fold­ed its tent, dis­missed their $250 mil­lion up­front part­ner­ing pay­ment and hit the streets.

It was good, but just not good enough con­sid­er­ing the com­pe­ti­tion.

In­fin­i­ty suf­fered a thump­ing on Wall Street, but af­ter back-to-back re­struc­tur­ings that cost 146 jobs (for­mer “cit­i­zen-own­ers”) the com­pa­ny says it can work things out in its fa­vor. Perkins, top sci­en­tist Ju­lian Adams and every­one else still in for the ride can earn a re­ten­tion bonus for stay­ing on board. But af­ter three strikes for three top drugs, some may start to ques­tion why they still have the bat.


6. Celldex — Rin­te­ga rindopepimut

Hamp­ton, NJ
$CLDX

CEO: An­tho­ny Maruc­ci

Can­cer vac­cines have had a woe­ful record over the last cou­ple of years. Celldex added an­oth­er dose of dis­as­ter af­ter its try with Rin­te­ga proved so in­ef­fec­tive at treat­ing glioblas­toma the in­de­pen­dent mon­i­tors sug­gest­ed that in­ves­ti­ga­tors go ahead and pull the plug on the piv­otal study last March.

The over­all sur­vival rate ac­tu­al­ly fa­vored the con­trol arm over the drug.

This was a drug that had in­spired con­sid­er­able con­fi­dence from the Phase II, which some in­vestors thought should have been good enough to fu­el an at­tempt at an ac­cel­er­at­ed ap­proval. Some an­a­lysts were al­so let down at the time.

Celldex has sev­er­al da­ta read­outs com­ing up. It’s in bad need of good news.


7. PTC Ther­a­peu­tics — Translar­na ataluren

CEO Stu­art Peltz

South Plain­field, NJ
$PTCT

CEO Stu­art Peltz

The prob­lem: The FDA doesn’t of­ten refuse to file an ap­pli­ca­tion, but it made an ex­cep­tion for PTC.

PTC gets some cred­it for ad­mit­ting that the agency said it didn’t have the da­ta need­ed for an ap­proval of Translar­na (ataluren), which pos­si­bly wasn’t too sur­pris­ing as their drug had failed a mid-stage and piv­otal study for Duchenne mus­cu­lar dy­s­tro­phy.

Reg­u­la­tors have carved out a spe­cial sta­tus for ex­per­i­men­tal drugs that treat Duchenne, though. That helps ex­plain why the Eu­ro­peans gave it a con­di­tion­al ap­proval two years ago and still have done noth­ing af­ter the lat­est set­back. Even NICE is ne­go­ti­at­ing over what it will pay to cov­er the drug, while it has gath­ered sig­nif­i­cant ev­i­dence that the drug doesn’t work well at all.

PTC may have thought that same reg­u­lar­i­ty gen­eros­i­ty would ex­tend to Wash­ing­ton DC. But that was wrong.


8. Io­n­is Phar­ma­ceu­ti­cals — IO­N­IS-TTRR

CEO Stan­ley Crooke

Carls­bad, CA
$IONS

CEO Stan­ley Crooke

The prob­lem: Io­n­is changed its name from Isis to put a lit­tle dis­tance be­tween it­self and the no­to­ri­ous ter­ror­ist group. But late­ly, it’s been ter­ror­iz­ing in­vestors with a safe­ty haz­ard on its lead an­ti­sense pro­gram.

Io­n­is CEO Stan­ley Crooke took the lead role in the dra­ma, ex­plain­ing dur­ing a call with an­a­lysts in May that their drug – at high dos­es — had been linked to per­plex­ing low platelet counts in pa­tients. That caused the FDA to trig­ger a clin­i­cal hold on a pro­gram, spurring Glax­o­SmithK­line to put a planned Phase III on a back burn­er.

Rather than re­as­sure in­vestors, Crooke seemed on­ly to make mat­ters steadi­ly worse on his call, de­clin­ing to an­swer some ques­tions, such as whether any pa­tients had died. He pled for more time, but in­vestors are im­pa­tient with un­cer­tain­ty and fear.

Fur­ther com­pli­cat­ing Io­n­is’ po­si­tion is its close com­pe­ti­tion with Al­ny­lam, which was boost­ed on the tra­vails of its ri­val.


9. Ab­b­Vie — Ro­va-T

CEO Richard Gon­za­lez

North Chica­go, IL
$AB­BV

CEO: Richard Gon­za­lez

The prob­lem: Ab­b­Vie is de­vel­op­ing a rep­u­ta­tion as an undis­ci­plined buy­er. And you can put much of that down to Ro­va-T now.

Ab­b­Vie paid $5.8 bil­lion in cash to buy Stem­cen­trx, large­ly based on the promise of the lit­tle-known can­cer drug, which plays along a path­way for stem cells. And it has promised $4 bil­lion more in mile­stones.

But at AS­CO the pre­lim­i­nary da­ta for small cell lung can­cer showed a one-month sur­vival ad­van­tage over his­tor­i­cal trends, caus­ing more than a few an­a­lysts to do a dou­ble take on the drug and the deal. Ab­b­Vie can still turn this around, but the pub­lic de­but of this drug turned in­to a prat­fall.


10. Reg­u­lus — RG-101

CEO Paul Grint

La Jol­la, CA
$RGLS

CEO: Paul Grint

The prob­lem: Reg­u­lus got start­ed nine years ago as a promis­ing joint ven­ture of Al­ny­lam and Io­n­is, which you passed in the num­ber eight spot on this list. Now in the lead up to its 10th an­niver­sary, the com­pa­ny is faced with a fresh clin­i­cal hold on its lead pro­gram.

The biotech’s whole rea­son for be­ing cen­ters on its mi­croR­NA tech. The plat­form led it to a drug, RG-101, that is billed as a po­ten­tial one-time treat­ment for he­pati­tis C. It’s al­so now been linked to two cas­es of jaun­dice, which trig­gered the hold.

The reg­u­la­to­ry ac­tion raised all sorts of thorny is­sues for the com­pa­ny, in­clud­ing why it would have a top pipeline drug in a field where sev­er­al new cures dom­i­nate the field. Even if RG-101 turns out to be a suc­cess, it would still face tough com­pe­ti­tion. (There is no tougher com­peti­tor than Gilead, which al­ways plays to win.)

He­pati­tis C is al­so a huge mar­ket with mil­lions of po­ten­tial pa­tients, of course, but that al­so means the reg­u­la­to­ry bar on safe­ty is high. And now it has to face these tra­vails with a bad­ly beat­en down stock price.

That’s not a pret­ty pic­ture.

Michel Younatsos, Biogen CEO (via YouTube)

Bio­gen scores a pri­or­i­ty re­view for its Alzheimer's drug ad­u­canum­ab, mov­ing one gi­ant leap for­ward in its con­tro­ver­sial quest

Biogen scored a big win at the FDA today as regulators accepted their application for the controversial Alzheimer’s drug aducanumab and gave it a priority review.

The PDUFA date is March 7, 2021.

That’s the ideal scenario Biogen was looking for as disappointed analysts wondered aloud about the delayed application.

The big biotech also notes that the “FDA has stated that, if possible, it plans to act early on this application under an expedited review.”

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Ryan Watts, Denali CEO

Bio­gen hands De­nali $1B-plus in cash, $1B-plus in mile­stones to part­ner on late-stage Parkin­son’s drug

Biogen is handing over more than a billion dollars cash to partner with the up-and-coming neurosciences crew at Denali on a new therapy for Parkinson’s. And the big biotech is ready to pile on more than a billion dollars more in milestones — if the alliance is a success.

For Biogen $BIIB, the move on Denali’s small molecule inhibitors of LRRK2 puts them in line to collaborate on a late-stage program for DNL151, which is scheduled to start next year.

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Covid-19 roundup: No­vavax inks vac­cine deals with Japan and In­dia; As­traZeneca near­ing agree­ments with Japan and Brazil

Following the release this week of promising early data for their Covid-19 vaccine candidate, Novavax has announced collaborations to supply it to two countries — Japan and India.

The Maryland-based biotech announced a deal Friday morning with Takeda to develop and manufacture up to 250 million doses per year of its adjuvanted vaccine. And late Thursday afternoon, Novavax entered into an agreement with the Serum Institute of India to provide up to 1 billion doses to India and low- and middle-income countries.

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In sur­pris­ing set­back, com­bo of Roche’s Tecen­triq and chemo fails to help pa­tients with triple-neg­a­tive breast can­cer

Roche broke ground last year when they secured the first FDA approval for a checkpoint therapy in triple-negative breast cancer, a notoriously difficult-to-treat indication that has been passed over by the wave of targeted therapies.

Now, though, doctors are puzzling over why a combination of drugs meant to make that therapy more potent instead appeared to make it less effective.

Roche said Thursday that in a Phase III trial, combining their PD-1/L1 checkpoint therapy Tecentriq with the chemotherapy paclitaxel, did not significantly improve progression-free survival for patients with locally advanced or metastatic triple-negative breast cancer over giving those patients chemotherapy alone. In fact, patients on the Tecentriq-chemo arm had lower overall survival than patients on chemo, although the drugmaker cautioned that the trial was not powered for that endpoint and the data were immature.

President Trump (AP Images)

FDA takes the lead on defin­ing es­sen­tial un­der Trump's 'Buy Amer­i­can' ex­ec­u­tive or­der — as in­dus­try warns of sup­ply chain dis­rup­tion

President Donald Trump has signed an executive order detailing how the federal government should help on-shore drug manufacturing — and the FDA will play a central role.

The agency now has three months to draw up the list of “essential medicines, medical countermeasures, and their critical inputs” that the US must have available at all times. Various departments and agencies are then directed to buy these drugs and their ingredients from American manufacturers.

Jan Hatzius (Photographer: Christopher Goodney/Bloomberg via Getty Images)

When will it end? Gold­man econ­o­mist gives late-stage vac­cines a good shot at tar­get­ing 'large shares' of the US by mid-2021 — but the down­side is daunt­ing

It took decades for hepatitis B research to deliver a slate of late-stage candidates capable of reining the disease in.

With Covid-19, the same timeline has devoured all of 5 months. And the outcome will influence the lives of billions of people and a multitrillion-dollar world economy.

Count the economists at Goldman Sachs as optimistic that at least one of these leading vaccines will stay on this furiously accelerated pace and get over the regulatory goal line before the end of this year, with a shot at several more near-term OKs. That in turn should lead to the production of billions of doses of vaccines that can create herd immunity in the US by the middle of next year, with Europe following a few months later.

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J&J gets a fresh OK for es­ke­t­a­mine, but is it re­al­ly the game-chang­er for de­pres­sion Trump keeps tweet­ing about?

Backed by an enthusiastic set of tweets from President Trump and a landmark OK for depression, J&J scooped up a new approval from the FDA for Spravato today. But this latest advance will likely bring fresh scrutiny to a drug that’s spurred some serious questions about the data, as well as the price.

First, the approval.

Regulators stamped their OK on the use of Spravato — developed as esketamine, a nasal spray version of the party drug Special K or ketamine — for patients suffering from major depressive disorder with acute suicidal ideation or behavior.

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Douglas Fambrough, Dicerna CEO (Boehringer Ingelheim via YouTube)

Roche-backed Dicer­na push­es in­to the pack rac­ing to­ward the block­buster hep B goal line, armed with PhI da­ta

Dicerna has lined up a set of proof-of-concept data from a small cohort of hepatitis B patients in a match-up against some heavyweight rivals which got out in front of this race. And right in the front row you’ll find a team from Roche, which paid $200 million in cash and offered another $1.5 billion in milestones to partner with Dicerna $DRNA on their RNAi program for hep B.

Right now it’s looking competitive, with lots of big challenges ahead.

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Lund­beck sounds taps on an­oth­er CNS drug, re­treat­ing from a mine field still oc­cu­pied by a Mer­ck team

Lundbeck has snipped another clinical-stage branch of its CNS research, dumping a schizophrenia program after determining that their therapy would have no positive influence on the disease.

Designed originally as a 240-patient study, researchers set out in early 2019 to see if a homegrown drug dubbed Lu AF11167 could make it through a proof-of-concept study. The drug is a PDE10Ai inhibitor, targeting an enzyme which it said at the time offered a new pathway to retuning the body’s neurotransmitter dopamine. The big idea was that by hitting their target, the drug would modulate “dopamine D1 and D2 receptor-mediated intraneuronal signaling without binding to these receptors,” influencing negative symptoms of schizophrenia.

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