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.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

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Covid-19 vac­cine boost­ers earn big thumbs up, but Mod­er­na draws ire over world sup­ply; What's next for Mer­ck’s Covid pill?; The C-suite view on biotech; 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.

You may remember that at the beginning of this year, Endpoints News set a goal to go broader and deeper. We are still working towards that, and are excited to share that Beth Snyder Bulik will be joining us on Monday to cover all things pharma marketing. You can sign up for her weekly Endpoints MarketingRx newsletter in your reader profile.

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Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'

 

Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

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Amit Etkin, Alto Neuroscience CEO (Alto via Vimeo)

A star Stan­ford pro­fes­sor leaves his lab for a start­up out to re­make psy­chi­a­try

About five years ago, Amit Etkin had a breakthrough.

The Stanford neurologist, a soft-spoken demi-prodigy who became a professor while still a resident, had been obsessed for a decade with how to better define psychiatric disorders. Drugs for depression or bipolar disorder didn’t work for many patients with the conditions, and he suspected the reason was how traditional diagnoses didn’t actually get at the heart of what was going on in a patient’s brain.

Roche's Tecen­triq cross­es the fin­ish line first in ad­ju­vant lung can­cer, po­ten­tial­ly kick­ing off gold rush

While falling behind the biggest PD-(L)1 drugs in terms of sales, Roche has looked to carve out a space for its Tecentriq with a growing expertise in lung cancer. The drug will now take an early lead in the sought-after adjuvant setting — but competitors are on the way.

The FDA on Friday approved Tecentriq as an adjuvant therapy for patients with Stage II-IIIA non small cell lung cancer with PD-(L)1 scores greater than or equal to 1, making it the first drug of its kind approved in an early setting that covers around 40% of all NSCLC patients.

Rahul Singhvi, Resilience CEO

A Bob Nelsen start­up turns to Har­vard to help sharp­en its tech, in­spir­ing first spin­out

One of Bob Nelsen’s latest projects is headed to Harvard.

Resilience, a company started with the goal of establishing itself as a “one-stop-shop” for companies looking to scale manufacturing, including for hard-to-develop cell and gene therapies, is less than a year old. Friday, it announced a five-year R&D deal with Harvard University that includes $30 million to develop biologics, including vaccines, nucleic acids and cell and gene therapies.

Tillman Gerngross, Adagio CEO

Q&A: Till­man Gern­gross ex­plains why his Covid mAb will have an edge over an al­ready crowd­ed field

If anyone knows about monoclonal antibodies, it’s serial entrepreneur, Adimab CEO, and Dartmouth professor of bioengineering Tillman Gerngross.

Even the name of Gerngross’ new antibody startup Adagio Therapeutics is meant to reflect his vision behind the development of his Covid-19 mAb: slowly, he said, explaining that “everyone else, whether it’s Regeneron, Lilly, or AstraZeneca, Vir, they all valued speed over everything.”

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Susan Galbraith speaking at Endpoints News' virtual EUBIO21 summit

Imfinzi/treme­li­mum­ab com­bo scores As­traZeneca an­oth­er OS win — this time in liv­er can­cer

Is the tide turning on AstraZeneca’s battered PD-L1/CTLA4 combo?

A single priming dose of the experimental tremelimumab, followed by Imfinzi every four weeks, beat Nexavar (sorafenib) in helping a group of liver cancer patients live longer in a Phase III study, the company reported, meeting the primary endpoint.

Specifically, the two drugs extended overall survival for patients with unresectable hepatocellular carcinoma who had not received prior systemic therapy and were not eligible for localized treatment.

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