Eli Lil­ly con­ducts an au­top­sy of an Alzheimer’s megaflop

For four years Eli Lil­ly $LLY com­mit­ted one of the biggest clin­i­cal ef­forts in the com­pa­ny’s his­to­ry to prov­ing that it could get solanezum­ab right on Alzheimer’s. Hav­ing nav­i­gat­ed through mul­ti­ple tri­al fail­ures al­ready, in­ves­ti­ga­tors were con­vinced that if they took what they had learned, changed the pa­tient pop­u­la­tion, stick­ing to on­ly pa­tients with a mild form of the dis­ease while us­ing bet­ter di­ag­nos­tics — even chang­ing the end­points in the lead up to the fi­nal read out — they could make a case that this drug could make a sig­nif­i­cant im­prove­ment for pa­tients.

In­stead, they came up with a set of mod­est fig­ures in­di­cat­ing that at best they had mere­ly tapped the brakes on the dis­ease. And to­day they spelled it all out in what will like­ly be the post mortem on what once fac­tored in as one of the biggest clin­i­cal gam­bles in the his­to­ry of bio­phar­ma.

Solanezum­ab was de­signed to flush amy­loid be­ta, a tox­ic pro­tein which of­ten clus­ters in the brains of Alzheimer’s vic­tims. The in­ves­ti­ga­tors of­fered some mixed mes­sages on just how ef­fec­tive so­la was in re­duc­ing a-be­ta de­posits. In­ves­ti­ga­tor tracked sig­nif­i­cant changes in plas­ma lev­els of the pro­tein, but check­ing amy­loid de­posits with PET imag­ing pro­duced no sig­nif­i­cant changes. Re­searchers in oth­er pro­grams will be fol­low­ing that close­ly as they make their own as­saults on amy­loid, which re­mains a key fo­cus. There is a grow­ing con­sen­sus in the field, though, that it will take com­bi­na­tion ther­a­pies to have a re­al im­pact on the mem­o­ry-wast­ing dis­ease that af­flicts mil­lions.

Look­ing for a dom­i­nant new block­buster, they had to set­tle for en­cour­ag­ing pa­tients to hope for some­thing bet­ter.

Lawrence S. Honig, MD, PhD, Co­lum­bia

“Alzheimer’s is a chal­leng­ing dis­ease that re­searchers have been com­mit­ted to study­ing for some years,” said Lawrence S. Honig, MD, PhD, pro­fes­sor of neu­rol­o­gy at Co­lum­bia Uni­ver­si­ty Med­ical Cen­ter and prin­ci­pal in­ves­ti­ga­tor of the EX­PE­DI­TION3 study, pre­sent­ed the da­ta at the meet­ing. “Now is not the time to give up. While the out­come of this study is not what we had hoped for, it is rea­son­able to be­lieve that dis­ease mod­i­fy­ing ther­a­pies to slow down the pro­gres­sion of Alzheimer’s dis­ease will be dis­cov­ered.”

The key fail­ure point was on ADAS-Cog14, which mea­sures a per­son’s cog­ni­tive func­tions, in­clud­ing mem­o­ry, at­ten­tion and lan­guage abil­i­ties. In­ves­ti­ga­tors tracked an 11% re­duc­tion in the rate of de­cline, a clear miss with a p-val­ue of .095.

The sec­ondary end­points weren’t that much dif­fer­ent.

  • There was the Mi­ni-Men­tal State Ex­am­i­na­tion, or MMSE, with a 13% slow­ing in cog­ni­tive de­cline.
  • The Clin­i­cal De­men­tia Rat­ing-Sum of Box­es (CDR-SB) scale showed a 15 per­cent slow­ing in de­cline (p=0.004) be­tween pa­tients treat­ed with solanezum­ab and pa­tients treat­ed with place­bo.
  • There was a 14 per­cent slow­ing of de­cline (p=.019) as mea­sured by the Alzheimer’s Dis­ease Co­op­er­a­tive Study- In­stru­men­tal Ac­tiv­i­ties of Dai­ly Liv­ing (AD­CS-iADL). The AD­CS-iADL scale mea­sures a per­son’s in­de­pen­dent per­for­mance in com­plex ac­tiv­i­ties of dai­ly liv­ing such as par­tic­i­pat­ing in a con­ver­sa­tion, prepar­ing a meal or shop­ping.
  • The Func­tion­al Ac­tiv­i­ties Ques­tion­naire did not show a sta­tis­ti­cal­ly sig­nif­i­cant dif­fer­ence be­tween pa­tients treat­ed with solanezum­ab and pa­tients treat­ed with place­bo (7 per­cent re­duc­tion in de­cline, p=0.140). The FAQ scale is a dif­fer­ent in­for­mant-based mea­sure of func­tion­al abil­i­ties. In­for­mants pro­vide per­for­mance rat­ings of the pa­tient on ten com­plex high­er-or­der ac­tiv­i­ties.

There was, though, a greater chance that the drug arm would suf­fer from spinal os­teoarthri­tis: 1.1 per­cent in the solanezum­ab group, 0.4 per­cent in the place­bo group. And there was a 0.9 per­cent rate of dy­suria in the solanezum­ab group.

In the mean­time, you can rack up an­oth­er set­back in a field that has known on­ly late-stage fail­ure in the past decade.

Martin Shkreli [via Getty]

Pris­on­er #87850-053 does not get to add drug de­vel­op­er to his list of cred­its

Just days after Retrophin shed its last ties to founder Martin Shkreli, the biotech is reporting that the lead drug he co-invented flopped in a pivotal trial. Fosmetpantotenate flunked both the primary and key secondary endpoints in a placebo-controlled trial for a rare disease called pantothenate kinase-associated neurodegeneration, or PKAN.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology
ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development
CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Hal Barron. GSK

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive piv­otal for cru­cial an­ti-BC­MA ther­a­py, point­ing to a push for quick OKs in a crowd­ed field

Hal Barron has his second positive round of Phase III data in hand for his anti-BCMA antibody drug conjugate belantamab mafodotin (GSK2857916). And GSK’s research chief says the data paves the way for their drive in search of an FDA approval for treating multiple myeloma.

It’s hard to overestimate the importance of this drug for GSK, a cornerstone of Barron’s campaign to make a dramatic impact on the oncology market and provide some long-lost excitement for the pharma giant’s pipeline. They’re putting this BCMA program at the front of that charge — looking to lead a host of rivals all aimed at the same target.

We don’t know what the data are yet, but DREAMM-2 falls on the heels of a promising set of data delivered 5 months ago for DREAMM-1. There investigators noted that complete responses among treatment-resistant patients rose to 15% in the extra year’s worth of data to look over, with a median progression-free survival rate of 12 months, up from 7.9 months reported earlier. The median duration of response was 14.3 months.

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UP­DAT­ED: An em­bold­ened As­traZeneca splurges $95M on a pri­or­i­ty re­view vouch­er. Where do they need the FDA to hus­tle up?

AstraZeneca is in a hurry.

We learned this morning that the pharma giant — not known as a big spender, until recently — forked over $95 million to get its hands on a priority review voucher from Sobi, otherwise known as Swedish Orphan Biovitrum.

That marks another step down on price for a PRV, which allows the holder to slash 4 months off of any FDA review time.

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Bob Smith, Pfizer

Pfiz­er is mak­ing a $500M state­ment to­day: Here’s how you be­come a lead play­er in the boom­ing gene ther­a­py sec­tor

Three years ago, Pfizer anted up $150 million in cash to buy Bamboo Therapeutics in Chapel Hill, NC as it cautiously stuck a toe in the small gene therapy pool of research and development.

Company execs followed up a year later with a $100 million expansion of the manufacturing operations they picked up in that deal for the UNC spinout, which came with $495 million in milestones.

And now they’re really going for it.

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Video: Putting the AI in R&D — with Badhri Srini­vasan, Tony Wood, Rosana Kapeller, Hugo Ceule­mans, Saurabh Sa­ha and Shoibal Dat­ta

During BIO this year, I had a chance to moderate a panel among some of the top tech experts in biopharma on their real-world use of artificial intelligence in R&D. There’s been a lot said about the potential of AI, but I wanted to explore more about what some of the larger players are actually doing with this technology today, and how they see it advancing in the future. It was a fascinating exchange, which you can see here. The transcript has been edited for brevity and clarity. — John Carroll

As­traZeneca’s Imfinzi/treme com­bo strikes out — again — in lung can­cer. Is it time for last rites?

AstraZeneca bet big on the future of their PD-L1 Imfinzi combined with the experimental CTLA-4 drug tremelimumab. But once again it’s gone down to defeat in a major Phase III study — while adding damage to the theory involving targeting cancer with a high tumor mutational burden.

Early Wednesday the pharma giant announced that their NEPTUNE study had failed, with the combination unable to beat standard chemo at overall survival in high TMB cases of advanced non-small cell lung cancer. We won’t get hard data until later in the year, but the drumbeat of failures will call into question what — if any — future this combination can have left.

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Why would Am­gen want to buy Alex­ion? An­a­lysts call hot­ly ru­mored takeover un­like­ly, but seize the mo­ment

A rumor that Amgen is closing in on buyout deal for Alexion has sparked a guessing game on just what kind of M&A strategy Amgen is pursuing and how much Alexion is worth.

Mizuho analyst Salim Syed first lent credence to the report out of the Spanish news outlet Intereconomía, which said Amgen is bidding as much as $200 per share. While the source may be questionable, “the concept of this happening doesn’t sound too crazy to me,” he wrote.