Mer­ck study may sig­nal doom for a broad group of piv­otal Alzheimer’s stud­ies

The BACE the­o­ry in Alzheimer’s R&D is sim­ple. Cut off the flow of amy­loid be­ta to the brain and you can elim­i­nate what is wide­ly be­lieved — though not proven — to be a cause of the dis­ease. Do that, and you could bend the course of this dev­as­tat­ing ill­ness in mil­lions of peo­ple with mild to mod­er­ate forms of the dis­ease.

And Mer­ck $MRK just spent a for­tune to demon­strate that it may well be com­plete­ly wrong.

To be sure, Mer­ck ran a clean study for verube­ce­s­tat, the lead­ing BACE drug in the clin­ic, and dis­played the da­ta on 1,958 pa­tients for all to see to­day in the New Eng­land Jour­nal of Med­i­cine. In­ves­ti­ga­tors care­ful­ly tracked amy­loid be­ta flows in cere­brospinal cords and found that the drug did what it was in­tend­ed to do, with a dra­mat­ic re­duc­tion of the tox­ic pro­tein. 

It had no ef­fect, with pa­tients in the two dosage groups track­ing in par­al­lel de­cline on both cog­ni­tion and func­tion, the two clas­sic mea­sures for Alzheimer’s. 

The con­clu­sion they reached is that the dam­age al­ready present in the brains of pa­tients with Alzheimer’s may be too ex­ten­sive to treat with any BACE drug. And they al­so con­cede that the amy­loid the­o­ry it­self may be just flat wrong.

This sug­gests that once de­men­tia is present, dis­ease pro­gres­sion may be in­de­pen­dent of Aβ pro­duc­tion or, al­ter­na­tive­ly, that the amy­loid hy­poth­e­sis of Alzheimer’s dis­ease may not be cor­rect. Be­cause Aβ de­po­si­tion takes place years be­fore clin­i­cal symp­toms be­come ap­par­ent, it has been pro­posed that treat­ments tar­get­ing amy­loid should be im­ple­ment­ed ear­ly in the dis­ease process, be­fore the on­set of clin­i­cal symp­toms.

Soon af­ter this study failed, Mer­ck al­so threw in the tow­el on their sec­ond piv­otal tri­al, not­ing it too was a flop. Those da­ta are still be­ing eval­u­at­ed, but it un­der­scores the be­lief that all of the BACE stud­ies — in­clud­ing those at Eli Lil­ly $LLY, part­nered with As­traZeneca $AZN, or Bio­gen $BI­IB, al­lied with Ei­sai — are head­ed straight to fail­ure.

Bio­gen is al­so rolling the dice on ad­u­canum­ab, which the com­pa­ny has tout­ed as a lead­ing amy­loid be­ta ther­a­py. But with in­ves­ti­ga­tors in the field open­ly won­der­ing whether the amy­loid the­o­ry has lured a long line­up in­to a clin­i­cal dis­as­ter zone, it’s like­ly to face grow­ing skep­ti­cism that it can de­vel­op a safe, ef­fec­tive ther­a­py with just one drug.

This doesn’t by any means elim­i­nate work in the area. True, Pfiz­er re­cent­ly pulled out af­ter spend­ing hun­dreds of mil­lions of dol­lars on their pro­grams. But star­tups like De­nali be­lieve that new and bet­ter tech­nol­o­gy can give them bet­ter odds at suc­cess, while Cel­gene is jump­ing in with its own new pipeline. Oth­ers want to see if com­bi­na­tion ap­proach­es us­ing tau and amy­loid be­ta to­geth­er could work. 

Mer­ck’s sug­ges­tion about go­ing even ear­li­er in the dis­ease process has al­so prompt­ed a range of stud­ies in pre-symp­to­matic pa­tients, while the FDA has sig­naled its in­ter­est in com­ing up with bio­mark­ers to help speed new stud­ies.

Af­ter more than 200 R&D projects end­ed in dis­as­ter, though, Alzheimer’s is look­ing like an in­creas­ing­ly daunt­ing chal­lenge, with no clear path for­ward that would in­spire con­fi­dence among pa­tients with the dis­ease.

How one start­up fore­told the neu­ro­science re­nais­sance af­ter '50 years of shit­show'

In the past couple of years, something curious has happened: Pharma and VC dollars started gushing into neuroscience research.

Biogen’s controversial new Alzheimer’s drug Aduhelm has been approved on the basis of removing amyloid plaque from the brain, but the new neuro-focused pharma and biotechs have much loftier aims. Significantly curbing or even curing the most notorious disorders would prove the Holy Grail for a complex system that has tied the world’s best drug developers in knots for decades.

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Bob Bradway, Amgen CEO (Scott Eisen/Bloomberg via Getty Images)

Am­gen bel­lies back up to the M&A ta­ble for an­oth­er biotech buy­out, this time with a $2.5B deal for an an­ti­body play­er fo­cused on PS­MA

Five months after Amgen CEO Bob Bradway stepped up to the M&A table and acquired Five Prime for $1.9 billion, following up with the smaller Rodeo acquisition, he’s gone back in for another biotech buyout.

This time around, Amgen is paying $900 million cash while committing up to $1.6 billion in milestones to bag the privately held Teneobio, an antibody drug developer that has expertise in developing new bispecifics and multispecifics. In addition, Amgen cited Teneobio’s “T-cell engager platform, which expands on Amgen’s existing leadership position in bispecific T-cell engagers by providing a differentiated, but complementary, approach to Amgen’s current BiTE platform.”

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Ryan Watts, Denali CEO

De­nali slips as a snap­shot of ear­ly da­ta rais­es some trou­bling ques­tions on its pi­o­neer­ing blood-brain bar­ri­er neu­ro work

Denali Therapeutics had drummed up considerable hype for their blood-brain barrier technology since launching over six years ago, hype that’s only intensified in the last 14 months following the publications of a pair of papers last spring and proof of concept data earlier this year. On Sunday, the South San Francisco-based biotech gave the biopharma world the next look at in-human data for its lead candidate in Hunter syndrome.

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Art Levinson (Calico)

Google-backed Cal­i­co dou­bles down on an­ti-ag­ing R&D pact with Ab­b­Vie as part­ners ante up $1B, start to de­tail drug tar­gets

Seven years after striking up a major R&D alliance, AbbVie and Google-backed anti-aging specialist Calico are doubling down on their work with a joint, $1 billion commitment to continuing their work together. And they’re also beginning to offer some details on where this project is taking them in the clinic.

According to their statement, each of the two players is putting up $500 million more to keep the labs humming.

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Ugur Sahin, BioNTech CEO (Bernd von Jutrczenka/dpa via AP Images)

BioN­Tech is spear­head­ing an mR­NA vac­cine de­vel­op­ment pro­gram for malar­ia, with a tech trans­fer planned for Africa

Flush with the success of its mRNA Covid-19 vaccine, BioNTech is now gearing up for one of the biggest challenges in vaccine development — which comes without potential profit.

The German mRNA pioneer says it plans to work on a jab for malaria, then transfer the tech to the African continent, where it will work with partners on developing the manufacturing ops needed to make this and other vaccines.

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Why is On­col­o­gy Drug De­vel­op­ment Re­search Late to the Dig­i­tal Bio­mark­ers Game?

During the recent Annual ASCO Meeting, thousands of cancer researchers and clinicians from across the globe joined together virtually to present and discuss the latest findings and breakthroughs in cancer research and care. There were more than 5000+ scientific abstracts presented during this event, yet only a handful involved the use of motion-tracking wearables to collect digital measures relating to activity, sleep, mobility, functional status, and/or quality of life. Although these results were a bit disappointing, they should come as no surprise to those of us in the wearable technology field.

UP­DAT­ED: Pan­el of neu­ro­science ex­perts lays out the com­pli­ca­tions with us­ing Bio­gen's new Alzheimer's drug

Treatment of early Alzheimer’s patients with Biogen’s new drug Aduhelm should closely resemble how the drug was studied in its pivotal clinical trials, according to new recommendations from a panel of neuroscience experts led by UNLV’s Jeffrey Cummings.

“Those considering aducanumab therapy should understand that the expected benefit is slowing of cognitive and functional decline; improvement of the current clinical state is not anticipated,” they wrote Tuesday in The Journal of Prevention of Alzheimer’s Disease, noting that some of their recommendations are more specific or more restrictive than the information provided in the FDA’s prescribing information.

Christophe Weber, Takeda CEO (Kyodo via AP Images)

Take­da flesh­es out CNS pact with pep­tide drug­mak­er, set­ting aside $3.5B in fu­ture mile­stones

One of a suite of drugmakers looking to reinvest in the neuroscience space, Takeda has been aggressive in signing on new partners to help build up its pipeline in that space. But sometimes the best partner is the one you already have.

Takeda will set aside $3.5 billion in future milestones and an undisclosed upfront payment to build out its drug discovery deal with Japanese peptide conjugate maker PeptiDream, adding neurodegeneration to the partnership’s list of CNS targets, the companies said Tuesday.

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George Yancopoulos, Regeneron

Re­gen­eron's lat­est ge­net­ics dis­cov­ery hooks As­traZeneca — now all-in on de­vel­op­ing small mol­e­cules for obe­si­ty

Just weeks after its widely lauded genetics research arm tagged a promising new target for obesity, Regeneron has signed up an industry heavyweight to collaborate with on developing new drugs that can potentially act as a game-changer in what has proven to be a tough field for developers.

The Regeneron Genetics Center published a paper in Science at the beginning of this month highlighting how their work sequencing the genomes of 650,000 people highlighted how people with at least 1 inactive copy of the GPR75 gene weighed on average 12 pounds less than the rest of the population with a 54% reduction in risk of obesity.

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