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.

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.

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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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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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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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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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.

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.

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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