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.

The DCT-OS: A Tech­nol­o­gy-first Op­er­at­ing Sys­tem - En­abling Clin­i­cal Tri­als

As technology-enabled clinical research becomes the new normal, an integrated decentralized clinical trial operating system can ensure quality, deliver consistency and improve the patient experience.

The increasing availability of COVID-19 vaccines has many of us looking forward to a time when everyday things return to a state of normal. Schools and teachers are returning to classrooms, offices and small businesses are reopening, and there’s a palpable sense of optimism that the often-awkward adjustments we’ve all made personally and professionally in the last year are behind us, never to return. In the world of clinical research, however, some pandemic-necessitated adjustments are proving to be more than emergency stopgap measures to ensure trial continuity — and numerous decentralized clinical trial (DCT) tools and methodologies employed within the last year are likely here to stay as part of biopharma’s new normal.

Onno van de Stolpe, Galapagos CEO (Thierry Roge/Belga Mag/AFP via Getty Images)

Gala­pa­gos chops in­to their pipeline, drop­ping core fields and re­or­ga­niz­ing R&D as the BD team hunts for some­thing 'trans­for­ma­tive'

Just 5 months after Gilead gutted its rich partnership with Galapagos following a bitter setback at the FDA, the Belgian biotech is hunkering down and chopping the pipeline in an effort to conserve cash while their BD team pursues a mission to find a “transformative” deal for the company.

The filgotinib disaster didn’t warrant a mention as Galapagos laid out its Darwinian restructuring plans. Forced to make choices, the company is ditching its IPF molecule ’1205, while moving ahead with a Phase II IPF study for its chitinase inhibitor ’4617.

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An­oth­er failed tri­al for Or­p­hazyme's 'pipeline-in-a-pro­duc­t' leaves shad­ow on drug's fu­ture

The tumultuous ride for Orphazyme continued on Friday as the company announced that a pivotal trial for its lead drug arimoclomol failed yet again, this time in the treatment of ALS, seeding doubt in a drug that had recently been cleared by the FDA for priority review. The latest failure casts a darker shadow on the upcoming decision despite Orphazyme’s upbeat outlook.

In a statement, the Danish biotech announced that the drug did not meet its primary or secondary endpoints evaluating function and survival. But the company has not announced any data surrounding the failure, instead saying that it will publish the complete results later this year.

Angela Merkel (AP Photo/Michael Sohn)

Covid-19 roundup: Pfiz­er sub­mits vac­cine for full ap­proval; Merkel op­pos­es Biden pro­pos­al to sus­pend IP for vac­cines

Pfizer and BioNTech said Friday that they’ve submitted a biologics license application to the FDA for full approval of their mRNA vaccine for those over the age of 16.

How long it will take the FDA to decide on the BLA will be set once it’s been formally accepted by the agency.

Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, previously told Endpoints News that the review of the BLA should take between three and four months, but it may be even faster than that.

As­traZeneca caps PD-L1/CT­LA-4/chemo com­bo come­back with OS win. Is treme­li­mum­ab fi­nal­ly ready for ap­proval?

AstraZeneca’s closely-watched POSEIDON study continues to be the rare bright spot in its push for an in-house PD-L1/CTLA-4 combo.

Combining Imfinzi and tremelimumab with physicians’ choice of chemotherapy helped patients with stage IV non-small cell lung cancer live longer, the company reported — marking the first time the still-experimental tremelimumab has demonstrated an OS benefit.

For AstraZeneca and CEO Pascal Soriot, the positive readout — which is devoid of numbers — offers much-needed validation for the big bet they made on Imfinzi plus tremelimumab, after the PD-L1/CTLA-4 regimen failed multiple trials in head and neck cancer as well as lung cancer.

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Stéphane Bancel, Getty

Mod­er­na CEO brush­es off US sup­port for IP waiv­er, eyes more than $19B in Covid-19 vac­cine sales in 2021

Moderna is definitively more concerned with keeping pace with Pfizer in the race to vaccinate the world against Covid-19 than it is with Wednesday’s decision from the Biden administration to back an intellectual property waiver that aims to increase vaccine supplies worldwide.

In its first quarter earnings call on Thursday, Moderna CEO Stéphane Bancel shrugged off any suggestion that the newly US-backed intellectual property waiver would impact his company’s vaccine or bottom line. Still, the company’s stock price fell by about 9% in early morning trading.

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In­cyte ponies up $12M to set­tle char­i­ty foun­da­tion kick­back claims; US ex­er­cis­es op­tion for more dos­es of mon­key­pox vac­cine

One in a string of lawsuits targeting copay charity foundations, the DOJ has been hunting drugmaker Incyte for what prosecutors alleged was a kickback scheme to court patients. Now, Incyte is clearing its name.

Incyte will shell out $12.6 million to settle claims it funneled funds through a charity foundation to cover federal copays for patients taking its JAK inhibitor Jakafi, the DOJ said this week.

CEO Khurem Farooq (Gyroscope)

Hours be­fore ex­pect­ed de­but, Gy­ro­scope post­pones its IPO as 2 oth­er biotechs hold the line on their march to Nas­daq

Editor’s note: Interested in following biopharma’s fast-paced IPO market? You can bookmark our IPO Tracker here.

In a surprising turn of events, UK-based Gyroscope Therapeutics has postponed its IPO mere hours before it was set to debut on Nasdaq.

Working on a gene therapy for wet AMD, Gyroscope was all set and ready to go public earlier this week, setting terms for a $142 million raise with a price range of $20 to $22. But in the wee hours of Friday morning, the company put out a press release saying they would delay their debut “in light of market conditions,” CEO Khurem Farooq said in a statement.

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Karyopharm taps long­time Pfiz­er, Am­gen vet to steer the ship; With Mer­ck in the rearview mir­ror, Roger Perl­mut­ter stakes his claim to a CEO job — and it's a sur­pris­ing choice

Like many who work in biopharma, Richard Paulson got started in the field because of a love of science.

Paulson had just finished business school and was looking to start a career that married his two passions. While looking for jobs, he thought of his grandmother who had struggled with Alzheimer’s disease, recalling how he saw first-hand what innovative medicines can do for patients. Ultimately, he started his first job in the space as a sales rep at Glaxo Wellcome, one of GlaxoSmithKline’s predecessors before its merger with SmithKline Beecham in 2000.