Af­ter yet an­oth­er PhI­II Alzheimer's fail­ure, ex­perts try to map a path out of the wreck­ing field

Pushed by a 15-year record of clin­i­cal fail­ures and pulled by an FDA search­ing for a prac­ti­cal new path for­ward for Alzheimer’s drug re­search, a joint com­mit­tee or­ga­nized by the NIH’s Na­tion­al In­sti­tute of Ag­ing and the Alzheimer’s As­so­ci­a­tion is sug­gest­ing a bio­mark­er-based ap­proach to defin­ing the ill­ness that can guide new de­vel­op­ment ef­forts.

Eliez­er Masli­ah

In place of the old tox­ic pro­tein de­bate that once di­vid­ed the field in­to two camps for amy­loid be­ta and tau, the group be­lieves that the pres­ence of both should be a hall­mark of Alzheimer’s, along with phys­i­cal ev­i­dence of neu­rode­gen­er­a­tion or neu­ronal in­jury. By mix­ing and match­ing the bio­mark­ers, they want to be able to high­light the de­vel­op­ment of the dis­ease in­to a set of dis­tinct stages that can be used to test the ef­fec­tive­ness of new drugs and com­bi­na­tion ther­a­pies even be­fore symp­toms ap­pear.

So amy­loid be­ta by it­self would be ev­i­dence of dis­ease pathol­o­gy. Added to the pres­ence of tau you could di­ag­nose some­one as hav­ing Alzheimer’s. And signs of neu­rode­gen­er­a­tion could be used to high­light the ad­vance of the dis­ease. They’re al­so leav­ing the door open to oth­er bio­mark­ers for the dis­ease as re­search con­tin­ues and the field evolves.

By cen­ter­ing on bio­mark­ers that can be iden­ti­fied through brain imag­ing, along with a stan­dard ap­proach to defin­ing cog­ni­tion, they be­lieve they have a foun­da­tion to build a new wave of stud­ies that can find new drugs to help the mil­lions of peo­ple who un­know­ing­ly have the first tell­tale signs of a lethal dis­ease that wipes out a per­son’s mem­o­ries.

“We have to fo­cus on bi­o­log­i­cal or phys­i­cal tar­gets to ze­ro in on po­ten­tial treat­ments for Alzheimer’s,” ex­plained Eliez­er Masli­ah, di­rec­tor of the di­vi­sion of neu­ro­science at the NIA. “By shift­ing the dis­cus­sion to neu­ropatho­log­ic changes de­tect­ed in bio­mark­ers to de­fine Alzheimer’s, as we look at symp­toms and the range of in­flu­ences on de­vel­op­ment of Alzheimer’s, I think we have a bet­ter shot at find­ing ther­a­pies, and soon­er.”

Their pro­pos­al is crit­i­cal to a big R&D field that has been shak­en by a se­ries of ma­jor drug stud­ies that have gone far to prove that re­searchers don’t have a clear un­der­stand­ing of the bi­ol­o­gy of the dis­ease. 

Lon Schnei­der

“You can’t get around that peo­ple can have the pathol­o­gy of Alzheimer’s dis­ease and not have clin­i­cal symp­toms,” Lon Schnei­der, a re­searcher at USC’s Keck School of Med­i­cine, told me re­cent­ly as I ex­plored where the field was head­ed. “They can have a head full of amy­loid and be at risk of de­vel­op­ing de­men­tia,” but then nev­er ex­pe­ri­ence symp­toms of the dis­ease.

The news on Alzheimer’s R&D is all bad. Mer­ck’s re­cent de­ci­sive fail­ure on BACE, cut­ting off the sup­ply of amy­loid be­ta to the brains of pa­tients, has helped dis­prove a the­o­ry that has spurred bil­lions in fresh re­search spend­ing. Just yes­ter­day lit­tle vTv threw in the tow­el on an at­tempt to re­pur­pose a failed drug from Pfiz­er for the dis­ease, an­oth­er chron­ic los­er among var­i­ous de­vel­op­ment strate­gies. And Pfiz­er, af­ter spend­ing bil­lions of dol­lars on var­i­ous projects, opt­ed to sim­ply drop out, join­ing an in­dus­try re­treat that has al­ready claimed the li­on’s share of the work at As­traZeneca and Glax­o­SmithK­line. 

Richard Hodes

At the same time, the FDA has been en­cour­ag­ing the field to de­fine a stan­dard set or bio­mark­ers that could help de­fine a path for re­searchers to rea­son­ably de­fine the dis­ease and demon­strate progress in slow­ing it down, ahead of symp­toms de­fined by the gold stan­dard of Phase III pro­grams cen­tered on cog­ni­tion and func­tion. 

“In the con­text of con­tin­u­ing evo­lu­tion of Alzheimer’s re­search and tech­nolo­gies, the pro­posed re­search frame­work is a log­i­cal next step to help the sci­en­tif­ic com­mu­ni­ty ad­vance in the fight against Alzheimer’s,” said NIA Di­rec­tor Richard Hodes. “The more ac­cu­rate­ly we can char­ac­ter­ize the spe­cif­ic dis­ease process patho­log­i­cal­ly de­fined as Alzheimer’s dis­ease, the bet­ter our chances of in­ter­ven­ing at any point in this con­tin­u­um, from pre­vent­ing Alzheimer’s to de­lay­ing pro­gres­sion.”

Their work is in the April 10 is­sue of Alzheimer’s & De­men­tia: The Jour­nal of the Alzheimer’s As­so­ci­a­tion.

John Hood [file photo]

UP­DATE: Cel­gene and the sci­en­tist who cham­pi­oned fe­dra­tinib's rise from Sanofi's R&D grave­yard win FDA OK

Six years after Sanofi gave it up for dead, the FDA has approved the myelofibrosis drug fedratinib, now owned by Celgene.

The drug will be sold as Inrebic, and will soon land in the portfolio at Bristol-Myers Squibb, which is finalizing a deal to acquire Celgene.

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UP­DAT­ED: AveX­is sci­en­tif­ic founder was axed — and No­var­tis names a new CSO in wake of an ethics scan­dal

Now at the center of a storm of controversy over its decision to keep its knowledge of manipulated data hidden from regulators during an FDA review, Novartis CEO Vas Narasimhan has found a longtime veteran in the ranks to head the scientific work underway at AveXis, where the incident occurred. And the scientific founder has hit the exit.

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Ab­b­Vie gets its FDA OK for JAK in­hibitor upadac­i­tinib, but don’t look for this one to hit ex­ecs’ lofty ex­pec­ta­tions

Another big drug approval came through on Friday afternoon as the FDA OK’d AbbVie’s upadacitinib — an oral JAK1 inhibitor that is hitting the rheumatoid arthritis market with a black box warning of serious malignancies, infections and thrombosis reflecting fears associated with the class.

It will be sold as Rinvoq — at a wholesale price of $59,000 a year — and will likely soon face competition from a drug that AbbVie once controlled, and spurned. Reuters reports that a 4-week supply of Humira, by comparison, is $5,174, adding up to about $67,000 a year.

The top 10 fran­chise drugs in bio­phar­ma his­to­ry will earn a to­tal of $1.4T (tril­lion) by 2024 — what does that tell us?

Just in case you were looking for more evidence of just how important Amgen’s patent win on Enbrel is for the company and its investors, EvaluatePharma has come up with a forward-looking consensus estimate on what the list of top 10 drugs will look like in 2024.

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UP­DAT­ED: Sci­en­tist-CEO ac­cused of im­prop­er­ly us­ing con­fi­den­tial in­fo from uni­corn Alec­tor

The executive team at Alector $ALEC has a bone to pick with scientific co-founder Asa Abeliovich. Their latest quarterly rundown has this brief note buried inside:

On June 18, 2019, we initiated a confidential arbitration proceeding against Dr. Asa Abeliovich, our former consulting co-founder, related to alleged breaches of his consulting agreement and the improper use of our confidential information that he learned during the course of rendering services to us as our consulting Chief Scientific Officer/Chief Innovation Officer. We are in the early stage of this arbitration proceeding and are unable to assess or provide any assurances regarding its possible outcome.

There’s no explicit word in the filing on what kind of confidential info was involved, but the proceeding got started 2 days ahead of Abeliovich’s IPO.

Abeliovich, formerly a tenured associate professor at Columbia, is a top scientist in the field of neurodegeneration, which is where Alector is targeted. More recently, he’s also helped start up Prevail Therapeutics as the CEO, which raised $125 million in an IPO. And there he’s planning on working on new gene therapies that target genetically defined subpopulations of Parkinson’s disease. Followup programs target Gaucher disease, frontotemporal dementia and synucleinopathies.

But this time Abeliovich is the CEO rather than a founding scientist. And some of their pipeline overlaps with Alector’s.

Abeliovich and Prevail, though, aren’t taking this one lying down.

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Chi­na has be­come a CEO-lev­el pri­or­i­ty for multi­na­tion­al phar­ma­ceu­ti­cal com­pa­nies: the trend and the im­pli­ca­tions

After a “hot” period of rapid growth between 2009 and 2012, and a relatively “cooler” period of slower growth from 2013 to 2015, China has once again become a top-of-mind priority for the CEOs of most large, multinational pharmaceutical companies.

At the International Pharma Forum, hosted in March in Beijing by the R&D Based Pharmaceutical Association Committee (RDPAC) and the Pharmaceutical Research and Manufacturers of America (PhRMA), no fewer than seven CEOs of major multinational pharmaceutical firms participated, including GSK, Eli Lilly, LEO Pharma, Merck KGaA, Pfizer, Sanofi and UCB. A few days earlier, the CEOs of several other large multinationals attended the China Development Forum, an annual business forum hosted by the research arm of China’s State Council. It’s hard to imagine any other country, except the US, having such drawing power at CEO level.

As dis­as­ter struck, Ab­b­Vie’s Rick Gon­za­lez swooped in on Al­ler­gan with an of­fer Brent Saun­ders couldn’t say no to

Early March was a no good, awful, terrible time for Allergan CEO Brent Saunders. His big lead drug had imploded in a Phase III disaster and activists were after his hide — or at least his chairman’s title — as the stock price continued a steady droop that had eviscerated share value for investors.

But it was a perfect time for AbbVie CEO Rick Gonzalez to pick up the phone and ask Saunders if he’d like to consider a “strategic” deal.

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CEO Pascal Soriot via Getty Images

As­traZeneca's jug­ger­naut PARP play­er Lyn­parza scoops up an­oth­er dom­i­nant win in PhI­II as the FDA adds a 'break­through' for Calquence

AstraZeneca’s oncology R&D group under José Baselga keeps churning out hits.

Wednesday morning the pharma giant and their partners at Merck parted the curtains on a successful readout for their Phase III PAOLA-1 study, demonstrating statistically significant improvement in progression-free survival for women with ovarian cancer in a first-line maintenance setting who added their PARP Lynparza to Avastin. This is their second late-stage success in ovarian cancer, which will help stave off rivals like GSK.

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ICER blasts FDA, PTC and Sarep­ta for high prices on DMD drugs Em­flaza, Ex­ondys 51

ICER has some strong words for PTC, Sarepta and the FDA as the US drug price watchdog concludes that as currently priced, their respective new treatments for Duchenne muscular dystrophy are decidedly not cost-effective.

The final report — which cements the conclusions of a draft issued in May — incorporates the opinion of a panel of 17 experts ICER convened in a public meeting last month. It also based its analysis of Emflaza (deflazacort) and Exondys 51 (eteplirsen) on updated annual costs of $81,400 and over $1 million, respectively, after citing “incorrect” lower numbers in the initial calculations.