The FDA rais­es hopes for Alzheimer's drugs with a new set of draft rules. But are they go­ing too far?

Bioreg­num
The view from John Car­roll

For years now the gold stan­dard for R&D in Alzheimer’s has fo­cused on gen­er­at­ing con­vinc­ing ev­i­dence that any new ther­a­py be­ing stud­ied could slow the cog­ni­tive de­cline of pa­tients and help pre­serve their abil­i­ty to per­form the kind of dai­ly func­tions that can keep a pa­tient in­de­pen­dent for a longer pe­ri­od of time.

That’s a hur­dle no one has man­aged to clear for well over a decade. So now, with late-stage clin­i­cal fail­ures pil­ing up, the FDA has set off down a path to adapt those stan­dards as re­searchers are pushed in­ex­orably in­to ear­li­er and ear­li­er forms of the dis­ease, ahead of the brain dam­age in­flict­ed by Alzheimer’s.

In a set of draft guid­ances, the agency es­sen­tial­ly pro­posed to of­fer an ap­proval path­way for new drugs that could pre­vent the on­set of the dev­as­tat­ing symp­toms of Alzheimer’s if drug de­vel­op­ers could hit ac­cept­able bio­mark­ers that in­di­cate the drug is work­ing. And they’re like­ly go­ing to con­tin­ue with a new gold stan­dard that will fo­cus on long-term cog­ni­tion alone, low­er­ing the bar for drugs for an enor­mous and grow­ing mar­ket.

David Miller

David Miller, the clin­i­cal vice pres­i­dent of Brack­et, a tech provider which spe­cial­izes in Alzheimer’s stud­ies, tells me the draft guid­ance hit just af­ter a meet­ing of the Alzheimer’s As­so­ci­a­tion re­search group, which was dis­cussing how you might be able to use a mix of mark­ers for amy­loid be­ta and tau — two tox­ic pro­teins fre­quent­ly cit­ed as like­ly trig­gers — along­side  neu­rode­gen­er­a­tive mark­ers to iden­ti­fy pa­tients who could be en­rolled at a very ear­ly point in the dis­ease.

“It’s ahead of where it was,” Miller says about their un­der­stand­ing of pre-symp­to­matic bio­mark­ers. “There’s been an im­prove­ment in our un­der­stand­ing of how these bio­mark­ers work to­geth­er, where there might be im­prove­ment. That doesn’t mean we are where we need to be, but we are get­ting clos­er.”

“We need to fig­ure out ways to do mea­sure­ments bet­ter, sen­si­tive to ear­li­er stages of the dis­ease, look­ing at cog­ni­tion and func­tion for more sen­si­tive ways of do­ing it,” says Miller.

One of the big chal­lenges, he adds, will be to set up cri­te­ria for new stud­ies that al­low de­vel­op­ers to ac­cu­rate­ly track bio­mark­ers with a con­sis­tent fo­cus on a clear­ly de­fined group of pa­tients en­rolled in stud­ies around the world. And per­haps one way is to re­ly on more pa­tient re­port­ed out­comes, where the pa­tient them­selves track their con­di­tion.

The move “is a big deal to com­pa­nies,” Maria Car­ril­lo, chief sci­ence of­fi­cer for the Alzheimer’s As­so­ci­a­tion, told Bloomberg. “It is a clear state­ment that the FDA un­der­stands that the sci­ence of Alzheimer’s has evolved.”

What’s dri­ving the shift?

These draft guid­ances, which will have to be for­mal­ly re­viewed with time to gath­er more feed­back from pa­tients, physi­cians and de­vel­op­ers, come af­ter a drum­beat of late-stage fail­ures is rais­ing ques­tions about what sci­en­tists ac­tu­al­ly know about this dis­ease. Eli Lil­ly tried three times to pro­duce piv­otal ev­i­dence that solanezum­ab could in­flu­ence the course of the dis­ease by clear­ing amy­loid be­ta, and failed. The com­pa­ny now has so­la in a study to see if it can pre­vent the dis­ease in at-risk pa­tients.

Ear­li­er this week Mer­ck flagged a clear fail­ure for its BACE drug verube­ce­s­tat, which moves up­stream in the bi­ol­o­gy of de­vel­op­ing amy­loid be­ta. It has now failed in both mild-to-mod­er­ate as well as pro­dro­mal pa­tients. Ax­o­vant took a failed drug from Glax­o­SmithK­line and smashed in­to a sub­group flop re­cent­ly, leav­ing the biotech bad­ly wound­ed. And Pfiz­er added to the lat­est se­ries of set­backs with its de­ci­sion to dump its en­tire neu­ro­sciences ef­fort and move on in oth­er ar­eas — fol­low­ing the ex­its of big play­ers like As­traZeneca and Glax­o­SmithK­line over the years.

That doesn’t mean that R&D has stopped. Any new drug that can help pa­tients, or pa­tients at risk, is like­ly to be a block­buster win­ner, and that has helped fill the cash re­serves of new biotechs like De­nali, lin­ing up with longterm play­ers like Take­da, which had its own re­cent set­back.

The march to study­ing drugs at an ear­li­er and ear­li­er stage of the dis­ease has been un­der­way now for at least 5 years, so the move to­ward pre-symp­to­matic groups is a nat­ur­al step in that evo­lu­tion. How­ev­er, shift­ing away from gold stan­dard end­points to­ward an evolv­ing set of bio­mark­ers al­so rais­es the prospect that the FDA will ap­prove new drugs that even­tu­al­ly prove that they don’t ac­tu­al­ly do any­thing to af­fect the course of the dis­ease, rais­ing hopes and cost­ing bil­lions with­out any re­al ben­e­fit.

Stand­ing still, though, is no longer an op­tion.

The em­pha­sis at the FDA now is to en­cour­age suc­cess­ful drug de­vel­op­ment by rec­og­nized ex­perts. If they start toe­ing the line on pro­fes­sion­al stan­dards for ef­fi­ca­cy and safe­ty, you can ex­pect to see the pen­du­lum swing back again some­time in the fu­ture.

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; and more

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Usama Malik

Ex-Im­munomedics CFO charged with in­sid­er trad­ing, faces up to 20 years in prison af­ter al­leged­ly tip­ping off girl­friend and rel­a­tives of a PhI­II suc­cess

The former CFO of Immunomedics, who helped steer the company to its $21 billion buyout by Gilead last year, has been charged with insider trading, the Department of Justice announced Thursday.

Usama Malik tipped off his then-girlfriend and four others that a Phase III study for Trodelvy would be stopped early four days before Immunomedics publicly announced the result in April 2020, DoJ alleged in its complaint. The individuals then purchased Immunomedics shares, selling them after the news broke and Immunomedics’ stock price doubled.

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Merck's new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”

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Ab­b­Vie tacks on a new warn­ing to Rin­voq la­bel as safe­ty frets crimp JAK class

The safety problems that continue to plague the JAK class as new data highlight some severe side effects are casting a large shadow over AbbVie’s Rinvoq.

As a result of a recent readout highlighting major adverse cardiac events (MACE), malignancy, mortality and thrombosis with Xeljanz a couple of months ago, AbbVie put out a notice late Friday afternoon that it is adding the new class risks to its label for their rival drug.

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Biospec­i­men M&A: Dis­cov­ery ac­quires Al­bert Li's he­pa­to­cyte project; PhI­II tri­al on Bay­er's Nube­qa reached pri­ma­ry end­point

Discovery Life Sciences has acquired what claims to be the Maryland-based host of the world’s largest hepatocyte inventory, known as IVAL, to help researchers select more effective and safer drug candidates in the future.

The combined companies will now serve a wider range of drug research and development scientists, according to Albert Li, who founded IVAL in 2004 and is set to join the Discovery leadership team as the CSO of pharmacology and toxicology.

Pfiz­er, Am­gen and Janssen seek fur­ther clar­i­ty on FDA's new ben­e­fit-risk guid­ance

Three top biopharma companies are seeking more details from the FDA on how the agency conducts its benefit-risk assessments for new drugs and biologics.

While Pfizer, Amgen and Janssen praised the agency for further spelling out its thinking on the subject in a new draft guidance, including a discussion of patient experience data as part of the assessment, the companies said the FDA could’ve included more specifics in the 20-page draft document.

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Re­searchers move clos­er to de­ci­pher­ing blood clots from As­traZeneca, J&J's Covid-19 vac­cines

Researchers may be nearing an answer for the mysterious and life-threatening blood clots that appeared on very rare occasions in people who received the J&J or AstraZeneca Covid-19 vaccine.

The new work builds on an early hypothesis researchers in Norway put forward last spring, when the cases first cropped up. They proposed the events were similar to blood clots that can occur in a small subset of patients who receive heparin, one of the most commonly used blood thinners.

Janet Woodcock (AP Images)

Janet Wood­cock plots her fu­ture at FDA, with se­nior ad­vi­sor role to fall back on if Califf wins con­fir­ma­tion

Acting FDA commissioner Janet Woodcock has been the face of just about every drug approval decision at the agency since the turn of the century. Since the pandemic began, she’s moved between the top of the drugs center to the head of therapeutics at Operation Warp Speed, leading the drive for work on Covid-targeted mAbs and antivirals.

Looking forward — and pending a quick Senate confirmation to cement Rob Califf’s return to the top of FDA early next year — Woodcock’s role at the agency will again be in flux.

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