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.

A new era of treat­ment: How bio­mark­ers are chang­ing the way we think about can­cer

AJ Patel was recovering from a complicated brain surgery when his oncologist burst into the hospital room yelling, “I’ve got some really great news for you!”

For two years, Patel had been going from doctor to doctor trying to diagnose his wheezing, only to be dealt the devastating news that he had stage IV lung cancer and only six months to live. And then they found the brain tumors.

“What are you talking about?” Patel asked. He had never seen an oncologist so happy.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Adam Russell, ARPA-H's incoming acting deputy director

NI­H's new, in­de­pen­dent break­through drug ac­cel­er­a­tor ARPA-H gets its first em­ploy­ee

Despite the controversy of housing it in NIH, HHS Secretary Xavier Becerra on Wednesday afternoon formally announced the establishment of the Advanced Research Project Agency for Health (ARPA-H) as an independent entity within the NIH, as HHS had previously stipulated that “NIH may not subject ARPA-H to NIH policies.”

Becerra also announced the appointment of ARPA-H’s inaugural employee, Adam Russell, who will serve as acting deputy director.

ProFound Therapeutics founding team

Flag­ship's lat­est biotech could turn some of the thou­sands of new pro­teins it dis­cov­ered in­to ther­a­pies — and it has $75M to start

Flagship Pioneering, the incubator of Moderna and dozens of other biotechs, says it has landed upon tens of thousands of previously undiscovered human proteins. The VC shop wants to potentially turn them into therapeutics.

Like other drug developers that have turned proteins into therapeutics (think insulin for diabetes), Flagship’s latest creation, ProFound Therapeutics, wants to tap into this new trove of proteins as part of its mission to treat indications ranging from rare diseases to cancer to immunological diseases.

Richard Silverman, Akava Therapeutics founder and Northwestern professor

This time around, Lyri­ca's in­ven­tor is de­vel­op­ing his North­west­ern dis­cov­er­ies at his own biotech

Richard Silverman was left in the dark for the last five years of clinical development of the drug he discovered. The Northwestern University professor found out about the first approval of Lyrica, in the last few days of 2004, like most other people: in the newspaper.

What became one of Pfizer’s top-selling meds, at $5 billion in 2017 global sales before losing patent protection in 2019, started slipping out of his hands when Northwestern licensed it out to Parke-Davis, one of two biotechs that showed interest in developing the drug in the pre-email days, when the university’s two-person tech transfer team had to ship out letters to garner industry appetite.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 142,700+ biopharma pros reading Endpoints daily — and it's free.

David Ricks, Eli Lilly CEO (David Paul Morris/Bloomberg via Getty Images)

Eli Lil­ly set to in­vest $2.1B in home state man­u­fac­tur­ing boost

Eli Lilly is looking to expand its footprint in its home Hoosier State by making a major investment in manufacturing.

The pharma is investing $2.1 billion in two new manufacturing sites at Indiana’s LEAP Lebanon Innovation and Research District in Boone County, northwest of Lilly’s headquarters in Indianapolis.

The two new facilities will expand Lilly’s manufacturing network for active ingredients and new therapeutic modalities, including genetic medicines, according to a press release.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 142,700+ biopharma pros reading Endpoints daily — and it's free.

Up­dat­ed: US sees spike in Paxlovid us­age as Mer­ck­'s mol­nupi­ravir and As­traZeneca's Evusheld are slow­er off the shelf

New data from HHS show that more than 162,000 courses of Pfizer’s Covid-19 antiviral Paxlovid were administered across the US over the past week, continuing a streak of increased usage of the pill, and signaling not only rising case numbers but more awareness of how to access it.

In comparison to this week, about 670,000 courses of the Pfizer pill have been administered across the first five months since Paxlovid has been on the US market, averaging about 33,000 courses administered per week in that time.

Pfiz­er and CD­MOs ramp up Paxlovid man­u­fac­tur­ing with Kala­ma­zoo plant ex­pan­sion lead­ing the way

As the Covid-19 pandemic continues to evolve, pharma companies and manufacturers are exploring how to step up production on antivirals.

Pfizer is planning to expand its Kalamazoo-area facility to increase manufacturing capabilities for the oral Covid-19 antiviral Paxlovid, according to a report from Michigan-based news site MLive. The expansion of the facility, which serves as Pfizer’s largest manufacturing location, is expected to create hundreds of “high-skilled” STEM jobs, MLive reported. No details about the project’s cost and timeline have been released, but according to MLive, Pfizer will announce the details of the expansion at some point in early June.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 142,700+ biopharma pros reading Endpoints daily — and it's free.

FDA spells out the rules and re­stric­tions for states seek­ing to im­port drugs from Cana­da

The FDA is offering more of an explanation of the guardrails around its program that may soon allow states to import prescription drugs in some select circumstances from Canada, but only if such imports will result in significant cost reductions for consumers.

While the agency has yet to sign off on any of the 5 state plans in the works so far, and PhRMA’s suit to block the Trump-era rule allowing such imports is stalled, the new Q&A guidance spells out the various restrictions that states will have to abide by, potentially signaling that a state approval is coming.

Pfizer CEO Albert Bourla at the World Economic Forum (Gian Ehrenzeller/Keystone via AP Images)

All about ac­cess: Pfiz­er moves to a non-prof­it mod­el for drug sales in 45 low­er-in­come coun­tries

Leading the way to increase access to cheaper drugs worldwide, Pfizer said Wednesday it will provide all current and future patent-protected medicines and vaccines available in the US or EU on a not-for-profit basis to about 1.2 billion people in 45 lower-income countries.

Rwanda, Ghana, Malawi, Senegal and Uganda are the first five countries to sign on to this accord, which will also seek to blaze new paths for quick and efficient regulatory and procurement processes to reduce the usual delays in making new medicines and vaccines available in these countries.