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.

Hal Barron, GSK

Break­ing the death spi­ral: Hal Bar­ron talks about trans­form­ing the mori­bund R&D cul­ture at GSK in a crit­i­cal year for the late-stage pipeline

Just ahead of GlaxoSmithKline’s Q2 update on Wednesday, science chief Hal Barron is making the rounds to talk up the pharma giant’s late-stage strategy as the top execs continue to woo back a deeply skeptical investor group while pushing through a whole new R&D culture.

And that’s not easy, Barron is quick to note. He told the Financial Times:

I think that culture, to some extent, is as hard, in fact even harder, than doing the science.

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Michel Vounatsos, Getty Images

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Biogen came out with an upbeat assessment of their Q2 numbers today, discounting the arrival of a key rival for its blockbuster Spinraza franchise. But the top execs remain grimly determined to not say much anything new about the sore points that have dragged down its stock, including the future of its big investment in Alzheimer’s or how it plans to invest the considerable cash that the big biotech continues to reap.

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Why wait? Cel­gene re­struc­tures a big Jounce pact — ze­ro­ing in on new I/O path­way with $530M deal and bump­ing ICOS

Celgene’s business team isn’t waiting for the big merger with Bristol-Myers Squibb to go through before syncing its strategy with the new mother ship.

Tuesday evening the big biotech unveiled a $530 million deal — $50 million in upfront cash — to amend their alliance with Jounce Therapeutics $JNCE to gain worldwide rights to JTX-8064, an antibody that targets the LILRB2 receptor on macrophages. Their old, $2.6 billion deal is being scrapped, leaving Jounce with a pipeline that includes the lead drug, the ICOS-targeting vopratelimab.

PACT Phar­ma says it's per­fect­ed the tech to se­lect neoanti­gens for per­son­al­ized ther­a­py — now on­to the clin­ic

At PACT Pharma, the lofty goal to unleash a “tsunami” of T cells personalized for each patient has hinged on the ability to correctly identify the neoantigens that form something of a fingerprint for each tumor, and extract the small group of T cells primed to attack the cancer. It still has a long way to go testing a treatment in humans, but the biotech says it has nailed that highly technical piece of the process.

UP­DAT­ED: My­ovan­t's uter­ine fi­broid drug looks com­pet­i­tive in PhI­II — but can they van­quish mighty Ab­b­Vie?

Vivek Ramaswamy’s Myovant $MYOV has closely matched its positive first round of Phase III data for their uterine fibroid drug relugolix, setting up a head-to-head rivalry with pharma giant AbbVie as the little biotech steers to the market with a planned filing in Q4.

Here’s how Myovant plans to prevail over the AbbVie $ABBV empire.

In the study, 71.2% of women receiving once-daily relugolix combination therapy achieved the clinical response they were looking for, compared to only 14.7% in the control arm. The data comfortably reflected the same outcomes in the first Phase III — 73.4% of women receiving once-daily oral relugolix combination therapy achieved the responder criteria compared with 18.9% of women receiving placebo — which will reassure regulators that they are getting the carefully randomized data that qualifies for the FDA’s gold standard for success.

Lit­tle Mar­i­nus sees its shares eclipsed as the Sage ri­val fails to com­pare on PPD in PhII

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Little Marinus Pharmaceuticals $MRNS had sought to challenge the Sage drug with an IV formulation — followed by an oral version — of ganaxolone for postpartum depression. But researchers say their Phase II study failed to positively differentiate itself from a placebo at 28 days — leaving them to hold up “clinically meaningful” data within the first day of administration compared to the control arm.

Roche cuts loose Tam­i­flu OTC rights, hand­ing Sanofi the keys as the phar­ma gi­ant dou­bles down on Xofluza

Roche set out to make a better flu medicine than Tamiflu as that franchise was headed to a generic showdown. Now they’ll see just how well Xofluza stacks up against the mainstay drug after handing off over-the-counter rights in the US to Sanofi.

Sanofi $SNY says it will now step in to negotiate a deal with the FDA to steer Tamiflu into the OTC market, a role that could well involve new studies to ease passage of the drug out of doctor’s hands and into the consumer end of the market. And the French pharma giant will have first dibs over “selected” OTC markets around the world as they push ahead.

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Acadia’s late-stage program to widen the commercial prospects for Nuplazid has hit a wall. The biotech reported that their Phase III ENHANCE trial flat failed. And while they $ACAD did their best to cherry pick positive data wherever they can be found, this is a clear setback for the biotech.

With close to 400 patients enrolled, researchers said the drug flunked the primary endpoint as an adjunctive therapy for patients with an inadequate response to antipsychotic therapy. The p-value was an ugly 0.0940 on the Positive and Negative Syndrome Scale, which the company called out as a positive trend.

Their shares slid 12% on the news, good for a $426 million hit on a $3.7 billion market cap at close.

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Some Big Phar­mas stepped up their game on da­ta trans­paren­cy — but which flunked the test?

The nonprofit Bioethics International has come out with their latest scorecard on data transparency among the big biopharmas in the industry — flagging a few standouts while spotlighting some laggards who are continuing to underperform.

Now in its third year, the nonprofit created a new set of standards with Yale School of Medicine and Stanford Law School to evaluate the track record on trial registration, results reporting, publication and data-sharing practice.