Ex­pert pan­el re­view on Alzheimer’s drug ad­u­canum­ab be­comes a one-day tri­al by fire as crit­ics turn their guns on Bio­gen — and the FDA

Two days af­ter an en­thu­si­as­tic FDA in­sid­er re­view of Bio­gen’s ad­u­canum­ab pro­vid­ed a $15 bil­lion pop for the big biotech’s mar­ket cap, a pan­el of out­side ex­perts pro­vid­ed some fresh fire­works on the de­bate, with a big ma­jor­i­ty turn­ing thumbs down on the con­tro­ver­sial pitch that there are da­ta to prove the drug is ef­fec­tive — as well as the agency’s per­plex­ing en­dorse­ment.

Most of the ex­perts slapped down 3 ques­tions re­gard­ing whether there was any ev­i­dence to back the ef­fi­ca­cy of the drug — with a lone vote in fa­vor on one of the ques­tions.

The mon­ey ques­tion:

Con­sid­er­ing all the tri­al da­ta, the FDA asked, is it rea­son­able to con­sid­er the pos­i­tive study 302 “as pri­ma­ry ev­i­dence of ef­fec­tive­ness” for the treat­ment of Alzheimer’s dis­ease?

Ten said no, none said yes and there was one ab­sten­tion. Sev­er­al said the FDA pre­sen­ta­tion was heav­i­ly weight­ed in Bio­gen’s fa­vor, with no dis­cus­sion from the agency of the harsh­ly crit­i­cal sta­tis­ti­cal re­view from FDA staffers.

Any­one ex­pect­ing a dry and dis­pas­sion­ate re­view of the da­ta for Bio­gen’s Alzheimer’s drug ad­u­canum­ab at the FDA pan­el meet­ing Fri­day was in for a rude awak­en­ing.

Bil­ly Dunn

Both Bio­gen ex­ecs as well as Bil­ly Dunn, the head of the agency’s neu­ro­sciences di­vi­sion, of­fered a full-throat­ed en­dorse­ment of the drug, out­lin­ing the rea­sons why they found the da­ta back­ing the con­tro­ver­sial ap­pli­ca­tion “com­pelling.”

That ar­gu­ment, though, in­vit­ed a sharp shove back from mem­bers of the ad­vi­so­ry pan­el asked to weigh in on the ap­pli­ca­tion, es­pe­cial­ly from the sta­tis­ti­cians who re­peat­ed­ly probed why Dunn was so sup­port­ive when the FDA’s sta­tis­ti­cal re­view took the com­plete­ly op­pos­ing view, con­clud­ing that the da­ta were con­flict­ing, of­fered clear ev­i­dence that the drug doesn’t work and that Bio­gen’s ar­gu­ment in its fa­vor was hol­low.

“We brought in­no­v­a­tive think­ing to this un­usu­al sit­u­a­tion,” ar­gued Dunn, con­struct­ing sup­port for ad­u­canum­ab that dis­count­ed the ear­ly ter­mi­na­tion of the study due to fu­til­i­ty, of­fer­ing rea­sons why the 1 pos­i­tive late-stage study of­fered “ex­treme­ly per­sua­sive” rea­sons for an ap­proval, why the oth­er failed study could be ex­plained as pro­vid­ing sup­port­ing da­ta and why a small co­hort in an ear­li­er study al­so pro­vid­ed en­cour­age­ment for an OK — es­pe­cial­ly as Covid-19 de­mand­ed reg­u­la­tors to work co­op­er­a­tive­ly in sal­vaging tri­als.

Sev­er­al mem­bers of the pan­el were clear­ly out­raged by that.

G. Caleb Alexan­der, a Johns Hop­kins pro­fes­sor, blast­ed the FDA’s re­view as “strik­ing­ly in­con­gru­ous” which of­fered con­clu­sions that were at best com­pelling­ly con­flict­ed, rais­ing ques­tions on how the FDA could de­ter­mine there was ev­i­dence of ef­fec­tive­ness.

“It just feels like the au­dio and the video on the TV are out of sync,” he said.

For every point that sug­gests sup­port for the drug, he added, there are more that raise con­cerns.

At sev­er­al points, Alexan­der harsh­ly crit­i­cized Dunn’s team for skew­ing the brief­ing doc­u­ments and ques­tions in Bio­gen’s fa­vor. “I’m call­ing out the fact … that this ques­tion is open to elic­it­ing se­lec­tive in­for­ma­tion,” he not­ed at one point.

The Uni­ver­si­ty of Wash­ing­ton’s Scott Emer­son was an­oth­er per­sis­tent crit­ic with point­ed crit­i­cism of the drug and the da­ta used to back the ap­pli­ca­tion.

And Joel Perl­mut­ter, a pro­fes­sor of neu­rol­o­gy, warned the pan­el that if the FDA ap­proved some­thing with­out strong ev­i­dence of ef­fi­ca­cy they would pre­vent a good and ef­fec­tive treat­ment from be­ing ap­proved “for more than a cou­ple of years, for many years.”

The friend­liest ques­tion the pan­el faced con­cerned whether tri­al 302, count­ed as the on­ly pos­i­tive study of the 2 Phase III ef­forts, pro­vid­ed strong ev­i­dence of ef­fi­ca­cy — if you al­so ig­nore 301, the failed tri­al.

That went down hard, with 8 ‘no’ votes, 1 ‘yes’ and 2 ab­sten­tions. Even the ab­stain­ers, though, of­fered ob­jec­tions.

How about the small­er study 103, the Phase II tri­al Dunn cit­ed for of­fer­ing some sup­port­ive da­ta for the drug? Was it sup­port­ive in some way?

The ex­perts shot that one down as well, by a vote of 7 no, 0 yes and 4 un­cer­tain.

The one up­beat re­sult was on patho­phys­i­ol­o­gy, but sev­er­al not­ed ques­tions whether the drug’s abil­i­ty to re­duce amy­loid would ever trans­late in­to ef­fi­ca­cy or an im­pact on symp­toms. That earned some sup­port: 5 yes and 6 un­cer­tain.

“I view the ques­tion nar­row­ly,” said Chia­di Onyike, say­ing there was clear ev­i­dence it mopped up amy­loid be­ta. And oth­ers not­ed ques­tions whether that was enough to gain clin­i­cal ef­fi­ca­cy, or if it’s the cor­rect bio­mark­er to use at all.

The FDA doesn’t have to con­sid­er the pan­el vote in mak­ing its de­ci­sion. In this case, giv­en the heat­ed ob­jec­tions, it would be hard to ig­nore. But giv­en Dunn’s ear­li­er de­ci­sions sup­port­ing Sarep­ta, there is still a dis­tinct pos­si­bil­i­ty of an ap­proval.

Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Big week for Alzheimer’s da­ta; As­traZeneca buys cell ther­a­py start­up; Dig­i­tal ther­a­peu­tics hits a pay­er wall; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

You may start to notice more stories exclusively available to Premium subscribers. This week alone, paid subscribers can read our in-depth reporting on Alzheimer’s data, digital therapeutics and Allogene’s cell therapy for solid tumors, as well as scoops on Twitter ads and Catalent. With your support, we can keep growing our team and spend more time on quality work. We have both individual and company plans available — check them out to unlock the full Endpoints experience.

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John Evans, Beam Therapeutics CEO

Beam's base-edit­ed al­lo­gene­ic CAR-T gets FDA go-ahead af­ter four-month wait

The FDA wanted more information on four key areas before it would let Beam Therapeutics proceed with human testing for a cell therapy in a certain type of leukemia. It appears the biotech has answered the agency’s queries.

The US regulator cleared the base-edited, off-the-shelf CAR-T, Beam said Friday morning, lifting a hold from this summer. More details on specific next steps for the Phase I will come out next year, the Boston-area biotech said.

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Am­gen, years be­hind ri­vals, says PhI obe­si­ty drug shows dura­bil­i­ty signs

While NBC ran “The Biggest Loser” for 17 seasons, deemed toxic by critics for the reality show’s punishing exercise and diet upheavals, researchers in pharmaceutical labs have been attempting to create prescription drugs that induce weight loss — and one pharma betting it can require less frequent dosing is out with a new crop of data.

Amgen was relatively late to the game compared to its approved competitor Novo Nordisk and green light-approaching rival Eli Lilly. But early data suggested Amgen’s AMG 133 led to a 14.5% weight reduction in the first few months of dosing, buoying shares earlier this fall, and now the California pharma is out with its first batch of durability data showing that figure fell slightly to 11.2% about 150 days after the last dose. Amgen presented at the 20th World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease on Saturday afternoon.

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Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



Talk therapy didn’t help Lily with attention deficit hyperactivity disorder, or ADHD. But a video game did.

As the 10-year-old zooms through icy waters and targets flying creatures on the snow-capped planet Frigidus, she builds attention skills, thanks to Akili Interactive Labs’ video game EndeavorRx. She’s now less anxious and scattered, allowing her to stay on a low dose of ADHD medication, according to her mom Violet Vu.

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Eli Lil­ly’s Alzheimer’s drug clears more amy­loid ear­ly than Aduhelm in first-ever head-to-head. Will it mat­ter?

Ahead of the FDA’s decision on Eli Lilly’s Alzheimer’s drug donanemab in February, the Big Pharma is dropping a first cut of data from one of the more interesting trials — but less important in a regulatory sense — at an Alzheimer’s conference in San Francisco.

In the unblinded 148-person study, Eli Lilly pitted its drug against Aduhelm, Biogen’s drug that won FDA approval but lost Medicare coverage outside of clinical trials. Notably, the study didn’t look at clinical outcomes, but rather the clearance of amyloid, a protein whose buildup is associated with Alzheimer’s disease, in the brain.

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US month­ly costs for biosim­i­lars 'sub­stan­tial­ly high­er' than Ger­many or Switzer­land, JA­MA re­search finds

As the global biologics market is expected to hit nearly the half-trillion-dollar mark this year, new JAMA research points to the importance of timely biosimilar entry, particularly as fewer biosimilars are entering the US than in Europe, and as monthly treatment costs for biosimilars were “substantially higher” in the US compared with Germany and Switzerland.

Among the three countries, biosimilar market share at launch was highest in Germany, but increased at the fastest rate in the US, the authors from the University of Zurich’s Institute of Law wrote in JAMA Network Open today.

Kirk Myers is shown in a still image from a new film series showcasing the efforts of HIV advocates funded by Gilead.

Gilead spot­lights HIV projects and the com­mu­ni­ty lead­ers dri­ving them in new mi­ni-doc­u­men­tary films

Gilead is going behind the scenes of some of the HIV initiatives it funds through grants in a new film series narrated by the people helming the projects.

The first four films and leaders come from across the US — Arianna Lint in Florida and Puerto Rico, Cleve Jones in San Francisco, June Gipson in Mississippi and Kirk Myers in Texas. Their HIV-focused efforts range from addressing unmet needs of the transgender community to delivering social services and high-quality health care in underserved communities.

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EMA pulls an opi­oid from the 1950s used to treat dry cough

The European Medicines Agency said Friday that it’s pulling from all European markets pholcodine-containing medicines, which are an opioid used in adults and children for the treatment of dry cough and in combo with other drugs as a treatment for cold and flu.

The decision to pull the medicines comes as the EMA points to the results from the recent ALPHO study, which show that use of pholcodine during the 12 months preceding anesthesia is linked to a risk of an anaphylactic reaction related to the neuromuscular blocking agents (NMBAs) used (with an adjusted OR of 4.2, and a 95% confidence interval of 2.5 to 6.9).