Ei­sai, Bio­gen bat­tered by con­tro­ver­sy over PhII Alzheimer's study af­ter post­ing pos­i­tive re­sults

At first blush, Ei­sai and Bio­gen post­ed the kind of promis­ing da­ta for BAN2401 that might have over­come some doubts about its po­ten­tial as a treat­ment for Alzheimer’s, a field marked by the wreck­age of re­peat­ed, high pro­file fail­ures. But in­stead of cheer­ing on ev­i­dence of suc­cess, a large group of an­a­lysts last night ze­roed in on a cru­cial change in the study that could have con­found­ed the da­ta pre­sent­ed — and now we have a brand new con­tro­ver­sy to add to the lit­er­a­ture of Alzheimer’s.

Af­ter build­ing sky high ex­pec­ta­tions over the course of the past few days, Ei­sai in­ves­ti­ga­tors al­lied with Bio­gen $BI­IB said Wednes­day af­ter­noon that the high dose of BAN2401 pro­duced pos­i­tive da­ta in a mid-stage study with a sta­tis­ti­cal­ly sig­nif­i­cant 30% slow­ing in the rate of de­cline com­pared to the place­bo arm in the high dose arm of the study at 18 months.

That 30% slow­ing was based on a unique set of goals out­lined in their be­spoke AD­COMS mea­sure of the clin­i­cal de­cline ex­pe­ri­enced by pa­tients with Alzheimer’s, which is an­oth­er rea­son why there’s so much de­bate over the val­ue of the re­sults. But the re­search team al­so not­ed that there was a re­mark­able 47% im­prove­ment in the rate of de­cline at 18 months when the high dose arm was mea­sured by the stan­dard ADAS-Cog test.

A win­ner? No, be­cause it turns out there was a big catch.

Crit­ics quick­ly be­gan pulling apart the da­ta, find­ing enough holes in it to squelch Bio­gen’s share price, which plunged 12%. Ei­sai would quick­ly fol­low with its own drub­bing af­ter ques­tions were raised in a call with Bio­gen ex­ecs about a de­ci­sion by Eu­ro­pean reg­u­la­tors to move APOe4 car­ri­ers out of the high dose arm as they were wor­ried by the threat of brain swelling — or ARIA-E — which they are prone to. APOe4 car­ri­ers are at high­er risk of the dis­ease as well as faster pro­gres­sion, and putting them in low­er dose arms — while leav­ing APOe4 pa­tients in the place­bo group — raised the pos­si­bil­i­ty that the re­searchers had made it pos­si­ble for the high dose arm to hit sta­tis­ti­cal sig­nif­i­cance.

Oth­er­wise, it could have all been just an­oth­er fail­ure.

Ge­of­frey Porges notes this morn­ing:

The dis­par­i­ty be­tween the 30% rate of APOe4 car­ri­ers in the high­est 10mg/kg Q2 week arm, and the 71% rate in the place­bo arm, and the 73-91% rate of APOe4 car­ri­ers in the oth­er ac­tive arms, pro­vides a pu­ta­tive ex­pla­na­tion for the dif­fer­ence in cog­ni­tion de­cline seen in the high­est dose arm com­pared to place­bo and oth­er ac­tive arms. If Ei­sai’s sub group analy­sis sug­gests that this dif­fer­ence in de­cline per­sists even in the pa­tients in all the arms who are not APOe4 car­ri­ers, this pro­gram may have a fu­ture, but if not, it could eas­i­ly turn out to be an in­ter­est­ing arte­fact in the on­go­ing be­ta amy­loid Alzheimer’s dis­ease saga.

And Bio­gen CMO Al San­drock didn’t ex­clude the pos­si­bil­i­ty.

“It’s one of the first things we’re go­ing to look at, is the sub­group analy­sis of APOE4 car­ri­ers ver­sus non car­ri­ers,” he told an­a­lysts. “I’m sure my col­leagues at Ei­sai are work­ing on it right now.”

What Ei­sai want­ed to fo­cus on is this: The drug clear­ly sep­a­rat­ed from place­bo at 6 months for ADAS-Cog and con­tin­ued out for 18 months, as you can see here:


That hit a p-val­ue of 0.017, which was bet­ter than their own in­ter­nal­ly cre­at­ed mea­sure­ment, specif­i­cal­ly de­signed to pick up cog­ni­tive sig­nals in ear­ly-stage pa­tients.

The da­ta were re­viewed at the Alzheimer’s As­so­ci­a­tion In­ter­na­tion­al Con­fer­ence in Chica­go. And Ei­sai has been en­thu­si­as­ti­cal­ly seiz­ing on the pos­si­bil­i­ty of an ac­cel­er­at­ed ap­proval — which is now high­ly un­like­ly.

“The goal is to bring this to pa­tients as soon as pos­si­ble,” says Ivan Che­ung — who runs the US group for Ei­sai. But that’s go­ing to take some work, and close talks with the FDA.

The da­ta al­so re­mained pos­i­tive when pulled out at 6 and 12 months, he adds. “The curve ex­pands over time,” he notes, though the com­pa­ny is not de­tail­ing the hard num­bers on those end­points, oth­er than say­ing they are sta­tis­ti­cal­ly sig­nif­i­cant.

In­vestors, though, were in a crit­i­cal frame of mind, look­ing at the down­side af­ter all the chat­ter.

Ivan Che­ung

Why would the ADAS-Cog test look bet­ter than AD­COMS? 

“At this ear­ly stage of dis­ease you have more cog­ni­tive than func­tion­al de­cline,” Che­ung tells me, which is why a cog­ni­tive test is more like­ly to pick it up. 

Promis­ing da­ta in mid-stage Alzheimer’s are not new, but it’s al­so rare to see sta­tis­ti­cal­ly sig­nif­i­cant num­bers like these. Af­ter more than a decade of fail­ure, some skep­tics will re­quire sol­id piv­otal da­ta from two stud­ies to con­vince them, but the de­vel­op­ment part­ners say they are ready to start ex­plor­ing path­ways to an ac­cel­er­at­ed ap­proval at a time the FDA has been say­ing they are in­creas­ing­ly open to pro­vid­ing an ap­proval based on cog­ni­tion alone, rather than both cog­ni­tion and func­tion — a long­time gold stan­dard.

Baird’s Bri­an Sko­r­ney said Thurs­day morn­ing there’s no chance of that hap­pen­ing now.

Now that we have seen it, we’re ac­tu­al­ly shocked that Bio­gen hadn’t cleared up any spec­u­la­tion about fil­ing on this da­ta when it first came up fol­low­ing the top line an­nounce­ment a cou­ple of weeks ago. Ron Farkas may not be there any longer but Bil­ly Dunn and Er­ic Bast­ings are no pushovers in FDA’s Di­vi­sion of Neu­rol­o­gy Prod­ucts and we don’t see any way that this study meets the reg­u­la­to­ry thresh­old of “sub­stan­tial ev­i­dence of ef­fi­ca­cy.”

The Phase II con­tro­ver­sy comes as hopes for the amy­loid be­ta hy­poth­e­sis have dwin­dled, es­pe­cial­ly af­ter twin set­backs for BACE drugs by both Mer­ck and an Eli Lil­ly/As­traZeneca team.

Any ap­proval here would like­ly green-light an in­stant block­buster, with mil­lions of pa­tients ea­ger to try any­thing that might be able to bend the curve of this aw­ful, mem­o­ry-wast­ing dis­ease.

So here come some added caveats. The study failed the pri­ma­ry end­point at 12 months al­ready, which was es­tab­lished as a Bayesian analy­sis in­tend­ed to spot suc­cess at an ear­li­er stage. But push­ing ahead, they switched to more stan­dard tech­niques.

Here’s the way the mar­ket was bet­ting ahead of the re­view.

At a 10% im­prove­ment over the con­trol arm, you could ex­pect plen­ty of skep­ti­cism. Mizuho said it wouldn’t be sur­prised — but would be pleased — with a 15% slow­ing.  

But wait. Leerink’s Ge­of­frey Porges be­lieved that any­thing un­der 15% was like­ly to be seen as a weak re­sponse, with dam­ag­ing re­sults for the de­vel­op­ers’ stocks. Any­thing over 30%, he said, would dri­ve a ma­jor ral­ly, on top of the one al­ready seen on the top line da­ta.

I asked USC Alzheimer’s ex­pert Lon Schnei­der for his take. His re­sponse:

This is what I’ve been telling peo­ple.
Not a ver­dict. Not a bi­na­ry event. The spon­sors learned what they need­ed to re dose range, 64% prob­a­bil­i­ty of be­ing su­pe­ri­or to place­bo by a 25% re­duc­tion on their com­pos­ite score. The drug does what it was en­gi­neered to do.

It’s full speed ahead at Ei­sai.

Lynn Kramer

“We are do­ing a bunch of sub­group analy­sis,” says Ei­sai chief med­ical of­fi­cer for neu­rol­o­gy Lynn Kramer, “look­ing for big­ger ef­fects and so on. We will be tak­ing that to FDA in the fall about next steps and what we may do. Op­tions in­clude an ac­cel­er­at­ed ap­proval,” but that would re­quire an on­go­ing Phase III to nail down.

All that has yet to play out.

 

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.

Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



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