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.

 

The 20 un­der 40: In­side the next gen­er­a­tion of bio­phar­ma lead­ers

“Each generation needs a new music,” Francis Crick wrote in 1988, reflecting back on his landmark discovery. Crick was 35, then, in 1953, when he began working with a 23-year-old named James Watson, and 37 when the pair unveiled the double helix. Rosalind Franklin, whose diffraction work undergirded their metal model, was 32.

The model would become the score for a new era in biology, one devoted to cracking the basic structures turning inside life. Subsequent years would bring new conductors and new rhythms: Robert Swanson, 29 when he convinced a 39-year-old Herb Boyer to build a company off his work and call it Genentech; Phillip Sharp, 29 when he discovered RNA splicing and 34 when he co-founded Biogen; Frances Arnold, 36 when she pioneered directed evolution; Feng Zhang, 31 when he published his CRISPR paper.

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Chart-top­ping ven­ture cash? Strong deal flow? In the month Covid-19 ripped around the globe? Yup

It turns out that even sending everyone from the CEO to rank-and-file staffers home to work in the middle of a Category 5 pandemic wasn’t enough to put a crimp in the flow of venture cash into biopharma. And even dealmaking held its own against the howling winds of misfortune — largely because a group of savvy players was quick to adjust to the new reality.

Our deal expert Chris Dokomajilar ran the numbers for us on a month-to-month basis and found that not only was venture money flowing during the panicky month of March, but it was also hitting home in record sums compared to the last 26 months of deal flow.

Say what?

As you can see in the top chart below, Dokomajilar outlined how the industry racked up $2.41 billion in total for March, just barely ahead of one other topper during the heady days of August 2018.

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FDA Commissioner Stephen Hahn and President Donald Trump at a press briefing on March 19, 2020. (AP Images)

Biotech ex­ecs warn that the FDA is fum­bling their re­sponse to the Covid-19 open-door promise, de­lay­ing progress

A few days ago the FDA touted a procedure for Covid-19 meds that committed the agency to immediate action for developers, formalizing a high-speed response that’s been promised for weeks.

Bioregnum Opinion Column by John Carroll

Decisions that once required months would be measured in hours under the Coronavirus Treatment Acceleration Program. “In many cases” trial protocols could be hammered out in less than a single day. If you had a potential solution to the crisis, the appropriate staffer would be in touch “to get studies underway quickly.”

It would be the ultimate high-speed regulatory pathway from Phase I to approval. Red tape was banished.

But it’s clear that for some — and quite likely many — biopharma execs, the actual agency response has not measured up to the promise. Beyond the front ranks of advanced companies in the field, like Gilead, or for drugs endorsed by President Trump, it may not even come close.

“The first response is this form letter everyone gets,” says one biotech CEO who’s reached out to the FDA on Covid-19. And when you try to cut through that, the ball gets dropped as it is passed from top officials to the frontline staff actually charged with getting things done.

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GSK's Hal Bar­ron buys a $250M stake in George Scan­gos' Vir and makes a bee­line to the clin­ic with Covid-19 an­ti­bod­ies

GlaxoSmithKline is diving straight into the swirling waters of Covid-19 R&D work, and investing $250 million to grab a chunk of equity in one of the emerging stars in infectious disease research to make it official.

GSK put out word this morning that it is partnering with Vir Biotechnology $VIR, the infectious disease startup founded in the Bay Area by former Biogen CEO George Scangos. They’re planning a leap into Phase II studies for 2 preclinical antibody candidates — VIR-7831 and VIR-7832 — that have been engineered to target the SARS-CoV-2 spike protein.

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UP­DAT­ED: A small, ob­scure biotech just won big with their IPO. In this mar­ket. Are you kid­ding me?

How could a small, largely unknown biotech that emerged from stealth mode just months ago with early-stage cancer programs jump onto Wall Street in the middle of a Category 6 financial hurricane and sail through with a $165 million IPO?

And what does that mean for the rest of the industry waiting to see just how much damage global lockdowns will wreak on clinical development?

The biotech is a company called Zentalis. The crew there nabbed an $85 million crossover round late last year — notably waiting 5 years before waving the numbers around to attract attention, according to my read of a FierceBiotech story. Perceptive joined in, but the syndicate was not in general the kind of marquee affair that gets tongues wagging.

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Ready to de­clare a de­fin­i­tive come­back in two months, Im­munomedics stops PhI­II ear­ly, re­cruits new CEO

More than a year ago, hit by a surprise complete response letter from the FDA, Immunomedics bid its then-CEO, Michael Pehl, adieu and began a 15-month quest to resolve the manufacturing issues cited in the CRL and seek a new leader — all the while moving forward with a Phase III study on its lead drug for metastatic triple-negative breast cancer.

Today the biotech said their stars are finally aligning. Not only is Novartis Oncology vet Harout Semerjian coming on board as CEO to steer what they believe will be a smooth sail to a new PDUFA date in June, Immunomedics has also been informed that their late-stage trial can be stopped early due to “compelling evidence of efficacy.”

An­oth­er day, an­oth­er boat­load for biotech. Deer­field adds $840M to rush of ven­ture dol­lars

The biotech dollars just keep rolling in.

Even as the world economy faces an economic contraction unprecedented in nature, biotech venture capital firms are announcing huge new investment pots. The latest? Deerfield Management Co.

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Small mol­e­cules, bi­o­log­ics and now gene ther­a­pies: Ger­many's Evotec adds an­oth­er feath­er to its R&D cap

German drug discovery company Evotec — which has a thriving rolodex of biopharma partners such as Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda — is now venturing into gene therapies.

The company swallowed Seattle-based Just Biotherapeutics, a company focused on reducing the cost of manufacturing protein therapies last year. It is now setting up a dedicated R&D site for gene therapies in Austria, in an effort to achieve a “modality-agnostic” repertoire — small molecules, biologics and now gene therapies.

A pair of PhI­II fail­ures spells last rites for Men­lo’s once-promis­ing Mer­ck drug

Four months after an intercontinental merger, Menlo Therapeutics is counting yet another pair of trial failures — ones with significant consequences for the companies, their shareholders and the drug.

In two pivotal Phase III trials, Menlo’s lead drug serlopitant failed to treat pruritus associated with prurigo nodularis — basically itchiness from a particular skin disease that causes red lesions on a person’s arms or legs. Serlopitant has long been the company’s only drug and as recently as 2018, it looked promising enough to support a stock price of $37. In April of that year, a Phase II failure demolished the stock price overnight: $35 to $9. Other subsequent stumbles trickled the ticker down to just above $2.