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.

 

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

No­var­tis gets a boost in block­buster mul­ti­ple scle­ro­sis race with Roche

In the first step of what’s likely to be a long and uphill battle for the drugmaker, the FDA has accepted Novartis’s BLA submission for a new multiple sclerosis drug and given it priority review. The PDUFA date for the potential blockbuster drug is in June.

The drug, known as ofatumumab or Arzerra, has performed consistently well across late-stage trials in patients with the most common form of MS, including in head-to-head studies against Sanofi’s old blockbuster Aubagio. But, if the drug is approved, Novartis will find itself in a crosstown game of catch-up; since a 2017 approval, Roche’s Ocrevus has become the second best-selling MS drug on the market, nearly eclipsing Biogen’s Tecfidera last quarter with over a $1 billion in sales.

Coro­n­avirus out­break threat­ens short­age of 150 drugs — re­port

American patients who suffer from conditions other than Covid-19 could feel the impact of the coronavirus due to shortage of drugs — as 150 prescription drugs are now reportedly on a list of at-risk therapies. The list spans “antibiotics, generics and some branded drugs without alternatives,” Axios reported citing sources familiar with the list. The FDA declined to comment.

Although factories in China are gradually reopening, restrictions in travel and disruptions at transit hubs are still slowing down production. An Indian company that relies on active pharmaceutical ingredients (API) from China told Bloomberg last week that it’s seeing prices of commonly used drugs jump by 40% to 70%.

Juergen Horn

An­i­mal health vet Juer­gen Horn makes new an­ti­body play for pets, rak­ing $15M in Se­ries A haul

Zoetis forked over $85 million in 2017 to acquire Nexvet Biopharma and its pipeline of monoclonal antibodies. Juergen Horn, Nexvet’s former chief product development officer, has now secured $15 million for his own biologic company for animals: Invetx.

Buoyed by emerging advances in gene therapies for humans, scientists have started looking at harnessing the technology for animals setting up companies such as Penn-partnered Scout Bio and George Church-founded Rejuvenate Bio. But akin to Nexvet, Invetx is working on leveraging the time-tested science of monoclonal antibodies to treat chronic diseases that afflict man’s best friend.

Tim Mayleben (file photo)

Es­pe­ri­on's goldilocks cho­les­terol fight­er wins FDA ap­proval — will its 'tra­di­tion­al' pric­ing ap­proach spur adop­tion?

It’s more effective than decades-old statins but not as good as the injectable PCSK9 — the goldilocks treatment for cholesterol-lowering, bempedoic acid, has secured FDA approval.

Its maker, Esperion Therapeutics, is betting that their pricing strategy — a planned list price of between $10 to $11 a day — will help it skirt the pushback the PCSK9 cholesterol fighters, Repatha and Praluent, got from payers for their high sticker prices.

The sky-high expectations for the pair of PCSK9 drugs that were first approved in 2015 quickly simmered — and despite a 60% price cut, coupled with data showing the therapies also significantly cut cardiovascular risk, sales have not really perked up.

Esperion is convinced that by virtue of being a cheaper oral therapy, bempedoic acid will hit that sweet spot in terms of adoption.

“We’re kind of like the old comfortable shoe,” Esperion’s chief commercial officer Mark Glickman remarked in an interview with Endpoints News ahead of the decision date. “It’s an oral product, once-daily and nontitratable — these are things that just resonate so true with patients and physicians and I think we’ve kind of forgotten about that.”

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As coro­n­avirus out­break reach­es 'tip­ping point,' GSK lends ad­ju­vant tech to Chi­nese part­ner armed with pre­clin­i­cal vac­cine

As the coronavirus originating out of Wuhan spreads to South Korea, Italy and Iran, stoking already intense fears of a pandemic, GlaxoSmithKline has found another pair of trusted hands to place its adjuvant system. China’s Clover Biopharmaceuticals will add the adjuvant to its preclinical, protein-based vaccine candidate against SARS-CoV-2.

Clover, which is based in the inland city of Chengdu, boasts of a platform dubbed Trimer-Tag that produces covalently-trimerized fusion proteins. Its candidate, COVID-19 S-Trimer, resembles the viral spike (S)-protein found in the virus.

Deborah Dunsire

The fourth CGRP mi­graine drug is here. Time for Lund­beck to prove it's worth $2B

They may be late, but Lundbeck is now officially in the game for preventing migraine with CGRP drugs.

The FDA has OK’d eptinezumab, the prize in Lundbeck’s $2 billion acquisition of Alder. Like rival offerings from Amgen/Novartis, Eli Lilly and Teva, the antibody blocks the calcitonin gene-related peptide, which is believed to dilate blood vessels in the brain and cause pain.

It will now be sold as Vyepti. The company has yet to announce a price. Amgen and Novartis had set the wholesale acquisition cost of their pioneering Aimovig at $6,900 for a year’s supply before raising it slightly this year; Lilly and Teva had followed suit with Emgality and Ajovy.

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Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

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Drug ap­provals: FDA pub­lish­es dataset of CDER ap­provals since 1985

To provide researchers with more accurate and accessible data about historic drug approvals, the FDA on Friday released a dataset containing information about all new drugs and biologics approved by the Center for Drug Evaluation and Research (CDER) dating back to 1985.

“FDA created the compilation to facilitate data accessibility, transparency, and accuracy when researchers seek information about an approved drug,” the FDA writes, adding that the compilation should accurately reflect “the state of each application at the time of initial regulatory approval.”