That Alzheimer's drug that flunked a PhII? On sec­ond look, Bio­gen/Ei­sai say it's a win­ner

Sev­en months ago, Bio­gen and Ei­sai were forced to aban­don their plans for a quick piv­ot in­to Phase III as their Alzheimer’s drug BAN2401 failed a de­ci­sive Phase II. Now, with the full 18-month analy­sis in hand, the part­ners are say­ing they were right to per­sist.

Bio­gen’s stock $BI­IB surged 17.48% in pre-mar­ket trad­ing on an up­dat­ed snap­shot, a con­sid­er­able boost giv­en the size of the com­pa­ny. So far, the com­pa­ny has added rough­ly $10 bil­lion to its mar­ket cap since yes­ter­day. Mean­while BioArc­tic, the small Swedish biotech whose re­search al­liance with Ei­sai first gave birth to the prod­uct, saw their shares (CPH: $BIOA-B) sky­rock­et 209% as of press time.

Here’s what changed: When eval­u­at­ed by the Alzheimer’s Dis­ease Com­pos­ite Score (AD­COMS), the high­est dose of BAN2401 showed to cause “sta­tis­ti­cal­ly sig­nif­i­cant slow­ing of dis­ease pro­gres­sion” af­ter 18 months of treat­ment. The tri­al re­cruit­ed 856 pa­tients with ear­ly Alzheimer’s dis­ease (and con­firmed amy­loid pathol­o­gy in the brain), a co­hort com­pris­ing those with mild cog­ni­tive im­pair­ment due to Alzheimer’s and oth­ers with mild Alzheimer’s de­men­tia.

Lynn Kramer, Ei­sai

What does this mean for a field fraught with fail­ures, a field that ab­sorbed the mil­lions of dol­lars thrown at it by big phar­mas and biotechs alike and churned out noth­ing in re­turn? While past fail­ures have re­peat­ed called the amy­loid hy­poth­e­sis — the idea that tar­get­ing the plaques ob­served in the brains of most Alzheimer’s pa­tients could change the tra­jec­to­ry of the dis­ease — in­to ques­tion, for Ei­sai CMO Lynn Kramer, their da­ta are “fur­ther val­i­dat­ing the amy­loid hy­poth­e­sis.” Some might al­so see it as a val­i­da­tion of ad­u­canum­ab, the much-tout­ed late-stage drug that’s al­so hit­ting the amy­loid be­ta path­way.

“We will dis­cuss these very en­cour­ag­ing re­sults with reg­u­la­to­ry au­thor­i­ties to de­ter­mine the best path for­ward,” Kramer said in a state­ment.

It would be a huge feat to demon­strate im­prove­ment in cog­ni­tion linked with a de­cline in amy­loid be­ta clus­ters. But un­til the full da­ta is out at a fu­ture med­ical con­fer­ence, ex­perts are care­ful­ly man­ag­ing their ex­pec­ta­tions.

“Giv­en the state of the field we have to be cau­tious­ly op­ti­mistic about a find­ing like this,” Mayo Clin­ic Alzheimer’s Dis­ease Re­search Cen­ter di­rec­tor Ron Pe­tersen told Forbes.

Leerink’s Ge­of­frey Porges is more skep­ti­cal, point­ing out how lit­tle in­for­ma­tion was giv­en in the press re­lease.

We do not feel that Bio­gen, Ei­sai or the whole amy­loid field de­serves much cred­it for this dis­clo­sure, par­tic­u­lar­ly giv­en the lack of ex­ter­nal val­i­da­tion of the AD­COMS end­point. There is very lit­tle de­tail about oth­er more val­i­dat­ed cog­ni­tive mea­sures in the joint press re­lease and we find no rea­son to be­lieve this ei­ther proves or dis­proves the amy­loid hy­poth­e­sis or has any im­pact on the like­li­hood that ad­u­canum­ab will suc­ceed in its on­go­ing phase III tri­al.

A few de­tails in the tri­al de­sign may al­so prove prob­lem­at­ic.

For one, the turn­around comes down to sta­tis­tics. When Bio­gen and Ei­sai re­port­ed in De­cem­ber that the study failed its pri­ma­ry end­point, it was re­fer­ring to a Bayesian analy­sis, in which the drug would have to hit a cer­tain prob­a­bil­i­ty for caus­ing a cer­tain out­come to be deemed ef­fec­tive. Be­cause of that, and an adap­tive tri­al de­sign, re­searchers could make changes dur­ing the tri­al and pa­tients could be switched to dif­fer­ent dos­es. That didn’t work, so they wait­ed un­til the stan­dard 18-month mark to eval­u­ate the re­sults again with “con­ven­tion­al sta­tis­ti­cal meth­ods.” Look­ing back with this new frame­work, the part­ners now say their drug showed sta­tis­ti­cal­ly sig­nif­i­cant clin­i­cal ben­e­fit as ear­ly as six months.

The pos­i­tive out­come be­ing high­light­ed to­day al­so con­cerns on­ly the 10mg/kg bi­week­ly dose, which was one of five dos­es test­ed in the tri­al. It’s un­clear how many pa­tients end­ed up on that dos­ing scheme.

And fi­nal­ly there’s AD­COMS, the cho­sen mea­sure of cog­ni­tion, which was a nov­el end­point that com­bines a few stan­dard scales in Alzheimer’s.

But if there’s one thing we’re sure about, it’s that Bio­gen and Ei­sai are all in. The Japan­ese com­pa­ny re­cent­ly wa­gered more than $100 mil­lion on a be­spoke Alzheimer’s re­search cen­ter in its part­ner’s home of Cam­bridge, MA. And Bio­gen just tossed in an ex­tra $50 mil­lion for a big­ger slice of the roy­al­ties for ad­u­canum­ab.

Mi­no­ryx and Sper­o­genix ink an ex­clu­sive li­cense agree­ment to de­vel­op and com­mer­cial­ize lerigli­ta­zone in Chi­na

September 23, 2020 – Hong Kong, Beijing, Shanghai (China) and Mataró, Barcelona (Spain)  

Minoryx will receive an upfront and milestone payments of up to $78 million, as well as double digit royalties on annual net sales 

Sperogenix will receive exclusive rights to develop and commercialize leriglitazone for the treatment of X-linked adrenoleukodystrophy (X-ALD), a rare life-threatening neurological condition

PhII Alzheimer's fail­ure deals new blow to Roche, AC Im­mune — but the tau hy­poth­e­sis is far from dead

The leading anti-tau antibody has failed its first Phase II testing, casting a shadow on a popular target (just trailing amyloid beta) for Alzheimer’s disease.

Roche and AC Immune are quick to acknowledge disappointment in the topline readout, which suggested that semorinemab did not reduce cognitive decline among patients with early Alzheimer’s disease, who are either just starting to have symptoms or have mild manifestations.

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FDA commissioner Stephen Hahn at the White House (AP Images)

Un­der fire, FDA to is­sue stricter guid­ance for Covid-19 vac­cine EUA this week — re­port

The FDA has been insisting for months that a Covid-19 vaccine had to be at least 50% effective – a measure of transparency meant to shore public trust in the agency and in a vaccine that had been brought forward at record speed and record political pressure. But now, with concerns of a Trump-driven authorization arriving before the election, the agency may be raising the bar.

The FDA is set to release new guidance that would raise safety and efficacy requirements for a vaccine EUA above earlier guidance and above the criteria used for convalescent plasma or hydroxychloroquine, The Washington Post reported. Experts say this significantly lowers the odds of an approval before the election on November 3, which Trump has promised despite vocal concerns from public health officials, and could help shore up public trust in the agency and any eventual vaccine.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

News brief­ing: PureTech plans Nas­daq de­but with sec­ondary list­ing; GoodRx prices $725M IPO

London Stock Exchange-listed PureTech Health announced Wednesday that it’s looking to extend to Nasdaq. But due to its “strong cash position,” the biotech says it isn’t issuing any new shares in the potential secondary listing.

The company’s shares closed at £256.50 Tuesday on the London Stock Exchange. Its candidate LYT-100 is currently in Phase I development for various indications, including lymphatic flow disorders and fibrotic and inflammatory disorders. PureTech is expecting a Phase Ib readout in lymphatic flow disorders later this year, and is also planning to launch a Phase II study for the drug to treat respiratory conditions experienced after Covid-19.

Rep. Andy Harris (R-MD) (Tasos Katopodis/Pool via AP Images)

The mi­cro-cap that tapped a mask-skep­tic con­gress­man for their Covid DSMB is ap­ply­ing for an EUA. Their ev­i­dence? 21 pa­tients

NeuroRx, the tiny biotech that came under fire last week after Politico reported they selected a congressman and two other acquaintances of the CEO to supervise their Covid-19 drug trial, announced today that they will ask the FDA to authorize their drug based on the results of just 21 patients.

Such an application would test the agency’s standards of evidence for an EUA, which have already come under scrutiny after controversial authorizations for convalescent plasma and hydroxychloroquine. The only other company to discuss their intention to file for an EUA, Eli Lilly, did so after results came back from a randomized control study testing their antibody in over 450 patients.

Covid-19 roundup: J&J be­gins piv­otal Phase III tri­al for vac­cine; Con­tro­ver­sial hu­man chal­lenge tri­als to be­gin in Lon­don — re­port

Johnson & Johnson announced it’s beginning a pivotal Phase III trial for its Covid-19 candidate, JNJ-78436735 — the first single-dose vaccine in this stage.

The Phase III trial, dubbed ENSEMBLE, will enroll 60,000 patients worldwide, making it the largest Phase III study of a Covid-19 vaccine to date. J&J said the candidate achieved positive interim results in a Phase I/IIa study, which will be published “imminently.” There’s a possibility that the first batches will be ready for potential emergency use in early 2021, according to the biotech.

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J&J re­leas­es PhI­II safe­ty blue­print for Covid-19 vac­cine tri­al. How does it stack up to Mod­er­na, Pfiz­er and As­traZeneca?

Along with the initiation of its Phase III Covid-19 vaccine study announced Wednesday morning, Johnson & Johnson also released its trial protocol, giving an inside look at how the company is conducting its late-stage research.

The move comes after the other three companies conducting Phase III’s in the US — Moderna, Pfizer and AstraZeneca — each disclosed their own trial blueprints within the last week. Though the release of such protocols is typically done after trials have been completed, drug developers had come under intense pressure after a brief safety scare in an AstraZeneca trial and amid growing concern of a politically motivated vaccine authorization.

Vas Narasimhan (AP Images)

UP­DAT­ED: Still held down by clin­i­cal hold, No­var­tis' Zol­gens­ma falls fur­ther be­hind Bio­gen and Roche as FDA asks for a new piv­otal study

Last October, the FDA slowed down Novartis’ quest to extend its gene therapy to older spinal muscular atrophy patients by slapping a partial hold on intrathecal administration. Almost a year later, the hold is still there, and regulators are adding another hurdle required for regulatory submission: a new pivotal confirmatory study.

The new requirement — which departs significantly from Novartis’ prior expectations — will likely stretch the path to registration beyond 2021, when analysts were expecting a BLA submission. That could mean more time for Biogen to reap Spinraza revenues and Roche to ramp up sales of Evrysdi in the absence of a rival.

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