Andrea Pfeifer, AC Immune CEO (AC Immune)

UP­DAT­ED: Cau­tious­ly op­ti­mistic, AC Im­mune de­liv­ers a mixed set of Alzheimer's da­ta — but in­vestors love it

Swiss biotech AC Im­mune is trad­ing sharply high­er Tues­day morn­ing fol­low­ing the re­lease of mixed topline Alzheimer’s da­ta.

First, the good news: In a dou­ble-blind­ed and ran­dom­ized Phase II study, AC Im­mune’s tau-tar­get­ing mon­o­clon­al an­ti­body met a pri­ma­ry end­point show­ing the can­di­date slowed cog­ni­tive de­cline at a sta­tis­ti­cal­ly sig­nif­i­cant rate in mild-to-mod­er­ate Alzheimer’s pa­tients com­pared to place­bo. It’s the first time an an­ti-tau an­ti­body has shown a ther­a­peu­tic ef­fect in Alzheimer’s, the com­pa­ny says, and the first-ever an­ti­body to show an im­pact on cog­ni­tion in this pop­u­la­tion.

But the Roche-part­nered pro­gram whiffed on the co-pri­ma­ry end­point mea­sur­ing the rate of func­tion­al de­cline, and al­so missed on sec­ondary end­points look­ing at men­tal state and de­men­tia ef­fects. CEO An­drea Pfeifer is re­main­ing cau­tious­ly op­ti­mistic about the topline da­ta and hopes to learn more about the drug’s im­pact on func­tion in a planned open-la­bel ex­ten­sion.

“These da­ta are sol­id, but we do not com­plete­ly un­der­stand them,” Pfeifer told End­points News in an in­ter­view. “This is what we will be work­ing on in No­vem­ber [at an up­com­ing con­fer­ence] and should give us a lit­tle bit more clar­i­ty.”

Nev­er­the­less, hit­ting one of the pri­maries was good enough for many in­vestors, as AC Im­mune shares $ACIU were up more than 75% ahead of Tues­day’s morn­ing bell.

As to why the drug passed the cog­ni­tive de­cline test but failed the func­tion­al de­cline end­point, Pfeifer point­ed to the study’s length, say­ing 12 months might have been too short a pe­ri­od to as­sess the func­tion mea­sure. She al­so fault­ed the end­point it­self, say­ing the cog­ni­tive end­point is “much more ob­jec­tive” be­cause it’s a pa­tient-re­port­ed out­come, rather than the care­giv­er-re­port­ed func­tion­al mea­sure­ment.

With pa­tients con­tin­u­ing to re­ceive treat­ment in the open-la­bel ex­ten­sion, Pfeifer said she hopes to ob­serve a pos­i­tive trend on func­tion here, but not­ed it’s still too ear­ly to say.

Tues­day’s re­sults come from a Phase II study eval­u­at­ing se­morinemab, a mon­o­clon­al an­ti-tau an­ti­body that tar­gets the N-ter­mi­nal por­tion of the tau pro­tein. AC Im­mune en­rolled 272 adults with mild-to-mod­er­ate Alzheimer’s, ran­dom­iz­ing pa­tients to ei­ther the se­morinemab or place­bo arms.

Re­searchers were aim­ing to clinch two co-pri­ma­ry end­points — the change from base­line at week 49 in cog­ni­tion, as mea­sured by the Alzheimer’s Dis­ease As­sess­ment Scale, Cog­ni­tive Sub­scale, 11-Item Ver­sion (ADAS-Cog11); as well as the change from base­line in ac­tiv­i­ties of dai­ly liv­ing, as mea­sured by the Alzheimer’s Dis­ease Co­op­er­a­tive Study-Ac­tiv­i­ties of Dai­ly Liv­ing (AD­CS-ADL) scale.

In the cog­ni­tion end­point, AC Im­mune says se­morinemab re­duced cog­ni­tive de­cline by 43.6% com­pared to place­bo. The biotech didn’t re­port an ex­act p-val­ue, on­ly say­ing it re­sult­ed in a p-val­ue of p<0.0025 — stel­lar by any mea­sure. On func­tion, AC Im­mune re­port­ed no da­ta at all, on­ly say­ing the co-pri­ma­ry end­point was not met. Pfeifer fur­ther de­clined to share these da­ta when pressed.

The re­sults mark a “sur­pris­ing” turn­around for the pro­gram, Jef­feries an­a­lyst Lucy Co­dring­ton wrote to in­vestors Tues­day, though Co­dring­ton not­ed the lack of ther­a­peu­tic ef­fect on func­tion left more to be de­sired. AC Im­mune’s da­ta were par­tic­u­lar­ly un­ex­pect­ed giv­en the pro­gram had pre­vi­ous­ly failed a tri­al last Sep­tem­ber look­ing at cog­ni­tion and func­tion in pa­tients with ear­li­er stages of Alzheimer’s, Co­dring­ton wrote.

SVB Leerink’s Marc Good­man agreed, writ­ing in­vestors “had min­i­mal ex­pec­ta­tions” for this read­out. Good­man now be­lieves the da­ta pro­vide ini­tial clin­i­cal val­i­da­tion of the an­ti-tau an­ti­body ap­proach, even though “the lack of con­sis­ten­cy re­mains a sig­nif­i­cant is­sue that needs to be fur­ther an­a­lyzed.”

At the time AC Im­mune re­port­ed those da­ta, the com­pa­ny said it was still wait­ing on fur­ther analy­ses from PET imag­ing to de­ter­mine whether se­morinemab re­duced tau in the brain. With­out that, there had been no way to know what specif­i­cal­ly caused the tri­al fail­ure, be it the par­tic­u­lar drug, the an­ti­body class, the pa­tient pop­u­la­tion or the tau hy­poth­e­sis it­self.

In an email to End­points on Tues­day af­ter­noon, Roche’s glob­al head of neu­rode­gen­er­a­tion Rachelle Doo­dy said the part­ners did not ob­serve a ben­e­fit here in PET sig­nal­ing. Like Pfeifer, Doo­dy said Tues­day’s da­ta rep­re­sent­ed a pos­i­tive step for­ward, though much work re­mains.

“Al­though we are en­cour­aged by the pos­i­tive out­come for one co-pri­ma­ry end­point mea­sur­ing cog­ni­tive per­for­mance, we will con­tin­ue our analy­ses of these da­ta and con­tin­ue the open la­bel por­tion of the study to bet­ter un­der­stand why se­morinemab didn’t show an ef­fect on the co-pri­ma­ry end­point mea­sur­ing func­tion­al de­cline in ac­tiv­i­ties of dai­ly liv­ing, or on the sec­ondary end­points,” Doo­dy wrote.

But with the pos­i­tive re­sults, Pfeifer — a long­time Alzheimer’s re­searcher — hy­poth­e­sized that tau-tar­get­ing an­ti­bod­ies may pro­duce dif­fer­ent ef­fects de­pend­ing on how much tau has built up in the brain. One an­swer could be that rather than pre­vent tau from ac­cru­ing, the an­ti­bod­ies sim­ply slow the spread in­stead. It’s still far too ear­ly to draw any con­clu­sions though, she said.

AC Im­mune is just an­oth­er biotech par­tak­ing the wild Alzheimer’s drug ride of 2021. There’s been the con­tro­ver­sial Aduhelm ap­proval and its own on­go­ing saga over how much in­sur­ers will be will­ing to pay, as well as the back-and-forth be­tween Cas­sa­va Sci­ences and some in­vestors, which called for an au­dit af­ter claims of ma­nip­u­lat­ed da­ta.

This ar­ti­cle has been up­dat­ed to in­clude com­ments from Roche glob­al head of neu­rode­gen­er­a­tion Rachelle Doo­dy. 

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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Michel Vounatsos, Biogen CEO (Credit: World Economic Forum/Ciaran McCrickard)

An un­ortho­dox pro­pos­al for Bio­gen's Medicare-man­dat­ed Aduhelm tri­al

Biogen has gone full blitz since Medicare announced it would only cover its new Alzheimer’s drug when used in clinical trials, accusing the agency of discriminating against Alzheimer’s patients and trying to get physicians to change regulators’ minds.  Critics, meanwhile, cheered what they see as a necessary wall protecting payers and patients from an unproven and unsafe drug.

Far less attention, though, has gone to what a Medicare-funded clinical trial would actually look like. Biogen has operated as if it would be a standard late-stage Alzheimer’s trial, enrolling a couple thousand patients and giving half placebo.

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