PhI­II Alzheimer’s drug goes bust — and a ma­jor set­back at Eli Lil­ly and As­traZeneca may doom the class

An­oth­er big Phase III Alzheimer’s pro­gram is be­ing scrapped at Eli Lil­ly $LLY and As­traZeneca $AZN, of­fer­ing fresh ev­i­dence that the en­tire BACE class may be com­plete­ly use­less in slow­ing or pre­vent­ing the dis­ease in symp­to­matic pa­tients.

Dan Skovron­sky

The drug this time is lan­abece­s­tat, which Lil­ly grabbed close to 4 years ago in a $500 mil­lion pact with As­traZeneca — a mod­est $50 mil­lion in cash. At the time, Lil­ly was plug­ging a gap in its Alzheimer’s pipeline af­ter the fail­ure of its own BACE ef­fort due to tox­i­c­i­ty is­sues with that par­tic­u­lar med­ica­tion.

This time, fin­gers are point­ing to the en­tire class in a flop that will like­ly cause fresh angst over a huge ques­tion: Is amy­loid be­ta re­al­ly the cul­prit here?

The BACE the­o­ry is easy enough to un­der­stand. Mov­ing up­stream in the bi­o­log­i­cal process for the pro­duc­tion of amy­loid be­ta, re­searchers hoped to bend the course of the dis­ease by clos­ing the tap on tox­ic pro­teins. Mer­ck was the first to try it in a pair of Phase III stud­ies and sim­ply con­clud­ed it was a bust, prob­a­bly on­ly the­o­ret­i­cal­ly use­ful now in pre-symp­to­matic pa­tients or as a com­bo.

Eli Lil­ly will now move to shut­ter two big tri­als — the AMA­RANTH tri­al, in ear­ly Alzheimer’s dis­ease, and the DAY­BREAK-ALZ tri­al, in mild Alzheimer’s dis­ease de­men­tia — af­ter the mon­i­tor­ing com­mit­tee called it on fu­til­i­ty.

The fail­ure of Lil­ly and As­traZeneca’s drug may sound the death knell on a so­lo BACE strat­e­gy in ear­ly and mild pa­tients, even though Bio­gen just tout­ed its Phase II BACE study herald­ing the bio­mark­er suc­cess on amy­loid be­ta along­side an ab­sence of a sta­tis­ti­cal­ly sig­nif­i­cant im­pact on cog­ni­tion — much the same as what Mer­ck was track­ing.

In lan­abece­s­tat’s case, we on­ly know that the drug ap­peared safe and in­ef­fec­tive, no hard da­ta are avail­able yet.

Why keep try­ing af­ter more than a decade of fail­ures? As­traZeneca an­swered that ques­tion when Pas­cal So­ri­ot once es­ti­mat­ed that this drug could earn $5 bil­lion a year. 

That’s not go­ing to hap­pen, of course. But de­vel­op­ers keep ham­mer­ing away at it — even as big play­ers re­main puz­zled about what caus­es the dis­ease. 

Fol­low­ing the fail­ure of solanezum­ab in three straight piv­otal stud­ies, Eli Lil­ly doesn’t have much of a cred­i­ble pipeline left in the field. And af­ter Pfiz­er bowed out fol­low­ing big re­treats at GSK and As­traZeneca, Big Phar­ma may be do­ing some ad­di­tion­al soul search­ing about its role in R&D. Lil­ly, though, vows to sol­dier on af­ter spend­ing bil­lions on fail­ure.

“Lil­ly re­mains ded­i­cat­ed to Alzheimer’s dis­ease re­search as we have been for the last three decades,” says R&D chief Daniel Skovron­sky. “We won’t give up on find­ing a so­lu­tion for Alzheimer’s pa­tients.”

Un­pack­ing the Aduhelm de­ci­sion, Ver­tex's half full glass, a $525M J&J breakup, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

By now you have surely read about the FDA’s controversial approval of Biogen’s Alzheimer’s drug and all its reverberations. But I’d still recommend checking out the meaty recap below to make sure you didn’t miss all the angles that the Endpoints team has covered. If you’d rather look ahead, look no further than our three-day virtual panels next week at BIO, where we will discuss what the new normal means for every part of the industry.

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What does a clear ma­jor­i­ty of the bio­phar­ma in­dus­try think of the FDA ap­proval of ad­u­canum­ab? 'Hor­ri­fy­ing' 'Dan­ger­ous' 'Con­fus­ing' 'Dis­as­ter'

Over the years, we’ve become used to seeing a consensus emerge early in our industry polls at Endpoints News. And when we took the pulse of drug hunters on the heels of a controversial FDA approval for aducanumab this week, it became immediately apparent that the vast majority of our readers — heavily concentrated among biopharma staffers and execs — were incensed by what they had just witnessed.

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Aaron Kesselheim (Scott Eisen/AP Images for AIDS Healthcare Foundation)

Har­vard’s Aaron Kessel­heim re­signs from ex­pert pan­el in wake of ad­u­canum­ab OK, blast­ing FDA for ‘worst drug ap­proval de­ci­sion in re­cent U.S. his­to­ry'

A third member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has resigned in the wake of Biogen’s controversial Aduhelm approval, slamming the agency as he left and further deepening the controversy surrounding the decision.

Harvard University professor Aaron Kesselheim quit in protest Thursday afternoon, calling the Aduhelm OK “probably the worst drug approval decision in recent U.S. history.” Kesselheim follows both Joel Perlmutter, a neurologist from Washington University in St. Louis, and David Knopman, a neurologist from the Mayo Clinic, out the door.

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David Knopman (Mayo Clinic via YouTube)

A sec­ond ad­comm mem­ber aban­dons his post in af­ter­math of con­tro­ver­sial ad­u­canum­ab de­ci­sion

As the fallout from the FDA’s approval of Alzheimer’s med aducanumab grows, a second member of the adcomm overseeing that drug’s review has walked away. But even with two experts now having resigned from that committee in protest, is there enough broad-level outrage to prevent another aducanumab from getting approved?

The FDA on Wednesday lost another member of its Peripheral and Central Nervous System Drugs Advisory Committee as Mayo Clinic neurologist David Knopman hit the exit over the agency’s decision to approve Biogen’s Alzheimer’s drug Aduhelm despite the committee’s near-unanimous vote against it.

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Reshma Kewalramani, Vertex CEO (BIO via YouTube)

UP­DAT­ED: Ver­tex strikes out on its lat­est big shot at a rare ge­net­ic dis­ease. But they're go­ing to keep on swing­ing

It’s been several months since Vertex culled one of its small molecules for alpha-1 antitrypsin deficiency (AATD), taking a big hit after evidence of liver damage surfaced in a key Phase II trial. Now we learned that the company has whiffed on its second shot, and there’s nothing left in the clinic to treat the rare genetic disease — but that won’t stop it from trying.

Despite avoiding the safety issues that plagued the last candidate, Vertex $VRTX is taking the axe to VX-864 after Phase II results revealed the magnitude of the drug’s response is “unlikely to translate into substantial clinical benefit.” As a result of the news, the company’s stock fell 12.5% after hours.

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FDA au­tho­rizes about 10M J&J vac­cine dos­es, trash­es 60M more from trou­bled Emer­gent plant

The FDA on Friday released about 10 million doses of J&J’s vaccine for use, and disposed of another 60 million doses that were manufactured at the now-shuttered Emergent BioSolutions facility in Baltimore where cross-contamination occurred.

The agency said it’s not yet ready to allow the Emergent plant to be included in the J&J EUA, but that may occur soon. FDA came to the decision to authorize some of the doses after reviewing facility records and quality testing results.

Paul Hudson, Sanofi CEO (Eric Piermont/AFP via Getty Images)

Months af­ter FDA re­jec­tion, Sanofi touts piv­otal win for rare dis­ease drug su­tim­limab as it preps to re­file

One of the pillar drugs of Sanofi’s $11.6 billion pickup of Bioverativ hit a big setback late last year when the FDA sent its application for approval back. Now, as Sanofi gears up to resubmit the drug for review, the drugmaker is touting pivotal data it hopes will help take it over the finish line.

Sanofi’s sutimlimab nailed all three of its primary endpoints in its Phase III CADENZA study for patients with cold agglutinin disease, a rare disorder that can cause severe anemia, without a recent history of blood transfusion, the French drugmaker said Friday. The topline results will be presented at this weekend’s virtual EHA meeting.

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Ver­tex and CRISPR Ther­a­peu­tics un­veil more pos­i­tive gene ther­a­py da­ta, but busul­fan again casts a shad­ow over the field

Less than 12 hours after revealing a flop on its second shot for alpha-1 antitrypsin deficiency, Vertex plowed ahead with another data drop from its partnership with CRISPR Therapeutics. And though the topline proved positive, concerns over conditioning agents continue to linger over the collaboration, as well as the entire gene therapy space.

Presenting data from two trials at the European Hematology Association annual meeting, the pair announced that follow-up data of at least three months for 22 patients with genetic blood disorders indicated a “consistent and sustained” response to the experimental drug CTX001. All 15 patients with transfusion-dependent beta thalassemia did not need further blood transfusions and all seven with severe sickle cell disease were pain free, the biotechs announced.

Janet Woodcock, acting FDA commissioner, at Thursday's Senate Appropriations hearing (Bill Clark/CQ Roll Call via AP Images)

Sen­a­tors lam­bast new Alzheimer’s drug’s price but give Janet Wood­cock a free pass on the ap­proval de­ci­sion

Senate Finance Democrats took aim at Biogen’s pricey new Alzheimer’s drug on Thursday, but members on both sides of the aisle at a separate appropriations hearing didn’t question acting FDA commissioner Janet Woodcock on the approval.

“I was appalled that Biogen priced their Alzheimer’s drug approved by the FDA at $56,000 per year — I’m not going to debate whether this is effective or not, but it’s double the household median income for Michiganders over the age of 65,” Sen. Debbie Stabenow (D-MI) said at the finance hearing.