Genen­tech dou­bles down on its PhI­II Alzheimer’s cam­paign for crenezum­ab

An­drea Pfeifer

Roche’s big biotech group Genen­tech is dou­bling down on one of the most promi­nent drugs in late-stage de­vel­op­ment for Alzheimer’s. The com­pa­ny is launch­ing a sec­ond Phase III study of crenezum­ab, ac­cord­ing to its part­ners at AC Im­mune $ACIU, in search of pos­i­tive da­ta in a field lit­tered with the wreck­age of ear­li­er clin­i­cal crash­es.

In­ves­ti­ga­tors for the CREAD2 study will now set out to re­cruit 750 pa­tients with pro­dro­mal or mild Alzheimer’s to test the drug, an­oth­er an­ti-amy­loid be­ta drug de­signed to sweep out tox­ic for­ma­tions that are be­lieved by many to cause the mem­o­ry-wast­ing ill­ness.

CREAD2 will start with all the hall­marks ex­pect­ed in an Alzheimer’s study. It failed a mid-stage pro­gram, but in­ves­ti­ga­tors were able to track a dis­tinct im­pact on cog­ni­tive and func­tion­al scores for pa­tients di­ag­nosed with the ear­li­est stages of this dis­ease. Re­turn­ing to Phase III proved to be a dis­as­trous mis­take for Eli Lil­ly’s solanezum­ab, a three time los­er. But AC Im­mune has been able to win over be­liev­ers that this time a piv­otal ef­fort can suc­ceed.

Jef­feries’ Pe­ter Welford not­ed that the launch of the sec­ond Phase III can now con­form to cur­rent FDA rules de­mand­ing two Phase III stud­ies for an ap­proval. And he out­lined the pro-crenezum­ab ar­gu­ment in a note this morn­ing, com­par­ing Roche’s drug with Lil­ly’s solanezum­ab.

(1) So­la tar­gets Abe­ta monomers on­ly, where­as crenezum­ab al­so tar­gets sol­u­ble Abe­ta oligomers, be­lieved by many to be the most neu­ro­tox­ic, in­hibits Abe­ta ag­gre­ga­tion and pro­motes dis­ag­gre­ga­tion of Abe­ta plaques; (2) The so­la study en­rolled mild AD pa­tients (base­line MMSE 20-26) some of whom may al­ready be too ad­vanced, with “treat­ment” pos­si­bly need­ed years be­fore clin­i­cal man­i­fes­ta­tions ap­pear as pre­ven­tion. The crenezum­ab Phase III stud­ies are en­rolling milder AD pa­tients, with base­line MMSE 22+ and CDR-GS 0.5 or 1.0. We note that Lil­ly has now al­so aban­doned an on­go­ing tri­al in pro­dro­mal AD; (3) Un­like oth­er promi­nent Abe­ta an­ti­bod­ies such as ad­u­canum­ab and so­la that have an IgG1 back­bone, crenezum­ab con­tains an IgG4 back­bone. Im­por­tant­ly, this IgG4 back­bone re­sults in clear­ance of Abe­ta with­out in­duc­ing an in­flam­ma­to­ry re­sponse, en­abling use of high­er dos­es and a bet­ter side ef­fect pro­file. High­er dos­es should re­sult in in­creased brain ex­po­sure and there­fore po­ten­tial­ly greater ef­fi­ca­cy.

Com­pa­nies in the field can re­ly on bet­ter di­ag­nos­tics to ac­tu­al­ly re­cruit the right pa­tients. But af­ter 15 years of de­feat and dis­as­ter in Alzheimer’s R&D, you can al­so ex­pect to see plen­ty of skep­ti­cism for a drug that al­ready failed hu­man stud­ies.

The litany of set­backs in­cludes Mer­ck’s re­cent de­ci­sion to scut­tle a Phase III study for the in­dus­try-lead­ing BACE drug. But any com­pa­ny which does man­age to get a drug across the fin­ish line can look for­ward to ma­jor sales. Mil­lions of Alzheimer’s pa­tients around the world are des­per­ate for some kind of dis­ease mod­i­fy­ing ther­a­py.

Jef­feries es­ti­mates peak sales for a crenezum­ab at $4.4 bil­lion in 2028, and oth­er an­a­lysts would stretch that fig­ure much high­er.

An­drea Pfeifer, the CEO of AC Im­mune, had this to say:

Giv­en the re­cent dis­ap­point­ing re­sults of oth­er ther­a­pies, all of us in the Alzheimer’s com­mu­ni­ty need to re­dou­ble our ef­forts to com­bat one of so­ci­ety’s biggest chal­lenges. We re­main con­fi­dent about the po­ten­tial of crenezum­ab giv­en it is dis­tinct from oth­er be­ta amy­loid an­ti­bod­ies, pre­dom­i­nant­ly block­ing oligomers in the brain, and has a clin­i­cal de­vel­op­ment pro­gram that is us­ing high­er dos­ing and tar­get­ing ear­li­er stages of Alzheimer’s dis­ease.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; 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.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 117,600+ biopharma pros reading Endpoints daily — and it's free.

President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

Mer­ck flesh­es out Keytru­da win in first-line cer­vi­cal can­cer, adding more fire­pow­er to its ear­ly can­cer push

Merck has worked hard to bring its I/O blockbuster Keytruda into earlier and earlier lines of therapy, and now the wonder drug appears poised to make a quick entry into early advanced cervical cancer.

A combination of Keytruda and chemotherapy with or without Roche’s Avastin cut the risk of death by 33% over chemo with or without Avastin (p=<0.001) in first-line patients with persistent, recurrent or metastatic cervical cancer, according to full data from the Phase III KEYNOTE-826 study presented Saturday at #ESMO21.

EQRx chairman Alexis Borisy and CEO Melanie Nallichieri

EQRx, CStone un­furl full lung can­cer da­ta for PD-L1 drug in what the part­ners are call­ing a first

As a self-stylized drug pricing disruptor, EQRx has high hopes for its lead PD-(L)1 to offer proof of concept for the entire business model. After touting a win back in May, the biotech is back with full data in lung cancer that could back up an approval.

Patients dosed with EQRx and CStone Pharmaceuticals’ sugemalimab posted median progression-free survival of 9 months compared with 5.8 months for patients given placebo (p=0.0026), according to full data from the Phase III GEMSTONE-301 study in Stage III non-small cell lung cancer set to be presented at this weekend’s #ESMO21.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 117,600+ biopharma pros reading Endpoints daily — and it's free.

As­traZeneca touts Imfinzi im­munother­a­py com­bos for lung can­cer in push to dri­ve PD-L1 drug up­take

Facing the big dogs in the PD-(L)1 space, AstraZeneca has taken its own contender Imfinzi into blockbuster territory in its four years on the market but sees even bigger things for the drug. Combinations could be the key, and early results from a mid-stage test are adding some fuel to that strategy.

Imfinzi combined with one of two investigational immunotherapies — a CD73 antibody dubbed oleclumab or an Innate’s anti-NGK2a named monalizumab — topped Imfinzi alone in terms of overall response and progression-free survival in patients with stage III non-small cell lung cancer whose tumors had not worsened during concurrent chemoradiation, according to interim data from the Phase II COAST trial set to be presented at #ESMO21.