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.

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Overview
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Roger Perlmutter, Merck

#ASH19: Here’s why Mer­ck is pay­ing $2.7B to­day to grab Ar­Qule and its next-gen BTK drug, lin­ing up Eli Lil­ly ri­val­ry

Just a few months after making a splash at the European Hematology Association scientific confab with an early snapshot of positive data for their BTK inhibitor ARQ 531, ArQule has won a $2.7 billion buyout deal from Merck.

Merck is scooping up a next-gen BTK drug — which is making a splash at ASH today — from ArQule in an M&A pact set at $20 a share $ARQL. That’s more than twice Friday’s $9.66 close. And Merck R&D chief Roger Perlmutter heralded a deal that nets “multiple clinical-stage oral kinase inhibitors.”

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Paul Hudson. Sanofi

New Sanofi CEO Hud­son adds next-gen can­cer drug tech to the R&D quest, buy­ing Syn­thorx for $2.5B

When Paul Hudson lays out his R&D vision for Sanofi tomorrow, he will have a new slate of interleukin therapies and a synthetic biology platform to boast about.

The French pharma giant announced early Monday that it is snagging San Diego biotech Synthorx in a $2.5 billion deal. That marks an affordable bolt-on for Sanofi but a considerable return for Synthorx backers, including Avalon, RA Capital and OrbiMed: At $68 per share, the price represents a 172% premium to Friday’s closing.

Synthorx’s take on alternative IL-2 drugs for both cancer and autoimmune disorders — enabled by a synthetic DNA base pair pioneered by Scripps professor Floyd Romesberg — “fits perfectly” with the kind of innovation that he wants at Sanofi, Hudson said.

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Game on: Re­gen­eron's BC­MA bis­pe­cif­ic makes clin­i­cal da­ta de­but, kick­ing off mul­ti­ple myelo­ma matchup with Bris­tol-My­ers

As J&J attempts to jostle past Bristol-Myers Squibb and bluebird for a landmark approval of its anti-BCMA CAR-T — and while GlaxoSmithKline maps a quick path to the FDA riding on its own BCMA-targeting antibody-drug conjugates — the bispecifics are arriving on the scene to stake a claim for a market that could cross $10 billion per year.

The main rivalry in multiple myeloma is shaping up to be one between Regeneron and Bristol-Myers, which picked up a bispecific antibody to BCMA through its recently closed $74 billion takeover of Celgene. Both presented promising first-in-human data at the ASH 2019 meeting.

FDA lifts hold on Abeon­a's but­ter­fly dis­ease ther­a­py, paving way for piv­otal study

It’s been a difficult few years for gene and cell therapy startup Abeona Therapeutics. Its newly crowned chief Carsten Thiel was forced out last year following accusations of unspecified “personal misconduct,” and this September, the FDA imposed a clinical hold on its therapy for a form of “butterfly” disease. But things are beginning to perk up. On Monday, the company said the regulator had lifted its hold and the experimental therapy is now set to be evaluated in a late-stage study.

Roche faces an­oth­er de­lay in strug­gle to nav­i­gate Spark deal past reg­u­la­tors — but this one is very short

Roche today issued the latest in a long string of delays of its $4.3 billion buyout of Philadelphia-based Spark Therapeutics. The delay comes as little surprise — it is their 10th in as many months — as their most recent delay was scheduled to expire before a key regulatory deadline.

But it is notable for its length: 6 days.

Previous extensions had moved the goalposts by about 3 weeks to a month, with the latest on November 22 expiring tomorrow. The new delay sets a deadline for next Monday, December 16, the same day by which the UK Competition and Markets Authority has to give its initial ruling on the deal. And they already reportedly have lined up an OK from the FTC staff – although that’s only one level of a multi-step process.

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KalVis­ta's di­a­bet­ic mac­u­lar ede­ma da­ta falls short — will Mer­ck walk away?

Merck’s 2017 bet on KalVista Pharmaceuticals may have soured, after the UK/US-based biotech’s lead drug failed a mid-stage study in patients with diabetic macular edema (DME).

Two doses of the intravitreal injection, KVD001, were tested against a placebo in a 129-patient trial. Patients who continued to experience significant inflammation and diminished visual acuity, despite anti-VEGF therapy, were recruited to the trial. Typically patients with DME — the most frequent cause of vision loss related to diabetes — are treated with anti-VEGF therapies such as Regeneron’s flagship Eylea or Roche’s Avastin and Lucentis.

UP­DAT­ED: Ob­sE­va makes case for best-in-class hor­mone sup­pres­sive ther­a­py in pos­i­tive uter­ine fi­broid study

About a month after the Swiss biotech disclosed a failed late-stage study in its IVF program, ObsEva on Monday unveiled positive pivotal data on its experimental treatment for heavy menstrual bleeding triggered by uterine fibroids.

ObsEva in-licensed the drug, linzagolix, from Japan’s Kissei Pharmaceutical in 2015. Two doses of the drug (100 mg and 200 mg) were tested against a placebo in the 535-patient Phase III study, dubbed PRIMROSE 2, in patients who were both on and off hormonal add-back therapy (ABT).

Samit Hirawat. Bristol-Myers Squibb

Bris­tol-My­ers is mak­ing a bee-line to the FDA with pos­i­tive liso-cel da­ta — but is it too late in the CAR-T game?

Bristol-Myers Squibb came to ASH this past weekend with a variety of messages on the new cancer drugs they had acquired in the big Celgene buyout, including liso-cel, the lead CAR-T program picked up in the $9 billion Juno acquisition. And one of the most important was that they had the pivotal efficacy and safety data needed to snag an approval from the FDA next year, with the BLA on track for a filing this month.