Drug Development

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.


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RAPS Regulatory Convergence 2017