Roche has stopped a pair of phase 3 Alzheimer’s disease trials after an interim analysis found they were unlikely to hit their primary endpoint. The setback wipes out near-term hopes of getting the AC Immune-partnered anti-Abeta antibody crenezumab to market.
Crenezumab failed to meet its co-primary endpoints in a midphase trial in 2014 but Roche rolled the dice on a phase 3 program on the strength of subgroup analysis and evidence that a higher dose would yield better results. The optimism that encouraged Roche to move crenezumab into phase 3 trials in patients with sporadic, prodromal-to-mild Alzheimer’s now looks to have been misplaced.
During a pre-planned interim analysis, the independent data monitoring committee found the drug was unlikely to improve Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, prompting Roche to stop the studies. Both 750-patient trials used CDR-SB as the primary endpoint.
Roche said no safety signals were observed and the overall safety profile was comparable to earlier studies. Beyond that, Roche is yet to provide details of the findings but whatever the committee saw was damning enough to torpedo the phase 3 program.
Headline data from the studies, which got underway in 2016 and 2017, were due to drop next year. That could have put crenezumab just ahead of Biogen’s rival anti-Abeta antibody aducanumab, a drug that has a similar mechanism to Roche’s prospect but has generally been tested at lower doses.
AC Immune attributed the ability to dose crenezumab at up to 60 mg/kg to its use of an IgG4 backbone. Most trials of aducanumab, which has an IgG1 backbone, have used 10 mg/kg and under. Biogen is expected to deliver data on aducanumab in the first half of 2020 but there is speculation that it will perform an interim analysis before then.
Analysts at Jefferies thought the jump in crenezumab dosing between phase 2 and 3 could result in a positive outcome, prompting them to give the pivotal program a 40% chance of success. Peak sales were penciled in at $4.4 billion.
Crenezumab now looks unlikely to achieve such sales but Roche is yet to dump it on the scrapheap. A phase 2 study of crenezumab in cognitively healthy subjects that are genetically predisposed to Alzheimer’s is continuing despite the late-phase blowup in more advanced patients.
Roche is also continuing other ongoing Alzheimer’s trials. A phase 2 study of AC Immune-partnered antitau antibody RG-6100 is ongoing, as is a phase 3 trial of the MorphoSys-partnered anti-Abeta antibody Roche resuscitated two years ago. That antibody, gantenerumab, missed the mark in an early clinical trial, only for Roche to resurrect it at a higher dose and enter phase 3.
With crenezumab joining the list of anti-Abeta failures despite a dose increase, there is considerable scope to doubt whether Roche’s gamble on gantenerumab will pay off. But it is far from the only organization to retain faith in the potential of drugs that target beta-amyloid.
“We continue to believe that interventions targeting beta-amyloid may be a key component of an effective treatment paradigm for Alzheimer’s,” AC Immune CEO Andrea Pfeifer said in an emailed statement.
AC Immune has an anti-Abeta vaccine in the clinic and is pursuing the target outside of Alzheimer’s. But the rest of its Alzheimer’s pipeline, which Jefferies thinks is perhaps the broadest in biotech, is focused on tau. Eli Lilly, Johnson & Johnson and Roche have all bet on AC Immune’s tau research, and the biotech has CHF 320 million ($321 million) in cash to ride out the crenezumab setback.