Roche is doubling down on its anti-amyloid beta antibody crenezumab. The Swiss Big Pharma is starting a second phase 3 trial in patients with prodromal to mild Alzheimer’s disease after getting a look at binding, dose escalation and drug-disease progression model data late last year.
A phase 2 trial of crenezumab, which Roche’s Genentech licensed from AC Immune in 2006, in mild-to-moderate Alzheimer’s failed to meet its co-primary endpoints in 2014. But Roche has pushed ahead regardless, kicking off its first phase 3 one year ago before following up with news of a second study today. Like the first phase 3 trial, the second study will enroll 750 patients with prodromal to mild Alzheimer’s.
AC Immune attributed Roche’s willingness to ratchet up the stakes of its Alzheimer’s program to data it presented late last year.
One pillar of Roche’s faith in the asset is built upon a drug-disease progression model. The model adequately described what Roche saw in the phase 2 trials. And, when used to simulate what will happen in phase 3, it predicts a “meaningful response” in patients.
The disconnect between the disappointing phase 2 data and the optimism for phase 3 stems from a change in dosing. Having given no more than 15 mg/kg of crenezumab in the phase 2, Roche has ramped up to 60 mg/kg for the two phase 3 trials. The simulation predicts this dose will move the needle, although given the long history of late-phase setbacks in Alzheimer's R&D the odds are stacked against crenezumab.
Roche supported the step up in dosing with a phase 1b showing the 60 mg/kg regimen is free from dose-limiting toxicities, and that it achieves serum concentrations fourfold higher than the 15 mg/kg given in the phase 2 trials. When paired to recent research into the crystal structure of crenezumab and its binding to the aggregated form of amyloid beta, Roche and AC Immune see the evidence as supporting the second phase 3 study.
“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,” AC Immune CEO Andrea Pfeifer said in a statement.
It will be years before Roche learns whether its bet has paid off. Data from the first phase 3 trial are due in 2020. The company is yet to disclose the timeline for the second study or details of its design beyond the barebones. Enrollment will start at least 12 months after the first phase 3 got underway.