31 Jan 2019

Yesterday, Roche announced a halt to the Phase 3 CREAD 1 and CREAD 2 trials of the anti-amyloid antibody crenezumab. According to a company press release, an interim analysis found the trial was unlikely to reach its primary endpoint of slowing decline on the CDR-SB. No safety issues cropped up. AC Immune developed the antibody and partners with Roche and Genentech for its clinical development. Roche noted that the Alzheimer Prevention Initiative Phase 2 trial of crenezumab in familial AD will continue. The company plans to present full findings at a to-be-determined scientific conference.

“This is certainly disappointing,” Dave Morgan at Michigan State University in Grand Rapids wrote to Alzforum. He noted that crenezumab has unique features, including a low rate of side effects and a purported ability to inhibit the aggregation of Aβ, that initially suggested it might work well (full comment below). However, other researchers noted crenezumab’s limitations. “This is not unexpected, because the Phase 2 studies were not positive,” said Lon Schneider at the University of Southern California, Los Angeles.

Crenezumab has high affinity for oligomeric forms of Aβ, but also recognizes monomers. Reportedly, Aβ oligomer levels in cerebrospinal fluid fell by half in AD patients who took a low dose of the drug in Phase 2 trials (July 2018 conference news). Despite this, those ABBY and BLAZE trials failed to detect any slowing of cognitive decline on the ADAS-Cog or CDR-SB, nor any drop in amyloid load as seen by PET.

Still, subgroup analyses had hinted at a benefit in participants with mild AD (Jul 2014 conference news; Dec 2014 conference news). This led Roche to go earlier for Phase 3, enrolling people with prodromal to mild AD and evidence of amyloid buildup. Roche also quadrupled the dose of crenezumab to 60 mg/kg, given intravenously once per month (Dec 2016 conference news). CREAD 1 was fully enrolled with 813 participants, while CREAD 2 was still enrolling, with a target of 750 participants. Both studies were planned to run for two years.

Why was crenezumab not working in these trials? Morgan speculated that any inhibitory effect of crenezumab on amyloid aggregation may come too late for people with early AD, whose brains already contain mature plaques. In addition, he noted that anti-amyloid antibodies that mop up plaque, such as aducanumab, gantenerumab, and BAN2401, also produce significant ARIA in the brain, unlike crenezumab. Perhaps this edema is a sign that antibodies are clearing plaque. “Thus, crenezumab’s failure in early AD is, nonetheless, helping identify antibody features that appear to be key to plaque removal, and, possibly, reduced cognitive decline,” Morgan suggested.

The API trial tests a different paradigm, enrolling 252 cognitively healthy people who carry the PS1 E280A familial AD mutation (May 2012 news). The primary outcome will be slowed decline on a sensitive cognitive composite. Dosing in this trial started low, but was boosted midway through to match the levels tested in the CREAD trials. That study is planned to run for at least five years.

Roche has two other AD programs: gantenerumab in Phase 3 and the anti-tau antibody RG6100 in Phase 2.—Madolyn Bowman Rogers