Crenezumab Fails to Prevent Decline in At-Risk Alzheimer’s Trial
Early treatment with crenezumab, an investigational anti-amyloid antibody, failed to significantly slow or prevent cognitive decline in a group of people with a genetic risk for early-onset Alzheimer’s disease, data from a Phase 2 trial show.
Numerical differences favoring crenezumab over a placebo were seen across several primary, secondary and exploratory goals, but none reached statistical significance, Genentech, the therapy’s developer, reported in a press release. Crenezumab was generally well tolerated.
“Although the results of the study are not what we hoped, we are confident that the rich data collected will enhance the broader scientific community’s knowledge of Alzheimer’s and inform future research efforts in the field,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, said in a statement to Alzheimer’s News Today.
While data analyses are ongoing, these initial trial findings will be presented at the Alzheimer’s Association International Conference (AAIC), which will run virtually and in-person from July 31 through Aug. 4 in San Diego. Findings were not detailed in the release.
The formation of protein plaques between nerve cells are a hallmark of Alzheimer’s disease. They are made of toxic forms of beta-amyloid — called oligomers — that stick together and accumulate between nerve cells, disrupting their function.
Crenezumab aims to target and neutralize beta-amyloid oligomers.
The Alzheimer’s Prevention Initiative (API), led by the Banner Alzheimer’s Institute in Arizona, launched the Phase 2 Autosomal Dominant Alzheimer’s Disease (ADAD) Colombia Trial (NCT01998841) in 2013 with the support of the National Institute on Aging, Roche, and the Banner Alzheimer’s Foundation. Genentech is the trial’s sponsor.
Its launch followed evidence that crenezumab could prevent the aggregation of beta-amyloid into its toxic oligomer forms.
The trial enrolled 252 members of an extended family in Colombia; two-thirds of these people carry the E280A mutation on the PSEN1 gene, one of the most common causes of early-onset familial autosomal dominant Alzheimer’s. Autosomal dominant means the mutation needs to be in only one of the two gene copies people inherit from their parents to be disease-causing.
Carriers of this mutation are at risk of developing Alzheimer’s at unusually young ages, typically around 44 years old.
“Our hope and hypothesis was that by evaluating people genetically predetermined to accumulate amyloid plaque and develop Alzheimer’s, we could intervene early and deliver a meaningful clinical benefit before they experienced cognitive decline,” Doody stated.
All trial participants had no cognitive impairment at the study’s start, including those with the PSEN1 E280A mutation, and were randomly assigned to crenezumab or a placebo, given every two weeks or once a month (depending on type of administration) for five to eight years.
Its main goal was to determine if crenezumab’s use prior to symptom onset could slow or prevent a decline in cognitive and functional abilities in this at-risk population.
“While this is a disappointing result, we would like to thank the participants and their families — they have made an enormous contribution to advancing both understanding and the search for new treatments for familial Alzheimer’s disease,” said Levi Garraway, MD, PhD, Genentech’s chief medical officer and head of global product development.
“We remain committed to contributing further scientific evidence to advance how Alzheimer’s disease is understood, diagnosed and treated,” Garraway added.
Roche recently opened a global Phase 3 trial evaluating the safety and efficacy of gantenerumab, also a candidate antibody therapy, in slowing Alzheimer’s progression in people who are cognitively unimpaired, but with confirmed brain amyloid accumulation that is considered an early biological sign of the disease.
The trial, called SKYLINE (NCT05256134), is recruiting 1,200 eligible adults, ages 60 to 80, at sites in the U.S., Europe, Canada and Australia. Those interesting in enrolling can use this link for trial contact and site information.
Participants will be randomized to either subcutaneous (under-the-skin) injections of gantenerumab or a placebo.
“We will continue to explore multiple molecules and approaches and look forward to the Phase III readout at the end of the year for gantenerumab, our investigational amyloid-beta targeting subcutaneously-administered medicine being evaluated for the treatment of early Alzheimer’s disease,” Doody said.
Two Phase 3 trials of crenezumab in people with early Alzheimer’s and confirmed evidence of beta-amyloid deposition — the CREAD 1 (NCT02670083) and CREAD 2 (NCT03114657) studies — were stopped by Genentech 2019 after an independent data monitoring board found them unlikely to meet the primary goal of halting dementia progression.