Disappointing Results for Investigational Alzheimer's Drug

Pauline Anderson

June 16, 2022

Crenezumab, an investigational medication designed to slow or prevent Alzheimer's disease (AD), provides no cognitive benefit in patients at high genetic risk, new research suggests.

Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early onset AD.

Genentech today announced the negative results together with Banner Alzheimer's Institute, Phoenix, Arizona.

During a press briefing, company representatives and researchers expressed disappointment with the initial results — but stressed numerous ongoing analyses have yet to be completed.

"This is the beginning of the story, but by no means the end of it," Pierre N. Tariot, MD, director, Banner Alzheimer's Institute, and one of the study leaders, said at the briefing.


The prospective, double-blind parallel group Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) phase 2 trial enrolled 252 members of the world's largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.

Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.

Study participants were randomly assigned to receive crenezumab or placebo over a period of 5 to 8 years. The dose of crenezumab was increased at different timepoints during the trial as knowledge about potential treatment approaches for AD evolved.

Tariot noted the maximum dose was not provided for the entire treatment period. "The longest people received the highest dose was about 2 years," he added.

Co-primary endpoints were rate of change in cognitive abilities, as measured by the API-ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.

Results showed these outcomes were not statistically significant for those receiving the active medication.

In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.

The investigators did find small numerical differences favoring crenezumab across the co-primary and multiple secondary and exploratory endpoints, but these were also not statistically significant.

Finally, no new safety issues were identified with crenezumab during the study.

Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer's Association International Conference (AAIC) on August 2.

While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.

"There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences," Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.

"We need to understand the biomarkers involved and what [they're] telling us about the disease and the timing of the intervention," Doody said.

Prevention "needs to be one of our targeted therapeutic approaches but probably not our only one," she added.

Beyond Amyloid?

Commenting on the negative results, Howard Fillit, co-founder and chief science officer of the Alzheimer's Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.

"This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient's Alzheimer's — and tailor combinations of drug therapies to provide precision medicine," Fillit, who was not involved with the research, said in statement.

Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer's in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.

The study was supported by the National Institute on Aging, contributions to Banner Alzheimer's Foundation, and Genentech.

Alzheimer's Association International Conference (AAIC) 2022. To be presented August 2, 2022.

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