Genentech Halts Phase 3 Trials Testing Crenezumab for Early Alzheimer’s Disease

Two Phase 3 trials — CREAD 1 and CREAD 2 — evaluating crenezumab as a therapy for early Alzheimer’s disease have been discontinued, Genentech announced.

The decision was based on an interim analysis by an independent data monitoring committee that ruled that crenezumab was unlikely to meet its primary goal of halting dementia progression as measured by the Clinical Dementia Rating-Sum of Boxes Score.

The overall safety profile of crenezumab was similar to that seen in previous trials, without any new safety signals.

Findings from the Phase 3 trials will help design and rethink strategies for future trials and research. Genentech will present these clinical results at upcoming medical conferences.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” Sandra Horning, MD, chief medical officer and head of global product development at Genentech, said in a press release.

Crenezumab is an investigational monoclonal antibody first discovered by AC Immune and now being developed by Genentech, a Roche Group company. It was designed to target all forms of beta-amyloid molecules, the hallmark of Alzheimer’s, and has been evaluated for the treatment of prodromal (early) to mild forms of the disease.

The antibody was also designed to minimize inflammation in the brain, which may lead to magnetic resonance imaging (MRI) abnormalities, collectively referred to as amyloid-related imaging abnormalities, or ARIA, the major severe side effect of beta-amyloid immunotherapy for Alzheimer’s disease.

CREAD 1 (NCT02670083), launched in early 2016, and CREAD 2 (NCT03114657) trials, begun in mid-2017, enrolled a total of 1,563 patients diagnosed with early Alzheimer’s disease and confirmed evidence of beta-amyloid deposition in the brain. Patients were randomized to a placebo or crenezumab, administered intravenously (into the vein) every four weeks.

These two studies used doses four times higher than those used in the Phase 2 trials, ABBY (NCT01343966) and BLAZE (NCT01397578).

Crenezumab is still being investigated in the Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease trial (NCT01998841). This Phase 2 study, anticipated to end in February 2022, enrolled cognitively healthy individuals carrying the E280A mutation on the PSEN1 gene, one of the most common causes of familial early-onset Alzheimer’s.

The trial, which is testing the efficacy and safety of crenezumab given either intravenously or under the skin for at least 260 weeks, enrolled about 200 members of an extended family in Colombia, where several members carry this genetic mutation that typically triggers Alzheimer’s symptoms around the age of 45.

Genentech is running clinical trials for its other two leading Alzheimer’s therapies — gantenerumab and RG6100.

Gantenerumab, similar to crenezumab, is a fully human antibody that binds to aggregated beta-amyloid, and is being tested in two Phase 3 trials, GRADUATE1 (NCT03444870) and GRADUATE2 (NCT03443973).

RG6100 is an investigational, monoclonal antibody targeting several species of tau protein, whose accumulation is also observed in the brain of Alzheimer’s patients.

The antibody is being tested in the Phase 2 TAURIEL trial (NCT03289143), currently looking for participants and taking place at more than 153 sites around the world.

In the trial, patients with early to mild Alzheimer’s disease will be randomized to a placebo or three different doses of RG6100 delivered into the blood. The treatment will continue for almost 1.5 years and will assess the therapy’s safety and its impact on dementia severity.

““We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program. We remain dedicated to the Alzheimer’s community and will continue our Phase III GRADUATE trials with gantenerumab and the Phase II TAURIEL trial with the anti-tau molecule RG6100, as well as our imaging and fluid-based diagnostic solutions,” Horning said.